CONTEMPORARY

MANAGEMENT
OF CORTICAL DYSPLASIAS

OF MALFUNCTIONS

PREFACE

Malformations
of cortical development
(MCDs) are increasingly
recognized
as substrates
of medically intractable epilepsy State of the art neuroimaging
techniques now demonstrate
cortical dysplasias on a routine basis. Neuroscientists
around the world have developed
experience in the diagnosis and treatment of the epilepsy associated with these seemingly
complex malformations.
The following
issue of Neuroswgety
Clinics of North America was
undertaken
to summarize the modern experience with treating this complex and intriguing
group of disorders.
Epilepsy surgery remains most successful for lesional
epilepsy. This conceptual model
implies that the abnormal electrical phenomena
underlying
the seizure disorder starts in
the cortex surrounding
the lesion. Removal of the lesion with or without some surrounding
cortex suffices to stop the seizures in a majority of cases. These non-neuronal
lesions do not
have the capacity to generate seizure activity within the tissue of the lesion; rather it is the
surrounding
neural tissue that seizes. MCDs are lesions with the ability to generate seizure
activity within themselves. In addition, this disordered cortex may support eloquent cortical
function. These features make surgical treatment challenging.
Despite this challenge, increasing experience demonstrates seizure-free outcomes approaching
other lesional epilepsies in
highly selected cases.
The following
pages are dedicated to the work-up and treatment of these malformations.
The role of scalp electroencephalography,
invasive and intraoperative
electrocorticography,
anatomic and metabolic neuroimaging,
and surgery are examined. In addition, a classification scheme is discussed that applies to the wide variety of malformations
seen clinically.
The pathology of these lesions will be presented, as well as a discussion of how and why
these lesions are epileptogenic.
I hope that the impression the reader is left with is how far we
have come and how far we have to go to better understand
a,nd treat the patient harboring
an MCD.
WILLIAM E. BINGAMAN, MD
Guest Editor
Department of Neurosurgery-S80
The Cleveland Clinic Foundation
9500 Euclid Ave.
Cleveland. OH 44195

xi

CONTEMPORARY MANAGEMENT
OF CORTICAL DYSPLASIAS

OF MALFUNCTIONS

1042-3680/02

$15.00 + .OO

PATHOLOGIC
CHARACTERISTICS
OF THE CORTICAL DYSPLASIAS
Richard A. Prayson, MD, Roberto Spreafico, MD, PhD,
and Harry V. Vinters, MD

Much has been written regarding the histopathologic findings associated with malformations caused by abnormalities
of cortical development (cortical dysplasia). There has been
continued controversy, however, regarding issues of terminology, definition, and ultimately
neuropathologic
classification of these lesions.
Unfortunately,
there is no universally agreed
on definition of what this group of disorders
represents and the types of lesion that should
or should not be included under the general designation of cortical dysplasia. Factors contributing
to this include the broad
phenotypic spectrum of these disorders, interobserver biases and variances, and the fact
that the cause of most forms of dysplasia is
still unrecognized and awaits elucidation.
Obviously, the incidence of cortical dysplasia encountered in surgical series varies and is
reflective in part of the indications for surgery
in various studies as well as the personal
biases of the pathologists involved in interpreting the resultant pathologic material. In
a series of 216 consecutive temporal lobe excisions for chronic epilepsy reported by Wolf

et a157in 1993, dysplasia was observed in approximately

15% of cases. In another series of
60 consecutive extratemporal
lobe resections,
dysplasia was noted in 12% of cases5* In a recent series of 133 consecutive extratemporal
lobectomies, dysplasia was identified in 37.6%
of cases.18
The following discussion reviews many of
the more commonly
encountered gross and
microscopic
pathologic
patterns of cortical
dysplasia and briefly examines some of its
known associations.
AGYRIA, PACHYGYRIA,
AND LISSENCEPHALY
This group of disorders is marked by a decreased number of sulci, usually resulting in
a smooth surface contour to the neocortex. In
the case of agyria or lissencephaly, there is a
total absence of convolutions.
Pachygyria is
characterized by a reduction in the number of
convolutions,
often marked by broad surface
gyri and an unusually thick cortex on cross
section (Fig. 1L4 The cortex may be of variable

From the Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio (RAP); Department
of Experimental Neurophysiology, Institute Nazionale Neurologico C. Besta, Milan, Italy (RS); and Department of
Pathology and Laboratory Medicine, and Neurology and Brain Research Institute, University of California at Los
Angeles Medical Center, Los Angeles, California (HVV)
NEUROSURGERY CLINICS OF NORTH AMERICA
VOLUME37.NUMBERl.JANUARY2002

17

18

PRAYSON et al

POLYMICROGYRIA

Figure
1. Pachygyric
and variably thickened

cortex
cortex.

with

reduced

convolutions

thickness, but there is generally a reduction in

the volume of white matter present. Both abnormalities may be accompanied by ventricular dilatation. In some cases, there is unequal
involvement of the cerebral hemispheres, resulting in hemimegalencephaly (i.e., hemilissencephaly).5,
Some divide lissencephaly into various
subtypes. 46Many of the type I lissencephaly
group belong to an autosomal dominant condition, the Miller-Dieker syndrome, which results from a deletion or abnormality on chromosome 17p13.3.2~25~30~5~52
One gene product
(LIS-1) on this chromosome encodes for a
subunit of intracellular
platelet-activating
factor acetyl-hydrolase.3 The Walker-Warburg
syndrome and cerebra-ocular dysplasia syndromes are autosomal recessive conditions
associated with lissencephaly type II3
Histologically, there is a wide array of cortical architectural abnormalities associated
with this group of abnormalities.,9,44*49 The
cortex may consist of three to five layers.
Neurons with their apical dendrites, which are
normally oriented perpendicular to the pial
surface of the cortex, are usually maloriented.
Neuronal cytologic abnormalities of size and
morphology may be present. Often, these
changes are accompanied by a prominent reactive astrocytosis. Type II lissencephaly or
cobblestone lissencephaly is marked by
the presence of an irregular group of neurons
separated by gliovascular septae.

Polymicrogyria or micropolygyria describes

a condition in which the cerebral surface is
composed of small irregular gyri separated by
shallow sulci (Fig. 2). Occasionally, gyri may
be focally broad. The process may be either
diffuse or focal. It has a particular predilection
for involvement of the perisylvian region.4
On cross section, the cortical ribbon is often
thin and has a festooned appearance.
Microscopically, the lesion is marked by the
presence of two- to four-layered cortex. The
most common pattern is four layers consisting
of a hypocellular molecular layer, an outer
granular cell layer, a sparsely cellular layer of
Ranke, and a fourth layer of variable thickness
composed of variably shaped neurons.9,J4
The leptomeninges overlying
the polymicrogyric cortex may demonstrate an abnormal
vascular@ related to the persistence of fetal
leptomeningeal vascularization.
The interface between the polymicrogyric
cortex and
the adjoining normal neocortex is usually
abrupt.

HETEROTOPIAS
Heterotopias refer to conditions in which
there may be either gross or microscopic
evidence of displaced gray matter (Fig. 3).
The nodular type heterotopias are the most

Figure
2. Focal polymicrogyria
(arrow)
marked
by small
irregular
gyri and shallow
sulci. The surrounding
cortex
demonstrates
irregularities
consistent
with dysplasia.

PATHOLOGIC

Figure 3. A, Multiple foci of nodular

variably
thickened
adjacent
cortex.
nodular heterotopia
occupying
deep
magnification
x 40).

CHARACTERISTICS

OF THE

CORTICAL

DYSPLASIAS

19

heterotopia
in the white matter with abnormal,
6, Microscopic
appearance
of multiple
small
white matter (hematoxylin-eosin
[H&E], original

common variety. These are typically situated

in the subependymal region adjacent to the
lateral ventricles. Less commonly, they can
be located in the deeper white matter. These
lesions are composed of neuronal cells that
vary in size and number; they are often seen
together with polymicrogyria.14, 19*
21,~2,27,41,
4.1
Two different phenotypes have been described7,13:unilateral and bilateral forms. The
latter has been associated with an X-linked
dominant inheritance pattern. The gene re-

sponsible was positionally cloned from Xq28r6

and identified as filamin 1 FLNl).
Less commonly, laminar type (band) heterotopias, which have been referred to as double
cortex, have been described.9*32,41,44
These lesions are marked by a linear or multinodular arrangement of neuronal cells in the white
matter often running parallel to the cortical
ribbon but separated by white matter tissue. The overlying cortex may be normal or
demonstrate evidence of dysplasia. Laminar

20

PRAYSON

et al

heterotopia has been associated with abnormalities on the X chromosome and on chro-
mosome 17.

MICROSCOPIC PATTERNS
OF DYSPLASIA
There have been a variety of approaches
to the histologic categorization of cortical
dysplasia that essentially differ from one
another with regard to definitions and
whether one prefers to be a lumper or
splitter. r,Z.6.6. lY.29,31.36, SO.54
The most common forms of dysplasia involve abnormalities of cortical architecture.
On the most severe end of this spectrum are
cases in which there is a gross abnormality
such as agyria, pachygyria, or polymicrogyria.

Figure 4. A, Abnormal
increased
highlighting
x 200).

These conditions are all characterized by an

abnormal number of cortical layers. In addition, these lesions are frequently accompanied
by a malorientation of neurons within the cortex itself (Fig. 4).
Other frequent histologic accompaniments
to the architectural disorganization are more
subtle defects that seem to have a predilection
for the molecular layer. These abnormalities
are variable and include entities such as persistence of the subpial granular cell layer,
increased numbers of molecular layer neurons, and marginal heterotopia (Fig. 5).3,36
Many of these subtle abnormalities were previously included under the general heading of
microdysgenesis, a term originally coined
by Meencke and Janz2 to describe these subtle
abnormalities in intracortical
architecture
in patients with generalized seizures. The

cortical
architecture
marked
by loss of identifiable
cortical
lamination
and
cellularity
(H&E, original magnification
x 100). B, Glial fibrillary
acid protein immunostain
increased
numbers
of reactive
astrocytes
in the superficial
cortex (original
magnification

PATHOLOGIC

Figure 5. Marginal
tending

heterotopia
into the pial-arachnoid

CHARACTERISTICS

OF

THE

(arrow)
characterized
by neural
region (H&E, original magnification

normal molecular layer of the cortex is

marked by a relative paucity of neuronal
cells. Marginal glioneuronal heterotopias are
characterized by excrescences of the neuroglial tissue that protrude through the pia
into the subarachnoid space. Most of these
forms of dysplasia are readily discernible
with routine hematoxylin-eosin staining. In
selective cases, silver stains or neurofilament
antibodies may be helpful in evaluating the
orientation of neurons within the cortex.
Correlation of a variety of clinical parameters
with these various subtle forms of dysplasia
has not been proved to be useful or reliable
up to this juncture. Somewhat akin to these
abnormalities are a variety of lesions, any
of which may not necessarily satisfy some
individuals
definition of dysplasia. These
include the presence of microscopic clusters of
individual neuronal cells in the white matter
or ectopic white matter tissue situated in the
cortex.
In addition to architectural abnormalities,
there may be derangements in neuronal cell
size and shape. Neuronal cytomegaly or the
presence of giant neurons may be seen. These
cells sometimes demonstrate no morphologic abnormality other than enlargement.
These are to be distinguished from large
dysmorphic neurons, which often exhibit

CORTICAL

parenchyma
x 100).

DYSPLASIAS

21

ex-

cytoskeletal abnormalities, including the presence of neurofibrillary

tangle-like cytoplasmic inclusions.,7 Small immature-appearing
neurons also may be encountered. These cells
often have round to oval nuclear configurations
with a thin rim of cytoplasm. These cells
do not typically demonstrate any dysmorphic
features. They may be encountered in association with giant or dysmorphic neurons.
These cells are frequently encountered in
association with heterotopic periventricular
and subcortical nodular heterotopias.
Most of the microscopic patterns of dysplasia described thus far, excluding the grossly
evident patterns, cannot be identified reliably
by current imaging techniques. In contrast,
there seems to be a subset of lesions, the Taylor type focal cortical dysplasias, which may
be identifiable by imaging studies. In addition
to the architectural abnormalities previously
described, these forms of dysplasia are often
characterized by the presence of either dysmorphic neurons or balloon cells.,33
Dysmorphic neurons are marked by cytologic atypia (Fig. 6). This may be manifested
by a variety of morphologic features, including cytoskeletal
abnormalities, alterations
in shape, and abnormal clumping of Nissl
substance in the cytoplasm. Cells may vary in
size and in shape. Kerfoot et aP have recently

22

PRAYSON

et

al

Figure
6. Dysmorphic
neurons
enlargement,
and hyperchromasia

in cortical
layer
(H&E, original

demonstrated
increased immunoreactivity
for
several excitatory
neurotransmitter
receptor
subunits
in these dysmorphic
neurons.
In
addition,
they demonstrated
variable
immunoreactivity
for y-aminobutyric
acid AB
and demonstrated
the expression
of several
proteins
that are normally
expressed
only
in immature
neurons or in those with the
potential for synaptic
plasticity.
Other immunohistochemical
studies of dysplasia have
demonstrated
a decrease in the number of
y -aminobutyric
acid-ergic
neurons
and an
increase in excitatory neurons in the cortex,
which may contribute to the epileptogenicity
of dysplasia lesions4*
Balloon cells are distinctive
morphologically and may be readily discernible
on
routine
hematoxylin-eosin
staining.
These
cells are marked by abundant eosinophilic
cytoplasm and eccentric nuclei (Fig. 7). Rarely,
they may be multinucleated.
Balloon cells are
frequently, although not invariably, enlarged
in size compared with normal cortical neurons. From an immunohistochemical
standpoint, these cells are of uncertain
lineage
in that they have been known
to stain with
markers
of neural differentiation
such as
neuron-specific
enolase as well as with markers of glial differentiation
such as glial fib-

3 marked
by cytomegaly,
magnification
x 250).

nuclear

rillary acidic protein. 9*14,53 Ultrastructurally,

these cells are characterized
by prominent
glial intermediate
filaments interspersed
with
non-membrane-bound
electron-dense
globose structures.,
Interestingly,
these cells
are similar to the balloon cells that are found
in the cortical tubers of tuberous
sclerosis;
thus, severe Taylor type cortical dysplasia
may represent
a forme
fruste
of this
disorder.31 Whether
the divergent
immunostaining suggests a failure of these cells to
commit to a specific phenotype or represents a
dedifferentiation
of cellular phenotype is not
known.

PATHOLOGIC
OF CORTICAL

ASSOCIATIONS
DYSPLASIA

Cortical dysplasia is a well-known

finding
in a variety of the neurocutaneous
disorders,
including tuberous sclerosis, neurofibromatosis type I, epidermal nevus syndrome, and hypomelanosis
of Ito.24, 39,42,43,45,
47,55 In general,
there is nothing characteristic
about the forms
of dysplasia observed in association with the
neurocutaneous
disorders
versus those arising outside of this setting, with exception of
the prominent
presence of balloon type cells,

PATHOLOGIC

CHARACTERISTICS

Figure 7. Balloon cells (arrows)

characterized
tric nuclei. (H&E, original magnification
x 400).

as previously mentioned, in association with

tuberous sclerosis.
In recent years, a number of neoplasms
have come to be recognized as being associated with cortical dysplasia. Most of these
neoplasms are low-grade tumors that most
commonly arise in the setting of chronic
epilepsy in younger patients. By definition,
the dysembryoplastic
neuroepithelial
tumor is almost invariably
associated with
mild forms of (usually adjacent) cortical
35 Other tumor types that have
dysplasia. OS
been reported in association with dysplasia
include gangliogliomas37*57and pleomorphic
xanthoastrocytomas. 26 The relation between
these tumors and dysplasia is not known (i.e.,
whether the tumor represents an exaggerated form of dysplasia, whether the tumor
arises out of a focus of dysplasia in which cell
regulatory mechanisms have gone awry, or
whether both lesions merely coexist and have
a maldevelopmental basis to their origin).
An association between hippocampal sclerosis and cortical dysplasia has also been
documented.2s,3*N In one series of 100 patients with evidence of hippocampal sclerosis
reported by Raymond et a140in 1994, 15% of
patients demonstrated evidence of subtle
cortical dysplasia. The basis of the relation

by abundant

OF

THE

cytoplasm

CORTICAL

DYSPLASIAS

23

and eccen-

between these two entities is still uncertain,

and whether the two anomalies merely coexist
or if one gives rise to the other is yet to be
resolved.

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Address reprint requests to
Richard A. Prayson, MD
Department of Anatomic Pathology (L25)
The Cleveland Clinic Foundation
9500 Euclid Avenue
Cleveland, OH 44195

CONTEMPORARY
OF CORTICAL

MANAGEMENT
DYSPLASIA!5

OF MALFUNCTIONS

104%3680/02

$15.00 + .OO

MECHANISMS
OF
EPILEPTOGENICITY
IN
FOCAL MALFORMATIONS
CAUSED BY ABNORMAL
CORTICAL DEVELOPMENT
Zhong

Malformations
caused by abnormal cortical development
(MCDs, also known as cortical dysplasias) are increasingly recognized
as a cause of medically
intractable epilepsy
that present predominantly
in childhood
or
adolescence and carry a less favorable prognosis for a seizure-free outcome after surgical resection.2, 14,I*, 24,60,75The presence of aberrantly laminated
neurons in autopsies from
patients with a history of chronic epilepsy was
first described by Alzheimer and Rahcke62 almost a century ago. The high incidence of dysplastic neurons in drug-resistant epilepsy has
been increasingly recognized following a detailed report by Taylor7r in 1971 who identified
the disorientated or giant neurons in temporal
cortex resected from patients with temporal
lobe epilepsy. Numerous studies showed that
MCDs consist of a broad spectrum of architectural anomalies that include cortical laminar
disorganization,
neuronal heterotopia in the
This article was supported
by grant 2 K08 NS02046
to Dr Najm
from
the National
Institutes
of Health,
Bethesda, Maryland.

From

the Section

of Epilepsy,

Department

of Neurology,

CLINICS

OF NORTH

AMERICA

NJXJROSURGERY
VOLUME

37 * NUMBER

1. JANUARY

2002

Ying, MD,

PhD, and Imad

M. Najm,

MD

subcortical white matter, neurons in the cortical lamina I, clustering of neurons in the gray
matter, nodular heterotopia, and the presence
of aberrant neurons, such as giant neurons and
balloon cells 11.15.19,21.30.35.49.64,73
Although
the
exact causes underlying
the development
of
MCDs are not known, it is believed that various insults during embryonic, and even perinatal, corticogenesis could lead to the development of MCD.41,70
The intrinsic
in situ epileptogenicity
of
MCDs was previously reported by Palmini
et aPO using intraoperative
electrocorticography (ECoG). Ictal or continuous epileptogenie discharges mostly were recorded from
electrodes overlying
dysplastic gyri. More
recently, using prolonged subdural grid video
electroencephalogram
(EEG) monitoring,
the
authors have demonstrated direct correlations
between focal MCDs and in situ epileptogenicity in patients who underwent presurgical invasive evaluation and subsequent focal
cortical resection for the treatment of chronic
epilepsy? Moreover, Mathern et al@ observed

The Cleveland

Clinic

Foundation,

Cleveland,

Ohio

2Y

28

YING

& NAJM

that dysplastic neurons display intrinsic cellular hyperexcitation

in whole-cell voltage
clamp recordings. Furthermore,
the causal
relationship
between cortical dysplasia and
seizure genesis has been validated through
the correlation of the completeness of epileptic
tissue surgical resection with seizure outcome
in chronic epilepsy patients.24*5g
The recent description and characterization
of various animal models of MCDs and the
availability
of well-characterized
neocortical
human tissue has enabled the cellular and molecular characterization of some of the mechanisms underlying
epileptogenicity
of focal
MCDs. In this article, the authors review the
cellular mechanisms
of epileptogenicity
in
MCDs as related to neuronal excitation, reduced inhibition,
disorganized synaptic connections, and glial function (or dysfunction).

IONOTROPIC
RECEPTORS

GLUTAMATE

The amino acid, L-glutamate,

is a major
excitatory neurotransmitter
in the central
nervous system; it is an integral part of physiologic functioning and specialized operations,
such as synaptic plasticity, long-term potentiation, and learned behavior. Once released into
the synaptic cleft, glutamate binds to one or
more of the postsynaptic glutamate receptors
and depolarizes the postsynaptic neuronal
membrane. Glutamate
receptors have been
the primary targets of intense investigation
because certain overexcited states were suggested to be pertinent to epilepsy.& Based
on preferred selective agonist activation and
antagonist blockade, the ionotropic glutamate
receptors have been pharmacologically
categorized into N-methyl-Daspartate
(NMDA),
u-amino-3-hydroxy-5-methyl-4-isoxazole
acid
(AMPA) and kainate.50,74

f&methyl-o-aspartate

Receptors

N-methyl-Daspartate
receptors
mediate
ligand-gated
ion channel responses with
voltage-dependent
properties. In addition to

the sodium ion (Na+) influx and potassium

ion (K+) efflux, the activation of NMDA receptors generates a substantial influx of calcium ion (Ca2+) that results in long-lasting
postsynaptic
depolarization
and synaptic
plasticity. 5p32*37,3g,45 Recent molecular biology
studies have shown that the NMDA receptors
(NRs) are heteromers consisting of subunits
from two distinct families termed NX.7 and
NR2.34,51f52 The NRl subunits, which are necessary for channel function
and activity,
consist of eight alternatively
spliced isoforms
(NRI-la,
-lb, -2a, -2b, -3a, -3b, -4a, and -4b)
that arise from different combinations
of a
single 5 terminal exon insertion or two 3
deletions.26,5255*6g The NR2 subunits confer
variability
in the functionality
of NMDA receptors and are composed of four homologous
subunits: NR2A, NR2B, NR2C, and NR2D.2g,5
Homomeric
NR2 subunit assemblies do not
yield any functional ion channels in contrast to
their NRl counterparts that do produce weak
currents. When combined in a heteromeric
configuration of both NRl and NR2 subunits,
however, the resultant channel produces currents up to lOO-fold greater than those of NRl
alone.

28.29,34,51

Because of its unique channel activity modulation property, altered expression of NR2
subunit proteins has been intensively studied
in dysplastic cortex resected from patients
with medically intractable epilepsy. Using an
immunocytochemical
approach in 17 patients,
the authors previously reported that in wellcharacterized human cortical dysplasia (not
necessarily detected by MR imaging) the cellular expression of NR2A/B subunit proteins
are selectively increased in the dysplastic neurons. n In contrast to the normal nondysplastic
neurons that have little immunoreactivity
to
NR2A/B
antiserum, the somata, long apical
dendrites and basilar dendrites of dysplastic
neurons were intensely labeled by NR2A/B.
By using two different NRl antibodies that
recognize different splicing variants, the same
cluster dysplastic neurons also were shown
to have increased immunoreactivities
differentially for NRI-la, -lb, -2a, and -2b. Furthermore, the dysplastic neurons and dendritic
processes had increased staining for Nissl

MECHANISMS

OF

EPILEITOGENICITY

substances, suggesting that dysplastic neurons synthesize receptor proteins more efficiently. Consistent with these findings are data
from other epilepsy centers6*31*67 that showed
prominently
increased NR2A/B and NRl immunostaining
in cortical dysmorphic neurons
and increased expression of NR2B subunit
messenger ribonucleic acid (mRNA1 in dysplastic neurons. In a subsequent study of
11 patients using confocal imaging of double
immunofluorescent
labeling of both NR2A/B
and NRl, the authors demonstrated
that the
NR2A/B immunoreactive
dysplastic neurons
and giant neurons were colabeled by NRl antibody, whereas nondysplastic
cortical neurons were labeled only by NR1.76 Given that
the heteromeric association of NR2 and NRl
subunits leads to a highly potent receptor
that produces larger focal currents on neurotransmitter
activation,
it is highly likely
that dysplastic neurons that preferentially
exhibit this NMDA combination
are differentially hyperexcitable.
They have partially
validated this hypothesis using direct subdural electrodes in electrocorticographic
recordings in patients with cortical dysplasia.% They
directly correlated the cellular density and
distribution
of NR2A/B with the presence of
in situ intrinsic epileptogenicity.
In addition
to the research on resected
human dysplastic tissue, animal models that
mimic human brain structural abnormalities
have proved useful in understanding
the underlying epileptogenic
mechanisms.
The rat
neonatal freeze-lesion modelI reproduces microgyria commonly found in human cortical
dysplasia. Zilles et aIs1 showed an increased
NMDA receptor binding in the dysplastic cortex. Moreover, using whole-cell voltage clamp
recordings, Defazio et al8 demonstrated
that
ifenprodil, a selective NR2B subunit antagonist, raises the threshold
for bicucullineevoked epileptiform
discharges. These in vitro
receptor binding and electrophysiologic
data
suggest that NR2B receptor function is enhanced in the microgyria from freeze-lesioned
cortex.
In summary, the various human and animal
studies suggest a possible role for the NMDA
receptor in the in situ hyperexcitability
of dys-

IN

FOCAL

MALFORMATIONS

29

plastic lesions and may be a contributing

factor in the pronounced expression of epileptogenicity in focal MCDs.
AMPA Receptors
Unlike
NMDA
receptors
that display
prominent voltage-dependent
calcium permeability and are activated only during times of
marked depolarization,
AMPA receptors are
characterized by their rapid kinetics to elicit
fast excitatory neurotransmission
and conduct
mainly sodium currents. AMPA receptors coexist with NMDA receptors in many synapses
and the depolarization
brought by the opening of AMPA receptors removes the magnesium blockade in the NMDA channels.56 Thus,
proper NMDA
channel functioning
is dependent on the presence of AMPA receptors.
Excessive excitation
resulting
from stimulation of AMPA receptors has been implicated in epileptogenicity
in mesial temporal
lobe epilepsy.2* 36*42,43,78,79 AMPA receptors are
made up of four subunits, GluRl,-R2,-R3,
and -R4.26
The expression of AMPA receptors in tissue
resected from patients with MCDs was studied previously
Immunocytochemical
studies
examining the distribution
of AMPA receptor
proteins have shown a predominant
increase
of GluR2/3 subunits in dysplastic and giant
neurons.23, 3* 67,~7,78 A more complete evaluation of the expression and distribution
of other
AMPA receptor subgroups and their correlation with epileptogenicity
is needed to assess
comprehensively
the potential role of these
receptors in MCDs.
GABAERGIC
RECEPTORS
AND CIRCUITS
Gamma-aminobutyric
acid (GABA) is the
major inhibitory neurotransmitter
in all cortical areas and is released by various types of
interneurons. Widespread inhibitory synapses
can be found at the axodendritic, axosomatic,
and axoaxonic segments. In contrast to the
excitatory neurotransmission
that links distant regions, most of the GABAergic networks

30

YJNG & NAJh4

are local circuitries.66 When GABA is released

into the synaptic cleft, it acts on two major classes of receptors, GABAA and GABAa.
GABA* receptors are l&and-gated
chloride
channels that induce hyperpolarizadon
of the
postsynaptic cell membrane through the influx of chloride ions from the extracellular
fluid5s; whereas GABAB receptors are coupled
to G-proteins, which can open potassium or
close calcium channels resulting in prolonged
postsynaptic hyperpolarization?3,57
GABAergic inhibition plays an important role in controlling excitatory circuits, preventing epileptiform discharges, and limiting
the intrinsic
bursting of neurons.4*486
The impairment
in GABAergic
function
could be attributed to a reduction in the number of inhibitory cells or an alteration in GABA
receptors. In the cerebral cortex, the calciumbinding proteins parvalbumin
and calbindinD28k are expressed in neurons that use GABA
as a neurotransmitter.3,0*,33
72 It has been
shown that most of the parvalbumin-labeled
cells are chandelier neurons and basket cells,
whereas the main calbindin-D28k
stained
cells are bitufed cells, multipolar neurons, and
double-bouquet
dendritic cells. Because chandelier cells innervate the somata proximal
dendrites and basket cells innervate axon
initial segments of pyramidal neurons, these
two types of intemeurons are most effective in
modulating
pyramidal cell excitability.g These
two proteins together with glutamic acid decarboxylase (GAD), which is the rate limiting
GABA-synthesizing
enzyme, have been used
widely as markers of GABAergic interneurons
and for the study of inhibitory circuits.20,40,68
The role of GABA receptors and GABAergic
circuits has been studied previously in human
tissue resected from patients with MCD and
in animal models of MCD. Ferrer et a116**7
reported on the absence of parvalbumin
and
calbindin-D28k-immunoreactive
neurons and
fibers in the dysplastic areas. Later studies20,68
showed a consistent decrease in the number of
parvalbumin
positive neurons, terminals, and
a widespread reduction of GAD immunoreactive elements in dysplastic regions resected
from patients with MCDs. These protein data
on the decreased synaptic inhibitory
circuits

in dysplastic areas were later confirmed using

in situ molecular techniques; the expression
of mRNAs for GABA* receptor /?l, (~1, and
(~2 subunits were shown to be diminished
in dysplastic neurons. 6 In concordance with
these findings, electron microscopic studies2
demonstrated
that the inhibitory
axosomatic
synapses were extremely scarce in dysplastic
tissue.
The human tissue data that suggested inhibitory circuit impairment
in MCD was further supported by studies on experimental
animal models of MCD. The alumina-induced
epileptic foci in monkeys were devoid of
GABAergic
axon terminals.27o 63 Moreover,
Roper et aP5 showed that the density of
parvalbumin
and calbindin D28k-immunoreactive neurons is reduced in rats with in utero
irradiation-induced
MCD. In addition to the
loss of GABAergic
neurons and axon terminals, reductions of GABA* and GABA
receptor binding have been reported in freezelesioned rats8 An additional
factor that
possibly contributes to decreased GABAergic
transmission
is the alteration of GABAergic
receptor subunit composition.
A GABA* receptor dysfunction was suggested in a recent
study because the affinity of pyramidal
cell
GABA* receptor for zolpidem was reduced
in the cortical areas immediately
adjacent
to the freeze-lesion. The authors suggested
that such a change in GABA* pharmacology could be mediated
by eliminating
the
type 1 benodiazepine
receptor by a change in
CYsubunit composition. In the neonatal freezelesioned animals, the prominent
features of
altered focal GABAergic inhibition
in MCD
were complemented
by studies on brain slice
from in utero irradiated animals.8O In wholecell patch-clamp
recordings,
as compared
with the normal cortex the neurons obtained
from dysplastic cortex show reduction
of
spontaneous inhibitory postsynaptic currents
(IPSCs) and increase of excitatory postsynaptic currents (EPSCs) in both amplitude
and
frequency. These results demonstrated
significant physiologic impairment
in inhibitory
synaptic transmission in supporting the immunocytochemical
and GABA receptor binding findings.

MECHANISMS

OF EPILEPTOGENICITY

SUMMARY
Through
extensive neuroanatomical,
biochemical, and electrophysiologic
research on
resected human dysplastic specimens and in
various experimental epileptic animal models,
a strong correlation between the presence of
dysplasia and intrinsic epileptogenesis
has
been documented.
The specific cellular and
molecular
mechanisms
underlying
epileptogenesis, however, remain unknown
with
recent data from resected human tissue showing evidence of alterations in the excitatory or
inhibitory receptor mechanisms.
Further studies are needed on human tissues and animal models to further confirm the
published results and to study other possible
mechanisms.
The availability
of microarray
gene-screening techniques presents a golden
opportunity
for the mass screening of dysplastic tissue to uncover other unsuspected
mechanism(s) and pathways that may be involved in the increased epileptogenesis intrinsically recorded from dysplastic tissues.

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I, Honore
T: Structureactivity
relationships
in the development
of excitatory ammo
acid receptor
agonists
and competitive
antagonists.
Trends Pharmacol
Sci 11:25-33,199O

ElILEPTOGENICITY

IN

FOCAL

33

MALFORMATIONS

75. Wyllie
E, Comair
YG, Kotagal
I, et al: Seizure
outcome after epilepsy
surgery
in children
and adolescents. Ann Neural 44:740-748,1998
76. Ying Z, Babb T, Mikuni
N, et al: Selective
coexpression of NMDAR2/B
and NMDARl
subunit
proteins
in dysplastic
neurons
of human
epileptic
cortex. Exp
Neurol159:409-418,1999
77. Ymg Z, Babb TL, Comair
YG, et al: Induced
expression of NMDAR2
oroteins
and differential
exoression
of NMDARl
splice variants
in dysplastic
nekons
of
human
epileptic
neocortex.
J Neuropath
Exp Neurol
57:47-62,1998
78. Ying Z, Babb TL, Comair
YG, et al: Increased
densities of AMPA
GluRl
subunit
proteins
and presynaptic mossy fiber sprouting
in the fascia dentata
of
human
hippocampal
epilepsy
Brain Res 789:239-246,
1998
79. Ying Z, Babb TL, Hilbig
A, et al: Hippocampal
chemical anatomy
in pediatric
and adolescent
patients
with
hippocampal
or extrahippocampal
epilepsy
Dev Neurosci
21:236-247,1999
80. Zhu WJ, Roper S: Reduced
inhibition
in an animal
model of cortical
dysplasia.
J Neurosci
20:8925-8931,
2000
81. Zilles K, Qu M, Schleicher
A: Characterization
of neuronal migration
disorders
in neocortical
structures:
Quantitative
receptor
autoradiography
of ionotropic
glutamate,
GABAA
and GABAs
receptors.
Eur J Neurosci 10:3095-3106,1998
Address

reprint

reqwsts

to

Zhong Ying, MD, PhD

The Cleveland
Clinic Foundation
NB-2
9500 Euclid Avenue
Cleveland,
OH 44195
e-mail:

yingz@ccf.org

CONTEMPORARY MANAGEMENT
OF CORTICAL DYSPLASIAS

OF MALFUNCTIONS

1042-3680/02 $15.00 + .OO

PREOPERATIVE
CLINICAL
EVALUATION
AND NONINVASIVE
ELECTROENCEPHALOGRAM
IN
CORTICAL DYSPLASIA
Monica

CORTICAL

DYSPLASIA

Overview
The terms cortical dysplasia and malformations of cortical development often are used interchangeably Cortical dysplasia is a nonspecific
term that signifies abnormal
formation
of
the brain cortex without implying
a specific
histologic
description.
Cortical dysplasia is
associated clinically with epilepsy, motor impairment,
and developmental
delay.= Malformation of cortical development
implies an
in utero abnormality
of proliferation,
migration, or cortical organization without indicating a specific histology Malformations
of cortical development
include gross macroscopic
abnormalities
on MR imaging, such as pachygyria/polymicrogyria,
hemimegalencephaly
and lissencephaly,or
microscopic
changes,
such as microdysgenesis,
which rarely produce distinct MR imaging findings and require microscopic visualization
for diagnostic
confirmation.
In 1971, Taylor *O described microscopic
changes in resected tissue of patients with

A. Koehn,

MD, and Michael

Duchowny,

MD

epilepsy consisting of large, bizarre neurons

in the cerebral cortex and white matter. These
features were similar to those findings seen
in tuberous sclerosis in that both demonstrate
cortical dyslamination
and balloon cells. They
are distinguished
only by associated genetic
markers and multisystem
involvement
in
tuberous sclerosis complex. Taylor postulated
that localized collections of exotic neurons
had electrical
and clinical
manifestations
contributing
to epilepsyzO These pathologic
findings have become known as Taylor-type
dysplasia.

Clinical

Presentation

The clinical presentation of malformations

of cortical development
is variable and depends on the function of the involved region.
Most presentations exhibit epilepsy, developmental delay, and motor impairment.
Epilepsy
usually is chronic and consists of partial or
generalized
episodes depending
on the extent of the lesion. Seizures often present in
early life and may manifest as infantile spasms

From the Department of Neurology, Miami Childrens Hospital,

Neurology, Marshfield Clinic, Marshfield, Wisconsin (MAK)

Miami,

Florida (MAK,

MD); and Department

of

NEUROSURGERY CLINICS OF NORTH AMERICA

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2002

35

36

KOEHN

& DUCHOWNY

or secondarily
generalized seizures.= All pa:
tients with malformations
of cortical development do not have seizures, and their response
to antiepileptic drugs is variable. Dysplasia of
the motor strip causes hemiparesis
of varying severity. Speech delay may re/sult from
malformation
of primary speech and language
areas. With diffuse or bilateral dysplasia, cognitive impairment
and microcephaly
are common. The functional imphcations of dysplastic
cortical involvement
in association areas are
poorly understood.

Neuropsychology
of
Cortical Dysplasia
Neuropsychologic
evaluations
of children
with cortical dysplasia
often reveal significant psychiatric,
behavioral, and intellectual
impairments.
These pervasive clinical abnormalities reflect the extent, degree, and location of the dysplasia and may be greater than
the observed abnormalities
on neuroimaging
studies. Rossi et alI7 found that a majority of
their 28 patients who were followed
for over
12 years exhibited mental retardation
(92%),
psychiatric disorders (42%), and social disability (57%). As expected, the severity of the cognitive impairment was directly proportional
to
the extent of dysplasia (i.e., profound mental
retardation is more common in patients with
agyria-pachygyria).
Two of 12 patients with
focal cortical dysplasia
had normal intelligence, but none were profoundly
mentally
retarded. Psychiatric
disorders
including inattentiveness
and hyperactivity
occurred in
nearly half of the patients and were identified
in focal and bilateral localized cases.17
The cognitive outcome of children
with
unilateral cortical dysplasia is a function of the
involved hemisphere and extent of pathology.
Diffuse brain lesions are significantly
more
harmful for nonverbal cognitive development
than circumscribed
mass lesions. The side
and extent of involvement
influence verbal
measures
in children
with
circumscribed
lesions, surpassing
patients with diffuse cortical dysplasia if the lesion involves the right
hemisphere.
Children with left hemispheric

lesions consistently
perform poorer on verbal
and performance
intelligence
testing compared with patients with dysplasia of the right
hemisphere.7

Neuroimaging
The use of MR imaging has dramatically
increased the ability to detect cortical dysplasia.*
MR imaging remains the undisputed
neuroradiologic
investigation
of choice for diagnosing cortical dysplasia and detects 50% to
70% of cortical malformations.23
MR imaging
often helps define specific syndromes,
many
of which present with epilepsy, developmental delay, or motor impairment.
The loss of
a distinct gray-white
junction, incomplete arborization,
presence of heterotopias,
or focal
gyral abnormalities
are common.
Rarely, cortical dysplasia
is found incidentally
on MR
imaging for an unrelated indication. The extent of cortical malformation
may be disproportionate to abnormalities
detected on neurologic examination.

ELECTROENCEPHALOGRAPHIC
FINDINGS
The electroencephalogram
(EEG) demonstrates features suggestive of cortical dysplasia but is not pathognomonic.
The most common feature, although neither sensitive nor
specific for diffuse cortical dysplasia,
is fast
frequencies
of 15 to 25 Hz15,16 of abnormal
amplitude.
This activity often predominates
over the central regions either continuously
or in bursts, replaces the background
activity or becomes intermixed,
is present during
wakefulness
and sleep, and is unresponsive
to
eye opening or closure.6 Other electrographic
features indicative of localized cortical dysfunction include low-amplitude
focal interictal sharp or spike-waves,
background
activity
of decreased amplitude,
absent or asymmetric sleep spindles, unilateral electrodecremental patterns, and electrographic
seizures.24 Localized polymorphic
slow activity is a frequent
finding in cortical dysplasia.16 Alpha activity

IREOPERAITVE

CLINICAL

is typically preserved unless the dysplasia involves the posterior regions. Various patterns
may be present in the same patient and disappear with time.
Electrocorticography
over the area of cortical dysplasia reveals frequent epileptogenicity consisting of prolonged trains of rhythmic
activity, repetitive bursts of spikes, or continuous rhythmic l- to ~-HZ sharp waves or
spikes. I There is a strong correlation between
continuous epileptiform
discharges on electrocorticography
and the presence of repetitive epileptiform
discharges on scalp EEG.
Repetitive epileptiform
discharges and continuous epileptiform
activity are highly specific
and sensitive indicators of localized cortical
dysplasia.5
In a study of the EEG findings in children with known cortical dysplasia,3 72% of
patients were shown to have abnormal patterns. Unusually high frequency activity was
most common followed by high-amplitude
waveforms.
EEG abnormalities
appeared
earlier in patients with diffuse cortical dysplasias and increased with advancing age.
Unusual waveforms in the neonatal period
were believed to be a reliable early indicator
of cerebral malformation
especially in diffuse
forms. Overall, the EEG was helpful for diagnosing epilepsy caused by cortical dysplasia
in 75% of patients.3

Electroencephalogram
in Disorders
with Associated Cortical Dysplasia
Many malformations
of cortical development are associated with abnormal EEG findings. The holoprosencephalic
disorders are an
important example of malformations
and consist of a group of midline
anomalies
that
range in severity from a single forebrain with
fused basal ganglia structures or cyclopsia, to
manifestations
as inconspicuous
as a single
central incisor tooth. Holoprosencephaly
results from chromosomal abnormalities
such as
trisomy 13 or 18 and are inherited as autosomal dominant,
autosomal recessive, or Xlinked recessive disorders. The karyotype and
family history are characteristically
unremark-

EVALUATION

AND

NONINVASIVE

EEG

37

able. The EEG findings in holoprosencephaly

usually are present at birth and subsequently
disappear. Mixed frequency activity consisting
of diffuse ,9 with interspersed T and S waves
are most common and typically unresponsive
to stimulation
and show little variation during sleep. With maturity, this pattern loses
its structured appearance and is replaced by
slow dysrhythmic, high-amplitude,
bilaterally
asynchronous
mixed frequencies. A second
pattern consists of high-amplitude
sharp- and
slow-wave complexes with intermixed
CYand
,f3 activity. Both patterns may alternate or appear in the same EEG tracing.3
Syndromes with associated malformations
of cortical development
constitute a spectrum
of severity that can be divided into the lissencephalic and nonlissencephalic
syndromes.13
Lissencephaly is characterized by a lack of gyral formation
(smooth brain) that is evident
by the third or fourth month of gestation. The
lissencephalies are divided into types I and 11,
each have distinct histopathologic
and clinical
features, imaging findings, genetic causes, and
implications.
Type I lissencephaly is characterized pathologically
by an arrest in the migration of neurons destined to compose deeper
layers of cortex, resulting in a four-layered
cortex.23 Syndromes associated with type I
lissencephaly include Miller-Dieker
syndrome
and isolated lissencephaly sequence. In type II
lissencephaly, the neocortex is disorganized
into ectopic clusters of neurons that form large
heterotopias.Z
In both types of lissencephaly,
the EEG
always is abnormal.
Typical EEG patterns
include (1) prominent
high-amplitude
fast
activity; (2) fast activity with a! or t frequencies (patterns that are too mature for age);
(3) bursts of high-amplitude
sharp- and slowwave complexes; (4) sharp- and slow-wave
complexes interrupted
by periods .of diffuse
voltage attenuation3* 15; and (5) chaotic succession of high-amplitude
r-S activity reminiscent of hypsarrhythmia,
but without spikes
or sharp waves. Rarely, the EEG does not
contain definitive
features despite radiographic confirmation
of agyria. Several patterns may exist in the same patient or even
during the same tracing. Some patterns seen

38

KOEHN

& DUCHOWNY

in the lissencephalies
are age dependent..
From ages 3 to 12 months, prominent
and
abnormally
fast rhythms
are seen alternating or mixed. Theta and rarely 6 activity may intermix
or alternate wit, a and
/3 activity.6 Slower activity often has a notched
appearance that can be misinterpreted
as
6
In
general,
the
frequencies
hypsarrhythmia.
increase with age. EEG abnormalities may not
be noted until ages 4 to 6 months. Waveform
amplitudes are always high (> 75 mV), typically 150 to 300 mV with frequent increases
and decreases . resembling
a paroxysmal
pattern.6 Typically, lissencephaly and its EEG
abnormalities
are bilateral; however, unilateral abnormalities
are common and appear
similar to hemimegalencephaly3
Diffuse migrational
disorders such as double cortex syndrome, consisting of band heterotopia underlying the cortical mantle with
associated epilepsy and mental retardation,
often are accompanied by electrographic features, such as generalized interictal epileptic
abnormalities,
slow spike-wave complexes,
poly-spike-wave
complexes,
sharp waves,
and repetitive spikes or multifocal epileptic
discharges.13
Familial diffuse cortical dysplasia is characterized clinically
by mental retardation,
and atypical absence, atonic, and generalized
tonic-clonic seizures. The EEG may demonstrate frequent bursts of bilateral symmetric
slow (2-2.5 Hz), spike, and wave discharges
that increase in frequency during drowsiness.g
Epilepsia partialis continua (EPC) is characterized by continuous rhythmic or irregular
jerking activity of a muscle group. Although
EPC is seen with multiple diverse causes that
affect cortical function, such as neoplasias,
focal infections,
inflammatory
lesions, or
vascular abnormalities,
cortical dysplasia is a
frequent cause. The EEG may reveal only focal
slowing with occasional epileptogenic
discharges or continuous repetitive epileptogenic
discharges within a limited field.s
The burst-suppression pattern is nonspecific
and can be associated with a variety of underlying causes including cortical dysplasia.
In early infantile epileptic encephalopathy
(Ohtaharas syndrome), the burst-suppression

may be asymmetric
and independent
of
state.i4 In dentato-olivary
.dysplasia, a presumed autosomal recessive disorder, the EEG
may demonstrate burst-suppression
or highamplitude diffuse slowing with frequent independent bihemispheric spikes.
Dermatologic
syndromes occasionally are
complicated by associated focal or widespread
cortical dysplasia. Hemimegalencephaly
has
been identified in a variety of patients with
neurocutaneous
disorders. Hemimegalencephaly is characterized by asymmetric hamartomatous enlargement of an entire abnormally
formed hemisphere and can occur in isolation
or in conjunction with other systemic disorders. The EEG findings are typically different
from those seen in other disorders of cortical malformation,
in that the abnormal fast
activity is infrequent, if not absent.
Hypomelanosis
of Ito is a rare syndrome
that typically presents with intractable seizures and mental retardation.*
Linear epidermal nevus syndrome is included in the
family of epidermal nevi, which arises from
the pluripotential
germinal cells in the basal
layer of the embryonic epidermis. This disorder also is associated with intractable epilepsy
and mental retardation.4 The EEG demonstrates asymmetric hypsarrhythmia,g
unilateral bursts of high-amplitude
sharp and slow
waves that are replaced during sleep by a
burst-suppression
pattern, focal epileptogenie activity,i2 or even organized electrographic sequences.4
Single case reports document the occurrence
of cortical dysplasia in multiple
syndromes.
In one patient with Noonan syndrome (characterized by dysmorphism,
congenital heart
disease, mental retardation, and skeletal abnormalities),
MR imaging revealed obscure
gray-white differentiation
of the left temporal
lobe, consistent with the seizure semiology
and EEG demonstrating
frequent spikes over
the left parietal and posterior temporal regions.18 Hemirnegalencephaly
was confirmed
radiographically
in a patient with congenital
intestinal aganglionosis. (Hirschsprungs
disease), leading to the speculation that common
insults may affect innervation
of the bowel
and formation
of the cerebral cortex. The

PREOPERATIVE

CLINICAL

EEG in this case demonstrated

asymmetric
hypsarrhythmia
during sleep, consisting of
background suppression and high-amplitude
irregular spike- and slow-wave discharges.

SUMMARY
Malformations
of cortical development
may
occur in isolation or as a feature of a multisystern disorder. A multimodal
presurgical evaluation including detailed neuroimaging,
functional imaging, clinical examination,
and EEG
continue to direct the localization of the area
of seizure onset. Focal fast activity and unusual high-amplitude
6 slowing are the most
frequently encountered EEG patterns.

References
1. Aicardi
J: The agyria-pachygyria
complex:
A spectrum
of cortical
malformations.
Brain Dev 13:1-8.
1991
2. Barkovich
AJ, Kjos BO: Nonlissencephalic
cortical
dysplasias:
Correlation
of imaging
findings
with clinical deficits. ATNR 13:95-103.1992
3. Bemardina
SD, Perez-Jimenez
A, Fontana
E, et al:
Electroencephalographic
findings
associated
with
cortical
dysplasias.
In Guerrini
R, Canapicchi
R,
Zifkin
BG (eds):
Dysplasias
of Cerebral
Cortex
and Epilepsy.
Philadelphia,
Lippincott-Raven,
1996,
pp 235-254
4. Bonioli
EV, Bertola
A, Stefano AD, et al: Sebaceous
nevus syndrome:
Report of two cases. Pediatr Neural
17:77-79,1997
5. Gambardella
A, Palrnini
A, Andermann
F, et al: Usefulness of focal rhythmic
discharges
on scalp EEG of
patients
with focal cortical
dysplasia
and intractable
epilepsy.
Electroencephalography
and Clinical
Neurophysiology
98:243-249,1996
6. Gastaut
H, Pinsard
N, Raybaud
C, et al: Lissencephaly (agyria-pachygyria):
Clinical
findings
and serial EEG studies.
Dev Med Child Neurol29:167-180,
1987
7. Klein B, Levin
BE, Duchowny
MS, et al: Cognitive
outcome
of children
with epilepsy
and malformations
of cortical development.
Neurology
55:230-235,200O

EVALUATION

AND

NONINVASIVE

EEG

39

R, Powers
R: Epilepsia
partialis
continua
8. Kuzniecky
due to cortical
dysplasia.
J Child Nemo1
8:386-388,
1994
9. Kuzniecky
R: Familial
diffuse cortical dysplasia.
Arch
Neural 51:307-310,1994
T, Harding
BN, Morton
RE, et al: Dentato10. Martland
olivary
dysplasia
in sibs: An autosomal
recessive
disorder? J Med Genet 34:1021-1023,1997
11. Morioka
T, Nishio
S, Ishibashi
H, et al: Intrinsic
epileptogenicity
of focal cortical
dysplasia
as revealed
by magnetoencephalography
and electrocorticography. Epilepsy
Research 33:177-187,1999
12. Ono J, Harada
K, Kodaka
R, et al: Regional
cortical
dysplasia
associated
with suspected
hypomelanosis
of Ito. Pediatr Neurol17:252-254.1997
A, Anderrnann
F, Aicardi
J, et al: Diffuse
13. Palmini
cortical
dysplasia
or the double
cortex
syndrome:
The clinical
and epileptic
spectrum
in 10 patients.
Neurology
41:1656-1662,199l
JM, Loiseau
H, Vital
A, et al: Surgical
14. Pedespan
treatment
of an early epileptic
encephalopathy
with
suppression-bursts
and focal cortical
dysplasia.
Epilepsia 36:37-40,1995
JA, Kendall
8, Kingsley
DPE, et al: EEG fea15. Quirk
tures of cortical
dysplasia
in children.
Neuropediatrics 24:193-199,1993
16. Raymond
AA, Fish DR: EEG features
of focal malformation
of cortical
development.
J Clin Neurophysiol
13:495-506,1996
17. Rossi PG, Parmeggiani
A, Santucci
M, et al: Neuropsychological
and psychiatric
findings
in cerebral
cortex
dysplasias.
In Guerrini
R fed): Dysplasias
of Cerebral
Cortex
and
Epilepsy.
Philadelphia,
Lippincott-Raven,
1996, pp 345-350
18. Saito Y, Sasaki M, Hanaoka
S, et al: A case of Noonan syndrome
with cortical dysplasia.
Pediah Neural
17:266-269,1997
19. Tagawa
T, Futagi
Y, Arai H, et al: Hypomelanosis
of Ito associated
with hemimegalencephaly:
A clinicopathological
study.
Pediatr
Neural
17:180-184,
1997
20. Taylor DC, Falconer
MA, Bruton CJ, et al: Focal dysplasia of the cerebral cortex in epilepsy. J Neural
Neurosurg Psychiatry
34:369-387,197l
21. Turkdogan-Sozuer
D, Ozek
MM,
Sehralti
V, et al:
Hernimegalencephaly
and Hirschsprungs
disease: A
unique association.
Pediatr Neural
18:452-455,1998
22. Volpe JJ: Neuronal
proliferation,
migration,
organization, and myelination.
In Neurology
of the Newborn.
Philadelphia,
WB Saunders,
1995, pp 43-92
23. Whiting
S, Duchowny
M: Clinical
spectrum
of cortical dysplasia
in childhood:
Diagnosis
and treatment
issues. J Child Neural
14:759-771,1999
24. Wyllie E: Surgery
for catastrophic
localization-related
epilepsy
in infants. Epilepsia
37(suppl):S22-S25,1996

Address reprint

requests

to

Michael
Duchowny,
MD
Department
of Neurology
Miami Childrens
Hosoital
3200 S.W. 60th Court
Miami,
FL 33155
e-mail:

michael.duchowny@mch.com

CONTEMPORARY MANAGEMENT
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OF MALFUNCTIONS

10423680/02

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ROLE OF FUNCTIONAL
MAGNETIC
RESONANCE
IMAGING
IN THE
EVALUATION
OF PATIENTS WITH
MALFORMATIONS
CAUSED BY
CORTICAL
DEVELOPMENT
Afraim

CLINICAL FUNCTIONAL
RESONANCE
IMAGING:
FACT AND FICTION

MAGNETIC

Blood oxygen level-dependent

functional
magnetic
resonance imaging
(BOLD-fMXI)
is performed using an ultrafast imaging sequence such as gradient-echo
echo-planar
imaging
to obtain susceptibility-weighted
images of the brain at short intervals. Wholebrain echo-planar imaging at 1.5 T may typically be achieved using 21-mm x 5-mm slices,
for example, each containing 64 x 64 voxels
and covering 25 cm*, at a repeat time of
3 seconds. Multiple
volumes (scans) are usually acquired during a lo- to 30minute experiment to construct a dynamic picture of signal
fluctuation at each voxel. In principle, changes
in BOLD partially reflect physiologic changes
in the intravoxel concentrations of paramagnetic deoxyhemoglobin,50
an ill-understood

Salek-Haddadi,

MRCP, Louis Lemieux,

PhD,
and David R. Fish, FRCP

consequence of neural activation*

ensuing
from a complex interplay between cerebral
blood flow, blood volume, and oxygen metabolism as orchestrated by the neurovascular coupling. I1 It should be noted, however,
that the largest physiologic
contributors
to
BOLD are draining veins as opposed to local
capillary beds; this brain or vein problemz6
imposes a fundamental
limit on resolution,
particularly
at lower field strengths,17 and responses are subject to variability.2s4,35
Various tasks may be performed
during
fMRI to target specific co&Cal networks by
introducing
discernible
patterns of neural
activity and hence BOLD changes within their
enclosing voxels. These task-related
BOLD
changes are subtle (a few percent at 1.5 T) and
More recently it has been shown that BOLD changes
may better favor the dendritic input and intracortical
processing of a given area (local field potential) over its
spiking output per se.46

From the Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College at London,
London (ASH, LL); MRI Unit, National Society for Epilepsy, Buckinghamshire (AS-H, LL); and Department of
Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, London (DRFl, England
NEUROSURGERY CLINICS OF NORTH AMERICA
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1 JANUARY
l

2002

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64

SALEK-HADDADI

et al

subject to extensive noise (scanner-related

and physiologic) such that statistical inference
is possible only within a complex framework. Statistical parametric
mapping2
for
example, allows knowledge and assumptions
regarding the anticipated BOLD changes to
be embodied within a general linear model,
which is tested at each and every voxel for
goodness of fit. Statistical images may then
be created and thresholded to reveal areas
of significant activation that may be overlaid onto high-resolution
structural
scans
for .anatomic localization.
The crucial point,
however, is that statistical hypothesis testing
approaches in functional neuroimaging
serve
only to protect against type I error, or the
likelihood
of false-positive
results. Type IL
error control against false-negative
results
cannot be provided (because of lack of an
alternate hypothesis); as a result, great caution
must be exercised in interpreting
negative
findings. This point is further highlighted
by the fact that gradient-echo
echo-planar
imaging scans are, in general, subject to extensive distortions and dropouts.
These occur
particularly
around the mesial temporal and
inferior frontal air-tissue interfaces and further
prohibit
negative inference. Coregistration
of results to high-resolution,
spin-echo, Tlweighted scans may also be misleading,
as
such features are not shared. Lack of activation
does not imply lack of function, in fact, nor
does activation imply essentiality (e.g., lesion
studies), and these are important
prevailing
themes.
Functional MR imaging is otherwise fast,
noninvasive, and nontoxic, combining wide
coverage with high spatial resolution. A growing number of centers now offer it as a clinical
service as imaging and processing techniques
continue to accelerate, but certain practical
considerations
still apply General contraindications to MR examination such as non-ML&
compatible implants and pacemakers may exclude certain patients, and a greater degree of
patient cooperation is required to ensure compliance with experimental
paradigms and to
avoid detrimental
head motion. This is particularly pertinent, as patients with malformations of cortical development (MCD) are more

likely to be impaired cognitively

and suffer
with attentional and behavioral impairment
and autism.ffi Pharmacotherapy
may also
complicate the interpretation
of results; task
performance may certainly be influenced, but
more direct effects on cerebral activity or neurovascular transduction
may also influence
results.36

CLINICAL QUESTIONS
IN
MALFORMATIONS
CAUSED
BY CORTICAL DEVELOPMENT
MCD is an important and underdiagnosed
cause of refractory epilepsy, the main consequence of MCD necessitating surgical intervention. The aims of presurgical evaluation
are to establish and weigh the risk : benefit
ratios of any potential intervention
so as to
plan the most appropriate
course of action.
The risks of surgery are dependent on the site
of surgery and its relation to eloquent cortex
as well as the benefit in terms of seizure control, which is a decisive factor. Theoretically,
the best outcome may be achieved by resecting
only sufficient tissue to eliminate seizures and
no more, provided that this may be done without causing additional deficit.= Key issues are
the identification
of an epileptogenic
zone+
in relation to any surrounding eloquent cortex
and designation of any overlap.

The Epileptogenic

Zone

Concepts of the epileptogenic

zone are
rapidly evolving in MCD. A comprehensive
recent review by Sisodiya62 found only 40% of
all patients with surgically treated MCD to
have been rendered seizure-free over a minimum folfow-up period of 2 years, which is in
sharp contrast to the proportion achieving excellent seizure outcome (70%-80%) in cases of

tThe epileptogenic zone, a theoretic concept, is defined

as the area of brain that is necessary and sufficient for
initiating seizures and whose removal or disconnection is
necessary for abolition of seizures.47

FUNCTIONAL

hippocampal
sclerosis and tumors, and such
figures underline the complex neurobiologic
profile.
Although
intrinsic epileptogenicity
is an
in vitro feature of human dysplastic neurons,
ictal scalp electroencephalography
(EEG) is often poorly localizing, and interictal EEG may
reveal widespread
or multifocal
spiking.56
Likewise, intracranial studies may often reveal
widespread interictal spiking with complex
ictal propagation patterns and unexpected interactions between noncontiguous
sites.% Histopathologic,
radiologic,
cognitive,
and behavioral evidence also points toward subtle
abnormalities
existing beyond the epileptogenie lesion in MCD as reviewed recently by
Duchowny et al, who re-emphasize the conceptualization
of focal epileptogenesis
as a
widespread and patchy disturbance of cortical
networks in MCD.
Concepts of distributed
epileptogenesis
dominate
as argued by Sisodiya62 and
others,5,8*27a whereby the epileptogenic
zone
may be regarded as a changing spatiotemporal
entity with networks functioning
in a hierarchic manner such that removal of a dominant
pacemaker
may allow activity to continue
through reorganization.

The Eloquent

Cortex

Functional
overlap between MCD and
normal brain tissue is well recognized as
is wider functional
reorganization
within
&iCD brains. Cortical stimulation
studies
demonstrate conserved temporal and frontal
language sites in dysplastic cortex even with
extensive dominant
hemisphere
malformation in children,20 and patients with normal
motor skills, for example, may possess atypical motor homunculi,
such as hand superior
to shoulder representation and shoulder representation above and below hand-finger as
revealed by cortical stimulation.*
In another
report, unilateral motor representation of both
hands in association with mirror movements
was described using transcranial
magnetic
stimulation
in a young girl with extensive
cortical dysplasia of the opposite hemisphere

MR WGING

IN PATIENTS

WJTH MCD

65

and a mild hemiparesis.49 Reorganization

of
somatosensory cortex on the affected side also
was shown despite normal sensory function.
Richardson et aP7 were able to demonstrate
cerebral activation in 8 of 10 patients within
affected brain regions using H2150 positron
emission tomography
with appropriate
tasks
as well as differences in activation patterns
compared with controls in 5 patients. These
issues pose obvious problems
for surgical
resection.

POTENTIAL
MAGNETIC

FOR FUNCTIONAL
RESONANCE
IMAGING

Task-Related
Functional
Resonance Imaging

Magnetic

The main application

of fMRI within the
clinical setting is in noninvasive
mapping
of brain function. Sensory-motor
or central
sulcus mapping
as performed
with fMRI
has repeatedly been found to be in agreement with intraoperative
cortical stimulation
studies 1*22*24,32,54,55,61*6g
and most centers now
possess an additional wealth of unpublished
experience.
More recently, Pinard et a15j were able to
demonstrate coactivation within the MCD itself in a child with subcortical laminar heterotopia (SCLH) during a finger-tapping
task,
and Spreer et aP have reported on three similar patients (also SCLH) showing coactivation
of the outer cortex of the inner neuronal band
during performance of a motor task. During
visual stimulation
in one patient, coactivation
also was evident inward along the route of
embryonic neuronal migration from the occipital cortex toward the ventricular wall. Such
observations in line with the previous work
further highlight
the potential for exploring
the participation
of aberrant tissue in physiologic functions using fMRI.
A number of studies have found lateralization indices for language dominance based on
fMRI to be in close agreement with measures
derived
from intracarotid
amylobarbitone
(Wada) testing6* * g*13r29*~3,66,68 and results from
intraoperative
cortical stimulation,25~4858~5q~67

66

SALEK-HADDADI

et al

and fMRI has long been hailed as the likely

successor. Paradigms differ widely, however,
depending on hardware and expertise with
subtle differences in the areas targeted. Like
many issues in fMRI, there is a general lack
of consensus, but a move toward integrating
information across paradigms is evident. Validation is also less well developed for patients
with mixed or right hemisphere
language
dominance, and we are as yet unaware of any
centers where Wada testing has been reduced
to a significant extent as a consequence of
fMRI.
Routine fMRI mapping of memory function is farther still from the clinical arena.
Structures such as the hippocampus are more
difficult to image technically and to target selectively with cognitive paradigms,O but the
benefits of new research techniquesO are destined to spill over soon.
Electroencephalographic-Correlated
Functional Magnetic
Resonance Imaging
The possibility of imaging epileptiform neural activity directly using fMRl represents one
of the most exciting and pioneering applications of MR technology. Early suggestions of
ictal fMRI changes15,6,33 have sparked considerable efforts to obtain concomitant EEG measures of seizure activity, a multifaceted
and
truly multidisciplinary
challenge?, 4,***30,3*38,45
In principle, a temporal knowledge of EEG
events should allow the detection of timelocked BOLD changes within fMRI data and
the identification
of instigating voxels. Interleaved recordings of interictal EEG activity using EEG-triggered fMR13g have already proved
feasible60 and clinically informative,3, 4, 42,52,@
but the recent advent of simultaneous
and
continuous EEG and fMRI in epilepsy bears
further promise still in answering a number
of fundamental
questions, including
which
EEG events or patterns are associated with detectable BOLD signatures, how consistent
these are, how best they may be derived or
modeled, and how they relate to pathologic
findings and outcome.

ictal
Clinically,
whereas EEG-correlated
fMRI may reveal the anatomic organization
of seizure activity inclusively in terms of epileptogenic
and propagation
zones (SalekHaddadi
et al, submitted),
practicability
is
somewhat limited. Conversely, interictal epileptiform
discharges are more amenable to
EEG and fMRI but (by definition) help to identify the !irritative
zone, generally regarded
as closely relating to the epileptogenic zone.47
Raymond and Fish56 reported interictal epileptiform discharges in most patients with MCD
and epilepsy, but they were often widespread
or multifocal with a poor tendency to localize
ictal onset, although focal continuous epileptiform discharges on electrocorticography
have
been correlated with outcome.51
A number
of interictal
EEG-triggered
fMRI studies have included
patients with
MCD37,40,42,@ and have reported activations in
relation to the identified structural pathologic
changes. An example from the authors own
work is provided in Figure 1 where, in brief,
bilateral activation was found within dysplastic cortex in response to several bilateral
bursts of interictal spike wave discharge in a
patient with mixed subependymal
nodular
heterotopia and SCLH. It has been suggested
that interictal activity may help define remote regions of epileptogenic
dysfunction
within the aberrant malformation
network,ig
but further data are required before the
significance of such findings may be ascertained in relation to pathologic changes and
outcome.
SUMMARY
The Neuroimaging
Subcommission
of the
International
League Against Epilepsy currently states that: At present, fMRl should not
be relied upon for clinical functional mapping
or seizure focus localisation, except in an ancillary role and when supported by other data.*
Further developments herald a diagnostic revolution through the noninvasive mapping of
physiologic
and pathophysiologic
brain activity, however, and there exists great scientific potential to unravel the mechanisms of

FUNCTIONAL

MR

IMAGING

IN

PATIENTS

WITH

MCD

67

Figure
1. Results
from a continuous
interictal
electroencephalogram
(EEG)-correlated
functional
MR imaging
(fMRI) experiment
are shown.
Frequent
runs of widespread
bilaterally
synchronous
spike-wave
EEG
discharges
were recorded
during
a 35-minute
fMRl experiment
from
a 29-year-old
man with complex
partial
seizures,
generalized
tonicclonic seizures,
and myoclonic
jerks. Structural
imaging
had shown
a widespread
MCD with extensive
subcortical
heterotopia,
thickened
gyri, and subependymal
nodules.
Statistical
parametric
maps, superimposed
onto high-resolution
Tl -weighted
images,
reveal two principal
spike-related
clusters
of activation
symmetrically
overlying
the occipitotemporal
grey matter (P < 0.001 corrected
cluster-level
statistic).
(See
also Color Plate 1, Fig. 1.)

epileptogenesis through synergism with other

imaging modalities. Future roles in rationalizing patient selection, guiding invasive study,
and surgical planning may all be envisaged.

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69

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Address reprint requests to
Afraim Salek-Haddadi, MRCP
MRI Unit, National Society for Epilepsy
Chalfont St Peter
Buckinghamshire SL9 ORJ
England
e-mail: A.Haddadi@ion.ucl.ac.uk

CONTEMPORARY MANAGEMENT
OF CORTICAL DYSPLASIAS

OF MALFUNCTIONS

1042-3680/02

$15.00 + .OO

CORTICAL DYSPLASIA
AND EPILEPSY
Functional Imaging Using Single Photon
Emission Computed Tomoaraphv and
Positrog Emission T6m&aDhv

Maria

T. Toczek,

Functional
imaging
using single photon
emission computed tomography (SPECT) and
positron
emission
tomography
PET) has
made important
contributions
to the understanding of certain epilepsies and has identified patients who were not previously considered surgical candidates. It also may provide
prognostic and functional information
essential to the presurgical evaluation.
Cortical dysplasia (CD) frequently is associated
with
medically
refractory
epilepsy46.
59,91.95
which may successfully
be
treated surgically
in a significant
number of cases.33,47.io8 CD is one of the most
common types of malformation(s)
of cortical development
(MCD) found in epileptic
surgical specimens, with some surgical series
demonstrating
the presence of CD in approximately 12% to 26% of cases,14,47,57,6*,66,9*and
even higher percentages in pediatric surgical
series.46,56,59,64,119

This article reviews the contributions

that
SPECT and PET imaging have made to the

MD,

and William

H. Theodore,

presurgical evaluation of patients

lepsy associated with CD.

CORTICAL

DYSPLASIA

Pathologic

Findings

with

MD

epi-

The term cortical dysplasia has been used

to refer to several different developmental
abnormalities,
including
abnormal
neuronal
and glial proliferation,
abnormal
neuronal
migration,
and abnormal
cortical organization. Focal cortical dysplasia(s) (FCD) was
first described by Taylor et aln4 in 1971 in
surgically resected tissue from patients with
medically refractory epilepsy. CD may be focal
or multifocal and has been characterized by a
wide spectrum of abnormalities
affecting gray
and white matter, including
disturbances in
normal cortical lamination
and organization,
presence of abnormally
large dysplastic neurons, large reactive astrocytes and balloon

From the Clinical Epilepsy Section, Epilepsy Research Branch, National Institute of Neurological
National Institutes of Health, Bethesda, Maryland

Disorders and Stroke,

NEUROSURGERY CLINICS OF NORTH AMERICA

VOLUME

37.

NUMBER

1. JANUARY

2002

71

72

TOCZEK

& THEODORE

cells, increased cellularity

of the molecular
layer as a result of increased neurons and glial
cells, and clustering of atypical neuronal and
glial cells within
the cortex and subcortical
white matter.. 39,.57-j9.j. 89.. Balloon cells are
large eosinophilic
cells with eccentric nuclei
similar to the type commonly seen in tuberous
immunocytochemistry
sclerosis@ 11* with
staining features characteristic
of neurons and
glial cells (Fig. 1). * FCD has been divided
into two typesS7: type I characterized
by an
alteration of cortical lamination and not associated with balloon cells and the more severe
type II associated with cortical disorganization
and the presence of white matter ectopias and
balloon cells., S. 59
Macroscopic
characteristics
of FCD include
thickening of the cortical gray matter, which
may be subtle (usually in the range of 5-8 mm
as opposed to normal cortical thickness with
a range of 3-5 mm); blurring
of the graywhite matter interface; and small subcortical dysplastic abnormalities
usually located at
the gray-white
matter interface but also seen
at the base of a sulcus or, less frequently, at
the top of a gyrus. , s7 These abnormalities
may be limited or more extensive, involving
multiple gyri. T2 prolongation
of the subcor-

tical white matter in association

with FCD
has also been demonstrated.,
, 37.h3.s, 85 FCD
(usually type I) may appear normal on highresolution magnetic resonance (MR) imaging,
however,, 48.95. 18 and may not be detected on
visual inspection, . or on palpation,, 47,
with diagnosis relying on histologic examination in some cases. The frontal lobe, central,
and insular regions are reportedly
the most
common sites for CD,5658, 73.. 89.9s although
they may occur throughout the cerebrum.
Cortical dysplasia may coexist with different forms of MCD9,5 and with neoplasia,
occurring
in 4% of the cases from one surCD also may be associated
gical series.
with hippocampal
atrophy (dual pathology)
(Fig. 2). 14.w~,~ Cendes et al reported a series of 25 patients with dual pathology
in
which 25% of the cases were associated with
neuronal migration
disorders,
2% with lowgrade tumors, 9% with vascular lesions, and
31% with porencephalic
cysts. The incidence
was similar to that in the series presented
by Levesque et al, who found that of the
54 of 178 patients who underwent
en bloc
temporal lobectomies for medically refractory
epilepsy and had evidence of dual pathologic findings, 13 (24%) had extrahippocampal

Figure
1. Balloon cell changes
(arrow).
Balloon cells have eccentric
nuclei and abundant eosinophilic
cytoplasm
(hemotoxylin-eosin
[H&E] original magnification
x 400).
(From Lee SK, Choe G, Hong KS, et al: Neuroimaging
findings
of cortical dyslamination with cytomegaly.
Epilepsia
42:852, 2001; with permission.)

CORTICAL

DYSPLASIA

AND

EPILEPSY

73

Figure 2. A patient who had only definite hippocampal

sclerosis
on MR image
but had an epileptogenic
zone in the left frontal lobe. A, Left hippocampal
sclerosis on MR image. B, Focal hypometabolism
of the left frontal lobe (arrow)
on
F-18 fluorodeoxyglucose-positron
emission
tomography
(FDG-PET).
C, Potential
but indistinct
blurring
of gray-white
matter interface
and shallow sulci in the left
frontal lobe on MR image. (From Lee SK, Choe G, Hong KS, et al: Neuroimaging
findings
of cortical
dyslamination
with cytomegaly.
Epilepsia
42:853,
2001; with
permission.)

neuronal heterotopia, with an additional

6 having neuronal heterotopia along with
glioma (1 patient), hamartoma (4 patients),
and other findings (1 patient). Levesque et aP5
also noted that the group with heterotopias
was associated with more severe hippocampal
cell loss than, for example, those patients with
glioma or hamartoma only. Cendes et al
noted that the location of the neuronal migration disorder could be anywhere in relation
to the atrophic hippocampal formation unlike vascular lesions, which were most likely
found close to the atrophic hippocampal
formation.
Malformation of cortical development may
result from various environmental and genetic insults occurring during the prenatal or

perinatal (either in utero-or after delivery)

period. 30.52.57.72,73The nature of the insult is not
as important as the timing and its effect on the
process of cerebral development.52,72,73

Epileptogenicity

of Cortical

Dysplasia

Patients with epilepsy as a result of FCD

are more likely to be medically intractable27,29,33.57,85and may have a disproportionate
incidence of status epilepticus.27,33.57*85
Palmini et a185,87
have suggested that FCD
may possess an intrinsic epileptogenicity
unlike other structural abnormalities associated with medically refractory neocortical epilepsy such as neoplasms, which are

74

TOCZEK

& THEODORE

considered to be epileptogenic
as a result of
their effect on adjacent cortex.*yO They compared the intraoperative
electrocorticography
(ECoG) recordings from 34 patients with localized cortical dysplastic lesions and 40 patients
with nondysplastic
structural
lesions (mainly
neoplastic)
being evaluated
for medically
intractable partial epilepsy. They found that
23 of the 34 patients (67%) with cortical dysplastic lesions and only 1 of the 40patients
(2.5%) with nondysplastic
structural
lesions
demonstrated
continuous
or frequent rhythmic epileptogenic discharges recorded directly
from the lesion during intraoperative
EcoG.~
Sasaki et aP observed
similar findings
in
their series of four patients with medically
refractory epilepsy caused by CD.
The surgical outcome of patients with medically refractory
epilepsy caused by CD also
supports
this theory of an intrinsic epileptogenicity. Several investigators
have reported
that patients in whom complete resection of
the dysplastic tissue could be performed experienced a more favorable outcome.33* 47,86,8g
The mechanisms
involved in the epileptogenicity of CD are not fully understood
and
are believed to be extraordinarily
complex.
It has been suggested that certain alterations
in the morphologic
and membrane properties
of dysplastic neurons, alterations in synaptic
circuitry
and in glutamate receptor subtypes,
and y-aminobutyric
acid-ergic (GABA) neurotransmission
may be involved.*

Functionality

of Cortical

Dysplasia

A number of investigators
have suggested
that CD may participate in normal cognitive
ac+g.#2,
41,60,93,98.106
or may alter the normal
organization of cortical function.2~53~93~98These
factors may have a significant impact on the
planning of surgery in patients with medically refractory
epilepsy and underscore
the
importance
of ECoG and brain mapping in
this population of patients.y3 Functional imaging allows for a noninvasive
method to identify potentially unpredictable
and possibly unsuspected problems of altered or preserved
*References 5,35,46,59,76,111,112,

and 121.

cortical function associated with CD. Data obtained from functional

imaging can then be
used to guide placement of intracranial
electrodes and to provide additional prognostic
information.

SINGLE PHOTON EMISSION

COMPUTED TOMOGRAPHY
Methodology
Single photon emission CT is a functional
imaging
technique
that uses a lipophilic
gamma-emitting
tracer such as technetium99m-hexamethazine
or
technetium-99methyl cysteinate
disethylester
PmTc-ECD
or
99mTc-bicisate) given as a bolus intravenous
injection that distributes
quickly throughout
the
brain (usually within 1 minute) according to
regional blood flow. The radiotracer is rapidly
metabolized to hydrophilic
compounds
after
crossing the blood-brain
barrier and remains
fixed in the brain for a sufficient
period of
time after administration
to allow for imaging,
thus providing an estimate of regional cerebral
perfusion during the period immediately
after
tracer administration.6
This feature of SPECT
imaging allows
for assessment
of cerebral
blood flow during the ictal period.6*8
The
development
of stabilized radiotracers
such as
99mTc-ECD that remain stable 6 to 8 hours after
constitution
and thus do not require mixing
immediately
before injection has made ictal
SPECT more practical. This differs from PET
imaging in which ictal assessment of cerebral
blood flow or metabolism is hampered by radioisotopes with a short half-life such as 150 or
15H20 or those that require a longer period
to be metabolized
and distributed
throughout the brain tissue such as [F]-fluorodeoxyglucose
(FDG).y*55~8 Other advantages
of SPECT over PET include the fact that
SPECT is based on a less expensive technology, SPECT gamma cameras are more widely
available, and a cyclotron is not necessary for
radioisotope
production.V,79 PET, on the other
hand, has better spatial resolution
and great
versatility
In addition, absolute blood flow
or metabolism
measurements
(not usually
necessary for purely clinical studies) can be

CORTICAL

obtained from PET, although

only relative
values can be derived from SPECT.
Single photon emission CT is most useful
when performed
in the ictal state and then
compared with the interictal state, thereby taking advantage of the fact that partial seizures
are associated with a focal transient increase
in blood flow at the site of seizure origin
(Fig. 3). 3, n, 79,lo SPECT injections should be
performed
before the seizure generalizes because this greatly reduces the localizing value
of SPECT. Interictal SPECT is an unreliable localizing procedure.
Obtaining a true ictal SPECT injection can
be logistically difficult, especially in extratemporal lobe epilepsy, because these seizures
often are brief, nocturnal, and not associated
with aura. Rapid propagation
of ictal discharges may result in a less focal and sustained increase in regional
cerebral blood
flo~.~ Also, the seizure semiology at the time
of injection may actually reflect the spread of
discharges
to neighboring
regions and not
those originating from the epileptogenic zone.
Another
factor that may interfere with intei-pretation
is postictal
switch.
Postictal
switch refers to the evolution of the regional
cerebral blood flow from the ictal state to the
early and late postictal states, which may be
variable and result in changes in perfusion
patterns
within
the lesion and in the surrounding areas. lo,78,13,la Postictal switch may

DYSPLASIA

AND

EPILEPSY

75

occur more quickly

in extratemporal
lobe
epilepsy., *
The timing of injection in SPECT is critical,
with
earlier
injection
times being associated with improved
sensitivity
and specificity. K, 55,79,13.la Monitoring
with video electroencephalography
(EEG), preferably
in the
setting of an epilepsy monitoring
unit, should
be performed
as part of the SPECT procedure, as correlation
of the EEG data with
timing of the injection is essential for proper
interpretation.
3.3 For a more detailed review
of SPECT methodology
and radiopharmaceutical agents, the reader is referred
elsewhere,10,77.79.80

Clinical Applications
Emission Computed

of Single Photon
Tomography

In general, the main role of SPECT imaging

is in the presurgical
evaluation of patients (including those with CD) with medically refractory localization-related
epilepsies of neocortical, especially extratemporal,
origin in whom
data from electrophysiologic
monitoring
or
other imaging
studies
fail to conclusively
localize ictal onset.U, 55.O
The localizing value of ictal SPECT has been
extensively
studied; although
the standards
for analysis
are varied (e.g., studies
using
EEG localization as the standard versus other

Figure
3. lnterictal
(A) and ictal (B) single photon emission
CT (SPECT)
in a patient
with a normal MR image demonstrating
left occipital
hyperperfusion
on ictal SPECT
(arrow).
(From Lee SK, Choe G, Hong KS, et al: Neuroimaging
findings
of cortical
dyslamination
with cytomegaly.
Epilepsia
42:855, 2001; with permission.)

76

TOCZEK

& THEODORE

studies
using
pathologic
verification
and
surgical outcome as the standard),
the sensitivity of ictal SPECT is in the range of about
77% to 97% in temporal lobe epilepsy and
about 60% to 92% in extratemporal
lobe
range
may
epilepsy 31.40, 4R. 70. ii. 110. II6 Tllis wide
be attributed in part to variability of injection
times and scanner resolution.
Recent advances
in neuroimaging
processing techniques
such as computer-aided
subtraction
of the interictal SPECT images
from the ictal SPECT images with subsequent
coregistration
to MR imaging (SISCOM) have

HVDerDerfUSiOn

SISCOM

improved
the localizing value of SPECT, especially in extratemporal
lobe epilepsies, by
providing
a more objective method of evaluating regional intensity differences during the
peri-ictal period. R43 As a consequence,
focal
hyperperfusion
on ictal SPECT may not be the
only potential localizing finding using SPECT.
Some authors have suggested that with the
use of subtracted
SPECT, areas of focal hypoperfusion
may also help to localize the
epileptogenic zone with ictal injection as well
as with postictal injection (Fig. 4).h.8. lo9 The
use of subtracted
SPECT and the recognition

HvDoDerfusion

SISCOM

Figure
4. SPECT
images
of a 21-year-old
man with nonlesional
intractable
partial
epilepsy who had late postictal injection of radiotracer
(88 seconds).
Conventional
sideby-side inspection
of the postictal
and interictal
SPECT images (A and 13) and evaluation of the hyperperfusion
SPECT images with subsequent
coregistration
to MR imaging (SISCOM)
(C) were determined
by reviewers
to be nonlocalizing.
The hypoperfusion
SISCOM
(D), however,
was localizing
to the right frontal lobe, consistent
with the scalp
and intracranial
electroencephalogram
(EEG)
localizations.
The patient was seizurefree at 40 months
after right frontal lobectomy.
(From OBrien
TJ, So EL, Mullan BP,
et al: Subtraction
SPECT co-registered
to MR.1 improves
postictal
SPECT localization
of
seizure foci. Neurology
52:523-528,
1999; with permission.)

CORTICAL

that focal hypoperfusion

and hyperperfusion
may have localizing
value may in part reduce
the potential impact of the phenomenon
of
postictal switch.
Reports of the localizing value of SPECT
in the presurgical evaluation of patients with
medically
refractory
epilepsy
specifically
caused by CD are limited. Some observations
have been made that may influence interpretation, including
the following: (1) perfusion
patterns associated with CD may differ from
other types of lesions and from other types
of MCD42~4g~71~74~75*103
and (2) there may also be
different perfusion patterns as seen on SPECT
associated with CD?,@ and this may be age
relatedF8
Single photon emission CT imaging provides a noninvasive method of identifying potential problems that may have an adverse effect on surgical outcome. The data obtained
from SPECT may influence whether or not
a patient is considered a surgical candidate
and may have a pivotal role in identifying
lesions and guiding placement of intracranial
electrodes when MR imaging
does not revkal a lesion. Ictal SPECT may also help to
delineate the epileptogenic
zone when EEG
and MR imaging findings do not overlap. In
addition, it may identify patients with more
extensive or multiple areas of dysplastic tissue
that might be microscopic and not appreciated
by MR imaging and in whom the surgical outcome may not be as good.

POSITRON

EMISSION

TOMOGRAPHY

Methodology
Positron emission tomography is a functional imaging technique that provides a method
of obtaining in vivo information
on various
biochemical
and physiologic
processes. PET
can be used to measure cerebral blood flow
and volume; to measure regional cerebral
metabolism
for glucose, 02, and protein; and
to assess neuroreceptor-neurotransmitter
systerns, tissue pH, and concentrations of radiolabeled drugs in the brain.26 PET uses a tracer of
physiologic interest that has been labeled with

DYSPLASIA

AND EPIL.EISY

77

a radionuclide
such as 150, F, or C. These
radionuclides
decay by emitting
a positron
from the nucleus and require a cyclotron for
production.
PET measurements
are based on
detection of the photon pair that results from
the annihilation
of the emitted positron when
it interacts with an electron. The annihilation
photons are emitted at 180 to each other and
are detected by two opposing radiation detectors connected by an electronic coincidence
circuit. A decay event is only recorded by the
circuit when both detectors sense the almost
simultaneous
arrival of both photons.26 This
coincidence detection localizes the positron
annihilation
to a point lying somewhere along
the line that connects the two detectors. A
typical PET scanner may contain hundreds of
such detectors. Quantification
of the physiologic processes under study can be achieved
from mathematic
models that describe the
in vivo behavior of the specific radiotracer
used and tomographic
measurements
of regional radioactivity.
For a more detailed discussion of the technical aspects of PET, the
reader is directed elsewhere.26,20 PET is usually performed
in the interictal
state, with
EEG monitoring
performed during the radiotracer uptake period (about 3045 minutes
for [18F] FDG as it becomes phosphorylated to FDG-6-phosphate)
to ensure proper
interpretation.
The most widely used PET radiopharmaceutic agents in the presurgical evaluation of
patients with medically
refractory epilepsy
are PFI FDG for evaluation of the regional
cerebral metabolic rate of glucose and [*Cl
flumazenil
for evaluation
of central benzodiazepine receptor distribution.

Clinical Contributions
and
Applications
of Positron
Emission Tomography
Localization-Related

Epilepsies

In temporal
lobe
epilepsy,
interictal
[Fl FDG PET with quantitative
analysis lateralized temporal hypometabolism
in greater
than 80% of cases45,70,102,118
and is considered
an important
component
of the presurgical

78

TOCZEK & THEODORE

evaluation, particularly in those patients in

whom scalp EEG recordings were nonlocalizing and MR imaging was considered
unremarkable.43,70,115,118
[sF]FDG PET may
provide confirmatory data of the,region of
ictal onset; in many patients with temporal
lobe epilepsy, this may preclude the need for
invasive monitoring with intracranial electrodes45*70
as well as provide prognostic information regarding surgical outcome.3, 69*
94,io2,I5
The localizing value of PET using [8FlFDG
in extratemporal lobe epilepsies is not as
goodOi,liO,i~sbut may be improved with the
use of [C]flumazenil,
especially in patients
with nonlesional MR imaging.97*101
The usual abnormality seen in localizationrelated epilepsies is an area of hypometabolism that is typically larger than the pathologic
abnormality.31,41,54This extension of the hypometabolic region is most likely a result of
diaschisis,31p41
which probably also accounts
for the presence of remote areas of hypometabolism sometimes seen in patients with
partial epilepsie@; however, the possibihty of
focal areas of CD must also be considered.
In patients with CD and seizures, the
[FIFDG PET abnormalities may consist of
either focal area(s) of hypometabolism or areas
of metabolic activity similar to normal gray
matter 6,34s62*74
often referred to as displaced
gray matter metabolic activity when the
abnormality is located or protrudes into the
white matter. Areas of hypermetabolism seem
to occur in the presence of persistent focal
interictal epileptiform activity during the uptake period and may reflect increased energy
demand in the active epileptogenic focus.16,24
This finding, which seems to be analogous to
the areas of hyperperfusion seen on interictal
SPECT42*68*71*74
might be a manifestation of the
%trinsic epileptogenicity
of CD described
by Palmini et al.87*88Another possible explanation may include increased neuronal
density.
The typical abnormality seen in [Clflumazenil PET is a reduction of central benzodiazepine receptor (cBZR) binding in the epileptogenic region that is more circumscribed
than the region of hypometobolism.31* lo5*lo
In two epileptic patients with pathologically

confirmed CD who became seizure-free after

partial frontal lobe resection, [Clflumazenil
PET revealed regional reduction of cBZR
binding that closely correlated to the seizure
zone documented by intracranial electrode
recordings. BZR autoradiography performed
on both surgical specimens revealed a focal reduction of BZR binding in the center of the FCD compared with the normal
cortex at the rim of the resected specimen3 In
patients with CD, increased cBZR binding in
the abnormal region has been reported.96,g7
In an earlier series of a more heterogeneous
group of epileptic patients with CD, Richardson et alq6reported cBZR binding abnormal
ities in 10 of 12 patients, which consisted
of increased or decreased binding or both.
For example, in all four patients with FCD,
a pattern of increased cBZR binding was
seen in the abnormal cortical regions, with
extensive areas of reduced binding seen in
the surrounding normal cortex. A subsequent
study using a voxel-based comparison of
cBZR binding with the distribution of cortical
gray matter in 10 patients from the previous
study demonstrated that the abnormalities of
cBZR binding were proportionate to changes
in cortical volume in four patients. Six of
the patients still had cBZR abnormalities
disproportionate to changes in cortical volume, however. This functional abnormality
is believed to be a unique feature of MCD.
Possible explanations for this finding include
increased neuronal density or the presence
of ectopic neurons bearing cBZR, increased
density or affinity of cBZR, or a response to the
abnormal architecture and circuitry intrinsic to
MCD.32.9.99
[Clmethionine PET has also been used to
study medically intractable epileptic patients
with CD, but the experience is limited.
[Clmethionine
is considered an effective
radiopharmaceutic agent for evaluating brain
tumors,28 with increased uptake in the region
of the tumor. In four patients with medically
refractory epilepsy because of CD (three of
whom had extratemporal
lobe epilepsy),
Sasaki et al demonstrated high uptake of
]Clmethionine
corresponding partially or
totally to the lesion imaged by MR. Three

CORTICAL

patients had [8FlFDG PET, and two patients

had 99mTc-ECD SPECT abnormalities
corresponding
to the same lesion seen on MR
imaging and [Clmethionine
PET. All four
patients underwent resection of FCD after
intraoperative
ECoG that recorded frequent
or nearly continuous epileptic spikes on the
lesions similar to the observation of Palmini
et al.= Three patients were seizure-free after
resective surgery, with the remaining patient
experiencing marked improvement
in seizure
control.w
Initially,
increased uptake of [Clmethionine was considered dependent on protein
synthesis, but other metabolic processes such
as transmethylation
processes and transmembrane
amino acid transport also may
be involved.
The mechanism for increased
uptake in this series of patients is not known
for certain.
Infantile Spasms
One of the most important contributions
of
PET is the understanding
of infantile spasm
(IS) based on the work of Chugani and his
colleagues.i7, z2*z3.2.5IS is an age-specific epilepsy usually occurring between 3 and 7 months
of age; it is characterized by brief flexor,
extensor, or combined
flexor-extensor
jerks
involving the muscles of the neck, trunk, and
extremities
typically
occurring in clusters.
When associated with hypsarrhythmia
and
developmental
delay, IS is referred to as West
syndrome. Hypsarrhythmia
is defined as an
EEG pattern characterized
by continuous
high-amplitude
generalized and polymorphic
slowing with no organized background associated with multifocal spikes. IS has traditionally been subdivided
into symptomatic
and
cryptogenic subgroups with possible causes
encompassing a wide spectrum of conditions,
including MCD,52* I7 which may account for
30% to 34% of cases.52IS has traditionally
been
considered a generalized epilepsy and treated
medically
In 1990, Chugani et al published
their
initial report on a series of five infants with
IS who had been evaluated with [8FlFDG
PET and in whom PET revealed unilateral
hypometabolism
involving
the parieto-

DYSPLASIA

AND EPILEPSY

79

occipitotemporal
region (Fig. 5). MR imaging
was normal in all but one infant, in whom
a subtle abnormality
in the occipital region
characterized by poor demarcation
between
the gray and white matter was noted.
Four of the five infants in this series subsequently underwent focal cortical resection under the guidance of intraoperative
ECoG,
which was in close agreement with the anatomic distribution
of hypometabolism
on
PET. Pathologic examination
of the resected
cortical tissue in all four cases revealed microscopic CD.
Subsequent larger series of patients further
supported the role of P8FlFDG PET as an
important
tool in identifying
unifocal abnormalities in infants with intractable
IS and,
frequently, normal MR imaging.17eZ In most
cases, pathologic analysis of the resected tissue revealed CD. In addition, by identifying
regions of multifocal
abnormalities,
[FIFDG
PET provided important prognostic information and identified patients in whom surgery
most likely would not produce a favorable
outcome.25
Aside from the localizing and prognosticating value of [r8F]FDG PET in the presurgical evaluation of an epilepsy not previously
considered amenable to surgery, [FIFDG PET
also has made significant contributions
to a
better understanding
of the mechanisms involved in IS. Chugani et al= studied 44 infants
with IS using [18F]FDG PET to determine the
neuroanatomic
substrates involved in the generation of IS. PET revealed a relative hypermetabolism of the lenticular nuclei in 32 of 44 infants and of the brain stem in 21 of 44 infants
irrespective of cause, EEG pattern recorded
during PET, or association with focal cortical hypometabolism
iobserved in 22 of 44 patients) or focal cortical hypermetabolism
(observed in 5 of 44 patients) (Fig. 6). This finding
seems to be unique to IS.6*20
Based on these findings and on the clinical features of IS, Chugani et ala proposed
the theory that the pathogenesis of IS may
be related in part to a neuronal circuit involving
interactions
between cortical and
subcortical structures. They suggested that a
focal or diffuse cortical lesion at some critical

Figure
5. Preoperative
MR image and FDG-PET
studies and postoperative
CT and FDG-PET
studies in patient with intractable
infantile spasms.
MR imaging at the time of evaluation
was normal,
but
PET revealed
right parieto-occipital
hypometabolism.
The postoperative
CT scan demonstrates
the extent of the surgical
excision,
which matched
the area of abnormality
on intraoperative
electrocorticography.
Repeat
PET at 15 months
postoperatively
revealed
normal
metabolic
activity
in remaining
brain regions.
(From Chugani
HT, Shields WD, Shewmon
DA, et al: Infantile spasms:
I. PET identifies
focal cortical dysgenesis
in cryptogenic
cases for surgical
treatment.
Ann Neurol 27:406-413,
1990;
with permission.)

CORTICAL

DYSPLASIA

AND

EPILEPSY

D
Figure
6. The three FDG-PET
images (A to C), illustrate
hypermetabolism
of the left frontotemportal cortex and bilateral
symmetrical
hypermetabolism
of the lenticular
nuclei and the brain
stem in a patient with intractable
infantile spasms.
D, The neuronal
circuitry proposed
by Chugani
et al to be involved
in the pathogenesis
of infantile spasms:
(1) noxious influence
of the abnormal cortical region on the brain stem (raphe area); (2) raphe-strial
pathway,
serotonergic
(5HTto)
under tonic control by corticosteroids;
(3) generation
of a hypsarrhythmic
pattern;
(4) spinal cord
propagation
(direct or indirect)
and lenticular
nuclei involvement,
resulting
in clinical infantile
spasms;
and (5) surgical resection
of the primary
cortical abnormality
to abolish activation
of the
circuitrv.
(From Chuoani
HT, Shields WD. Shewmon
DA. et al: Infantile soasms:
II. Lenticular
nuclei and brain stem-activation
on positron
emission
tomography.
Ann Neurol 31:216,
1992; with
permission.)

81

82

TOCZEK

& THEODORE

stage of maturation abnormally interacts with

the brain stem raphe nuclei. The serotonergic
neurons in the raphe nuclei project throughout the brain, and raphe-cortical projections,
they theorize, may be responsible for the
hypsarrhythmic
pattern seen on EEG. The
raphe-strial
pathway, which is prominent
in human beings, may result in metabolic
activation
of the lenticular nuclei and brain
stem, accounting for the findings on PET.
Descending spinal pathways from either the
raphe nuclei or reticular formation may then
result in the clinical manifestations of infantile
spasms (Fig. 6). 23 This theory would explain
why resection of a focal cortical lesion, by
interrupting
this proposed circuitry, would
result in cessation of spasms and a relative
normalization
of the EEG.
Positron emission tomography
also may
identify possible surgical candidates from
patients with medically
refractory epilepsy
and tuberous sclerosis complex (TSC). TSC is
a multisystem
neurocutaneous disorder clinically characterized by medically intractable
epilepsy
(frequently
IS), varying
degrees
of mental retardation, and retinal and skin
lesions. Many of the neuropathologic
findings seen in TSC such as cortical tubers have
characteristics similar to those of CD.52*73,117
In patients with TSC and focal seizures,
a single lesion such as a cortical tuber may
be identified as the source of seizures; if this
lesion is resected, the result may be improved
or complete seizure control.4,38 This may be
true even when multiple
lesions or more
diffuse EEG abnormalities
are present.38 Interictal [isFIFDG PET may reveal regions of
hypometabolism
corresponding to areas containing cortical tubers or calcificationsioo; however, it cannot distinguish
between epileptogenic and nonepileptogenic
lesions.19*21 In
an attempt to differentiate between epileptogenie and nonepileptogenic
tubers, Chugani
et a1i9e2i used c#C]methyl-L-tryptophan
WXMTl
PET to evaluate nine patients
with TSC and intractable epilepsy. [iBF]FDG
PET revealed multiple
areas of cortical hypometabolism
in all nine patients; however,
[CIAMT
PET revealed increased uptake
in one tuber in five patients, in two tubers
in three patients, and in three tubers in one

patient. All other tubers revealed decreased

uptake. Ictal EEG data were available in
eight patients, four of whom had ictal localization corresponding
to foci of increased
uptake.21
The exact process that is being evaluated
with [CIAMT
is not altogether clear. Initially,
it was thought to be a measure of serotonin
synthesis, but this does not seem to be the
case.18,107It has been suggested that [CIAMT
PET is rather an index of serotonin synthesis
and that it may be a tracer of metabolism
by the kynurenine pathway in certain pathologic conditions. I* The recent finding that the
concentration of quinolinic acid, a tryptophan
metabolite
of the kynurenine
pathway, was
five times higher in an epileptogenic
tuber
compared
with a nonepileptogenic
tuber
seems to support this theory.

SUMMARY

There are certain features of CD that

have made seizure localization
and surgical
planning
difficult and predispose to poor
outcome:
1. The area of CD may be subtle and not
visualized on MR imaging.
2. CD may be multifocal.
3. CD usually is located in extratemporal
regions.
4. CD often is located in regions less accessible to EEG recording such as the insular
region or the base of su1ci.36,5 The
histopathologic
alterations of these lesions also may result in distortion of EEG
potentials.55
5. Intrinsic
epileptogenicity
and surgical
outcome rely heavily on complete resection of dysplastic tissue.
6. The epileptogenic zone as determined by
surface and intracranial recordings may
be more extensive than the visualized
lesion.84, 85
7. CD may coexist with other lesions such
as neoplasms, hippocampal
a trophy, and
other types of MCD.
8. CD may participate in or alter the normal
organization of cortical function.

CORTICAL

Functional imaging with SPECT and PET

is an essential component
of the presurgical evaluation and provides information
that
(1) helps to localize and better delineate the
epileptogenic
region, (2) guides placement of
intracranial
electrodes, (3) provides prognostic information
and identifies potential problems that may preclude surgical treatment or
intracranial monitoring,
and (4) identifies patients who would not otherwise be considered
surgical candidates, particularly
those with
normal MR imaging or with epilepsy syndromes previously considered not amenable
to surgery. In addition, functional imaging,
particularly PET, has further enhanced the understanding of the potential mechanisms involved in epilepsy.

11.

12.

13.
14.
15.

16.

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Epilepsia
35(suppl6):572-S89,1994
R, Pasquier
B, Minotti
L, et al: Immuno111. Spreafico
cytochemical
investigation
on dysplastic
human
tissue from epileptic
patients.
Epilepsy
Res 3234-48,
1998
112. Spreafico
R, Tassi L, Colombo
N, et al: Inhibitory
circuits
in human
dysplastic
tissue.
Epilepsia
4l(suppl6l:S168-S173,2000
113. Stefan H, Hopp
P, Platsch
G, et al: SPECT
Ictal
perfusion
in localization
related
epilepsies.
Iti
Henry
TR, Duncan JS, Berkovic
SF (eds): Functional
Imaging
in the Epilepsies.
Philadelphia,
Lippincott
Williams
& Wins,
2000, pp 41-50
114. Taylor DC, Falconer
MA, Bruton CJ, et al: Focal dysplasia of the cerebral
cortex
in epilepsy.
J Neural
Neurosurg
Psychiatry
34:369-387,1971
115. Theodore
WI-I, Sato S, Kufta
C, et al: Temporal
lobectomy
for uncontrolled
seizures:
The role of
positron
emission
tomography.
Ann Neural
32:789794,1992
116. Treves ST, Connolly
LP: Single-photon
emission
computed
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(SPECT)
in
pediatric
epilepsy.
Neurosurg
Clin
North
Am 6:47-80,
1995
117. Vinters HV, Fisher RS, Comford
ME, et al: Morphological substrates
of infantile
spasms: Studies based
on surgically
resected
cerebral
tissue. Childs
Nerv
Syst 8:8-17,1992
118. Won HJ, Chang KH, Cheon JE, et al: Comparison
of
MR imaging
with PET and ictal SPECT in 118 patients with intractable
epilepsy.
AJNR Am J Neuroradio1 20:59>599,1999
119. Wyllie
E, Comair
YG, Kotagal
P, et al: Seizure outcome after epilepsy
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in children
and adolescents. Ann Neural 44:740-748,1998
120. Xiong J, Nickerson
L, Downs
JH, et al: Basic principles and neurosurgical
applications
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Neurosurg
Clin North
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8:293-306,1997
121. Ying Z, Babb TL, Comair
YG, et al: Induced
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proteins
and differential
expression of NMDARl
splice variants
in dysplasic
neurons of human
epileptic
neocortex.
J Neuropathol
Exp Neurol57:47-62,1998
Address

National

Institute

reprint

requests to

Maria T. Toczek, MD
Clinical
Epilepsy
Section
Epilepsy
Research Branch
of Neurolodcal
Disorders
and Stroke
Nitional
Institutes
of Health
10 Center Drive, Building
10
Room 5N250, MSC 1408
Bethesda, MD 20892-1408
e-mail:

toczekm@ninds.nih.gov

CONTEMPORARY
OF CORTICAL

MANAGEMENT
DYSPLASIAS

OF MALFUNCTIONS

1042-3680/02

$15.00 + .OO

THE USE OF SUBDURAL

GRIDS IN THE MANAGEMENT
OF FOCAL MALFORMATIONS
DUE TO ABNORMAL
CORTICAL DEVELOPMENT
Imad

Focal malformations
due to abnormal cortical development
(MCDs) are the pathologic
substrates in a large number of patients with
chronic epilepsy 3,18 These lesions are particularly frequent in children, who are referred
for surgical treatment. 14re The advent of more
sophisticated
neuroimaging
techniques has
shown that a significant percentage of patients
thought to have cryptogenic
epilepsy actually were found to have subtle alterations
in cortical architecture consistent with MCD
and that, not infrequently,
their pathologic
changes may extend well beyond the visible
magnetic resonance (MR) imaging abnormalities.3, 37,38,4 In surgical series, focal MCDs tend
to carry a worse prognosis for seizure-free
outcome.g*48
A comprehensive
review of the presurgical
evaluation
of patients with drug-resistant
epilepsy was recently published by Rosenow
and Liiders.36 The objective
of epilepsy
surgery is the complete resection (or complete
disconnection) of the cortical area responsible
From the Section of Epilepsy
Surgery,
Clinic Foundation,
Cleveland,
Ohio

NEUROSURGERY

CLINICS

VOLUME37.NUMLSERl

Departments

OF NORTH

*JANUARY2002

of Neurology

M. Najm,

MD, William
E. Bingaman,
MD,
and Hans 0. Liiders, MD, PhD

for the generation of seizures (epileptogenic

zone).21*36 Because some epileptogenic
areas
overlap with functional (eloquent)
cortex,
preservation
of essential brain functions is
also a main aim of any surgical resection.
Various noninvasive and invasive diagnostic
tools are available for the assessment of patients with epilepsy These tools currently include analysis of seizure semiologic findings,
video-scalp
electroencephalographic
(videoEEG) recordings, invasive subdural electrocorticographic
(ECoG) recordings
(intraoperative or extraoperative),
depth electrode
recordings (stereoencephalography
[SEEG]),
magnetoencephalography,
MR imaging, and
other neuroirnaging
(functional
and metabolic) techniques. The use of these methods
(or some of them) is usually complementary and can define various cortical zones,
including
the symptomatogenic
zone, irritative zone, ictal onset zone, eloquent cortex,
functional
deficit zone, and epileptogenic
lesion.21,36
(IMN,

HOL)

and Neurosurgery,

(WEB)

The Cleveland

AMERICA

87

88

NAJh4

et al

The same general principles

that guide
the presurgical
evaluation
of patients with
epilepsy are also applicable in patients with
focal MCDs. In this review, the authors briefly
discuss the methods used to confirm the diagnosis of epilepsy in focal MCDs and those
used for the identification
of the epileptogenic
zone. The role of subdural electrodes in the
localization of the epileptogenic zone and the
mapping of the functional cortex and its relations to the anatomic (histopathologic)
lesion
and the epileptogenic zone also are discussed
in detail.
DIAGNOSIS
OF FOCAL
EPILEPSY IN THE SETTING
OF FOCAL MALFORMATIONS
DUE TO ABNORMAL
CORTICAL
DEVELOPMENT
Video-EEG
monitoring
remains the gold
standard for the diagnosis of epilepsy.36 It is
a noninvasive
monitoring
technique that can
sample interictal and ictal abnormalities
from
extensive areas of the brain, giving an excellent overview
of the approximate
location and
extent of the epileptogenic
areas. The main
disadvantage
of EEG is its low sensitivity.
It only detects epileptiform
activity that has
synchronized
large areas of cortex estimated
in some studies to be between 6 and 8 cm2.8
Moreover,
EEG recordings
are disturbed
by
the smearing effect of bone and other highresistance
structures
(e.g., meninges
and
scalp) between
the cortical generators
and
the recording electrodes.4*33,34 Some of these
problems may be overcome through the use
of magnetoencephalography.
Most epileptic patients with MCDs
(85%-100%)
show
epileptiform
discharges
on their interictal
EEG recordings. c30 The interictal
and ictal
EEG changes range from lobar to lateralized,
nonlocalizing,
and diffuse (including
a generalized spike wave pattern in some cases of
subependymal
heterotopia).30
The interictal
spikes are usually more extensive than the
structural
abnormality
as assessed by intraoperative surgical inspection or MR imaging
visual analysis.*+z6, 3o In summary,
noninvasive EEG recordings
confirm
the presence
of focal epilepsy but cannot map the exact

location and extent of in situ epileptogenicity and its relation to the visible lesion and
neocortical eloquent functions.
IDENTIFICATION
OF THE
ANATOMIC (EPILEPTOGENIC)
LESION IN PATIENTS WITH
FOCAL MALFORMATIONS
DUE ~0 ABNORMAL
CORTICAL
DEVELOPMENT
Various MR imaging techniques have been
used to study MCDs. MR imaging anatomic
and signal abnormalities
have been described
in MCDs. An abnormal
gyral organization
or increased cortical thickness
is a common
finding in some types of MCDS.,~
The underlying white matter is often thin, with increased signal on T2-weighted
images. In
other cases, the gray-white
matter architecture
may show variable changes that include short
and indistinct
white matter digitations
with
asymmetric
cortical thickening.
T2-weighted
images may reveal minor white matter signal
abnormalities.6 The combination of overt gyral
abnormalities
and signal changes makes the
diagnosis of some dysplastic
lesions obvious.
Subtle unilateral focal cortical abnormalities
that are difficult to assess on conventional
Tl-weighted
two-dimensional
images may
be the only finding, however.
In addition,
histopathologic
changes of MCD lesions can
be seen in the setting
of normal
MR
imaging. 29 Some cases of mild MCDs characterized by cortical laminar and columnar
disorganization
in the absence of balloon
cellsI may not be seen on high-resolution
MR
imaging. In a recent review of the patients operated on at the Cleveland Clinic Foundation
between 1998 and 2000, the authors found that
two-dimensional
Ml? imaging studies were
normal on visual analysis in 25% of patients
with pathologically
confirmed
MCDs (Najm
et al, unpublished
data).
More recently, MR imaging-based
threedimensional
volume .reconstructions
were
used in an attempt to uncover sulcal or gyral
abnormalities
that may have gone undetected
on visual analysis
of the two-dimensional
images. 5,35*39,40*43The use of these postprocessing techniques
is yet to be validated

USE OF SUBDURAL

GRIDS IN MANAGEMENT

through careful outcome analyses and direct

ECoG and histopathologic
correlations.
Despite the use of various MR imaging
techniques, a sizable number of patients with
MCDs do not show a good outcome even after
complete resection of the MR-imaged
visible
lesion. These results suggest that the current
imaging
techniques do not accurately map
the extent of dysplastic and epileptogenic
regions in MCDs. For these reasons, additional
techniques that directly record epileptogenicity from the cortex and map the exact extent
of the abnormalities
such as prolonged extraoperative recordings using subdural grids (or
depth electrodes) are needed in some cases of
MCDs.
SUBDURAL
ELECTRODES
(STRIPS AND GRIDS)
Subdural electrodes consist of stainless steel
or platinum electrodes that are embedded in
strips or sheets of polyurethane
or other synthetic material and are implanted
subdurally
over the suspected epileptogenic or functional
dysplastic regions. i7, i9s45+7,49 Subdural grids
are inserted through either open craniotomy
or burr-hole
openings and are registered
stereotactically
for extraoperative
mapping.
The cortical covering may extend beyond the
visualized cortical area, because grids may be
slid beyond the edges of the craniotomy
to
cover adjacent areas for the purpose of better
ECoG or functional
sampling.
In addition
to the ECoG recordings and direct electric
stimulation
studies, grids can be used to
record somatosensory evoked potentials after
stimulation
of the trigeminal
(lip), median,
or posterior tibia1 nerves for central sulcus
localization.
Advantages of chronic extraoperative
subdural recordings include the ability to record
cortical ictal events and to determine the functionality of the underlying
cortex. Additionally, the monitoring
is done in the epilepsy
monitoring
unit with a relaxed and cooperative patient without the time constraints of the
operating room environment.
Because this procedure involves the insertion of foreign bodies into the cranial vault,
the risks include wound infection, flap os-

OF FOCAL MALFORMATIONS

89

acute meningitis,
cerebral edema,
and hemorrhage. 5*16Concerns about increased
intracranial pressure limit the maximal number of electrodes that can be inserted and
the ability to record from large cortical areas.
Other limitations
may include the anatomic
location of the proposed area of sampling
(e.g., mesial orbitofrontal)
and re-do surgeries with cortical adhesions.
teomyelitis,

General Indications
for Subdural
Electrode Implantation
in the
Evaluation
of Patients with Epilepsy
When noninvasive studies remain nonconcordant or inconclusive regarding the localization and the extent of the seizure onset zone
or the eloquent cortex, invasive studies using
subdural grids may be needed.T20 Jayakar
proposed the following relative indications for
the evaluation with subdural grids: normal
structural imaging, extratemporal
location, divergent noninvasive
data, encroachment
on
eloquent cortex, tuberous sclerosis, and cortical dysplasia. Rosenow and Li.iders36 recommended the use of subdural electrodes only
in patients with focal epilepsy (single focus)
in whom there is a clear hypothesis regarding
the location of the epileptogenic zone (derived
from noninvasive studies).
In patients with focal MCDs, there are two
main indications
for the use of extraoperative subdural electrode recordings: definition
of the epileptogenic
region and mapping of
the eloquent areas.

USE OF SUBDURAL
ELECTRODES
FOR THE DEFINITION
OF THE
EPILEPTOGENIC~ZONE
IN PATIENTS
WITH FOCAL MALFORMATIONS
DUE TO ABNORMAL
CORTICAL DEVELOPMENT
The epileptogenic
zone is the area of the
cortex that is indispensable for the generation
of epileptic seizures and whose resection or
complete
disconnection
leads to seizure
control.21*36 In most cases of focal MCDs,
the data generated
by noninvasive
EEG
recordings and other electrophysiologic
and

90

NAJM

et al

neuroimaging
techniques
are sufficient
to
define the approximate location of the epileptogenic zone.
Various studies using direct ECoG recordings showed
that focal MCD lesions are
intrinsically
epileptogenic.,
21.14,2b As shown
in Figure 1, the need for invasive monitoring
to define the location and extent of epileptogenicity in focal MCDs is warranted
by the
fact that the epileptogenic area in patients with
an MCD is frequently larger than the visually
identified
MCD., ** 31.32 Moreover,
in MCD
lesions with severe fluid-attenuated
inversion
recovery
(FLAIR)
signal increase
(balloon
cell-containing
dysplastic
lesions), epileptogenicity mainly arises from the surrounding
dysplastic
cortex which is devoid of balloon
cells.35

USE OF SUBDURAL
ELECTRODES
FOR THE LOCALIZATION
OF THE
FUNCTIONAL
(ELOQUENT)
CORTICAL
REGIONS IN
FOCAL MALFORMATIONS
DUE TO ABNORMAL
CORTICAL
DEVELOPMENT
MCD lesions are frequently
localized in
the pericentral
area (in potentially
eloquent

Figure

1. The relationships
between
MR imaging
lesion (fluid-attenuated
inversion
recovery
[FLAIR]
signal
increase),
epileptogenicity,
pathology,
and function
in focal malformations
due to abnormal
cortical development
(MCDs):
A, MR imaging signal increase,
nonepileptic
(no
ictal onset zone), MCD with balloon cells, nonfunctional.
B, Minimal
(gray white matter blurring)
or no MR image
FLAIR signal increase,
epileptic
(ictal onset zone), MCD
with no balloon cells, and cortical function
preserved.
C,
Normal cortex.

cortex), making an understanding of the functional status of the involved region(s) and its
anatomic and pathologic correlates of prime
importance. The authors recently assessedthe
functional status (as identified by direct cortical electric stimulation) of focal MCD lesions and its relation to imaging and in situ
ECoG characteristics in patients who underwent focal neocortical resection for the treatment of medically intractable epilepsy.Z This
study showed that focal MCD lesions located
in anatomically functional areas (e.g., primary
motor, Broca) were found not to be functional
on direct electric stimulation when they are
characterized by a significant FLAIR signal increase on MR imaging. The same lesions also
did not show evidence of intrinsic epileptogenicity as assessed through mapping of the
ictal onset zones. Conversely, MCD lesions
with mild or no FLAIR signal increase were
functional and at times epileptogenic. These
results are in agreement with the findings of
previous reports showing the persistence of
eloquent function in MCDs that are devoid
of balloon cells.~8 Similarly, low-grade glial
tumors (e.g., dysembryoplastic neuroepithelial tumor, ganglioglioma) were functionally
silent and nonepileptogenic, whereas dysplastic tissue found in the immediate surroundings of these lesions tended to be epileptogenic and eloquent. , 27,+I Moreover, these
results show that functional cortex may be
displaced within the same hemisphere and
may have direct implications on the options
for epilepsy surgery.

PROPOSED INDICATIONS FOR

THE USE OF SUBDURAL
GRIDS IN PATIENTS WITH
FOCAL MALFORMATIONS
DUE TO ABNORMAL
CORTICAL DEVELOPMENT
Because the limited success after surgical
resection in epileptic patients with MCDs is
likely related to the lack of an accurate definition of the true margins of the epileptogenic
lesion, direct ECoG recordings using subdural
grids are needed.

USE OF SUBDURAL

GRIDS IN MANAGEMENT

The authors believe that subdural electrodes

should be used in the evaluation of epileptic
patients with suspected focal MCDs after
the diagnosis of focal epilepsy is confirmed
through the careful analysis of the seizure
semiologic
findings, noninvasive
SEEG recordings, and other anatomic and functional
neuroimaging
techniques. The goals from the
invasive evaluation should be clear (mapping
of epileptogenicity
and function),
with an
understanding
of the limitations
and risks of
the evaluation.
They hope that the continuous
improvements in functional imaging techniques (e.g.,
EEG-triggered
functional MR imaging)
and
future development
of microimaging
techniques capable of mapping
the molecular
markers of epileptogenicity
eventually obviate
the need for invasive recordings.
ACKNOWLEDGMENT
This study was supported by grant K08 NS02046 to
Dr Najm from the National Institutes of Health.

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E, Liiders
H, Morris
H, et al: Subdural
electrodes
in the evaluation
for epilepsy
surgery
in children
and adults.
Neuropediatrics
19:80-86,
1988
Address

reprint

requests

to

Imad M. Najm, MD
Section of Epilepsy
The Cleveland
Clinic Foundation
9500 Euclid Avenue,
S51
Cleveland,
OH 44195
e-mail:

najmi@ccf.org

CONTEMPORARY
OF CORTICAL

MANAGEMENT
DYSPLASIAS

OF MALFUNCTIONS

1042-3680/02

$15.00 + .OO

SURGERY FOR FOCAL

CORTICAL DYSPLASIA
Katrina

Focal cortical dysplasia as a cause of lesional epilepsy has received greater attention
with the enhanced ability to detect such lesions preoperatively.
Before magnetic resonance (MR) imaging, focal cortical dysplasia
often remained undiagnosed until after a cortical resection, based on ictal electrophysiologic localization. Although a subset of lesions
continues to elude even the most advanced
imaging techniques, better detection has undoubtedly
facilitated
operative planning
in
most of the more recent cases.
This article focuses on operative techniques
in the management
of focal cortical dysplasia.
Other articles in this issue are devoted to the
topics of preoperative evaluation, imaging, invasive recordings, and surgical outcomes. In
addition, a separate article covers operative
techniques for diffuse rather than focal malformations of cortical development.
The existing literature on surgery for focal
cortical dysplasia
reflects the varied approaches and philosophies of epilepsy centers
around the world?* 5-9.* 13*15s* 18. In many
respects, the surgical issues and debates regarding this entity are similar to the issues
that surround other causes of lesional epilepsy
such as tumors (e.g., lesionectomy vs resection

S. Firlik,

MD,

and Dennis

VOLUME

37

CLINICS
NUh4BER

OF NORTH

1 *JANUARY

2002

MD

of additional epileptogenic
tissue, the value of
electrocorticography,
the correlation between
completeness
of resection and outcome).
Other issues, however, are more specific to
the entity of cortical dysplasia (e.g., intrinsic
epileptogenicity4* 6*I6 and functionality,
9 of
these lesions). In this discussion of the surgical techniques in the management
of focal
cortical dysplasia, the experience of the senior
author and the approaches practiced at Yale
University are highlighted.

SURGICAL
Preoperative

CONCERNS
Evaluation

It is generally agreed on that postoperative

seizure control is worse for patients with
cortical dysplasia than foi- patients with other
lesions such as tumors or mesial temporal
sclerosis.,6,418,19 For this reason, it is important to obtain as much anatomic, functional,
and physiologic
information
as possible in
these patients before deciding on surgical
strategy. Reasons for surgical failure include
failure to appreciate the extent of disease,
presence of multifocal
disease, and dual

From the Department

of Neurosurgery,
University
of Pittsburgh
Medical
Center, Pittsburgh,
Department
of Neurosurgery,
Yale University
School of Medicine,
New Haven,
Connecticut

NEUROSURGERY

D. Spencer,

Pennsylvania

(KSF);

and

(DDS)

AMERICA

93

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& SPENCER

pathologic findings. Equally important,

adequate resection is often hampered by the presence of functional cortex within or near the
lesion.
At Yale University,
all patient: who are
potential candidates for epilepsy surgery undergo the following: continuous audiovisual
electroencephalographic
(EEG) monitoring,
thin-cut MR imaging with multiple sequences
(including fluid-attenuated
inversion recovery
[FLAIR] sequences), and detailed neuropsychologic
testing. Intracarotid
amobarbital
testing is performed in any patient whose
lesion may affect language or memory and
who is able to cooperate with the examination.
In addition,
positron emission tomography
(PET) is performed for correlative purposes
and can also detect the possible presence of
focal cortical dysplasia in the setting of normal
MR imaging. Interictal and ictal single-photon
emission CT scans are obtained whenever possible as an adjunct to intracranial monitoring
and as further confirmation
of the epileptic
focus. MR imaging with the use of a phase
array coil (allowing a higher signal-to-noise
ratio underneath the coil) can be helpful when
focal cortical dysplasia is suspected but not
demonstrated
on routine MR imaging
(see
case study). As functional MR imaging technology continues to improve, it promises to
add valuable functional mapping information
to the preoperative evaluation. At this point,
the authors use functional MR imaging as
an adjunctive technology for language and
sensorimotor
localization,
but they do not
yet trust it to replace stimulation
mapping
using implanted subdural electrodes or awake
intraoperative mapping.

Invasive Monitoring
and Functional Mapping
If a lesion consistent with focal cortical dysplasia is evident on imaging and located in
noncritical cortex and if the patients seizures
are concordant with that location, resection
without prior functional mapping could be
contemplated.
In most cases, however, some
degree of functional mapping is an essential

aspect of surgical planning. There is evidence

that the dysplastic cortex itself can be functional and epileptogenic. The decision regarding whether or not to resect functional cortex
depends on the severity of the epilepsy, age
of the patient, degree of preoperative deficit,
and mutually
agreed-on goals of surgery. In
a young child with severe epilepsy, a preexisting neurologic deficit, and reasonable potential for plasticity, a generous resection, including functional cortex, may make sense.
In older children and adults, the operative
decision-making
process can be more complex
and must be tailored to the individual patient.
For most instances in which functional mapping is required, the authors prefer detailed
awake extraoperative
mapping using stimulation of implanted subdural and depth electrodes. This gives them the opportunity
to test
the patient while he or she is fully awake in a
more comfortable and natural setting than the
operating room. Furthermore, the testing can
be carried out over the course of 1 or 2 days
with the opportunity
to repeat any stimulations that elicited ambiguous responses. This
is especially helpful for children or patients
who are not fully cooperative.
The placement of subdural and depth electrodes, in addition to allowing for functional
mapping, allows ictal recordings within and
around the lesion. For the purposes of planning extent of resection, the authors rely primarily on ictal data rather than on interictal EEG or electrocorticography.
Although
they routinely perform electrocorticography,
the information
is used mainly for research
purposes rather than for intraoperative
decision making. The critical questions that they
hope to answer with the implanted electrodes
are (1) can we find a discrete seizure focus;
(21 what is the function of the surrounding
cortex; and (3) what are the spatial relations
between seizure focus, critical cortex, and the
lesion as detected on imaging studies.
Several authors have claimed that complete
resection of the lesion as evident on MR imaging is the most important
factor in seizure
control., 6,5,9 Others stress that the epileptogenic region frequently exceeds the boundaries of the obvious dysplastic cortex, leading

SURGERY FOR FOCAL CORTICAL

to the conclusion that lesionectomy alone may

be insufficient.6,4*19 Again, numerous individual patient-related
factors, including
age,
severity of epilepsy, presence of preoperative deficit, and goals of surgery, demand
an individualized
approach. If necessary, the
prospect of repeat, or staged, surgery can be
explored if lesionectomy alone or resection of
the focus alone is inadequate.
Surgical

Techniques

MR imaging-based
frameless stereotaxy has
greatly enhanced our ability to target the resection of lesions that are not obvious on direct visual inspection or palpation,
as is often the case with focal cortical dysplasia.*12
Even if the lesion is not visible on MR imaging but is suspected to be present based on
other data, frameless stereotaxy can still be
helpful in the verification of anatomic landmarks such as the central sulcus. For these reasons, frameless stereotaxy has rapidly become
a standard adjunct in the resection of these
lesions.
The resection techniques used for focal cortical dysplasia are straightforward
and similar
to standard corticectomy techniques. In general, it is important
to obtain relatively undamaged en-bloc specimens for detailed neuropathologic
evaluation
so as to ensure an
accurate diagnosis. The authors prefer to resect en-bloc specimens between cortical vessels, sparing as many vessels as possible so as
to avoid a local arterial or venous infarction.
They are careful to resect all cortical tissue underlying the vessels as well, leaving behind a
suspended latticework of vessels and arachnoid in the case of a larger resection. Bipolar
coagulation and suction are usually adequate
for the resection of smaller specimens, although ultrasonic aspiration is used for larger
specimens. Resection through the depth of the
cortex and just into the white matter should be
adequate. They prefer not to leave any hemostatic agents within the resection cavity. They
are typically unnecessary, and they are unsure
of their epileptogenic potential.
The use of multiple subpial transections for
dysplastic cortex is not well described in the

DYSPLASIA

95

literature.
They used the technique in one
older child with focal cortical dysplasia involving the primary motor cortex and were
disappointed
in the poor postoperative
control of his simple partial seizures.
Postoperative

Concerns

Some authors advocate obtaining a routine

postoperative MR imaging scan in patients after resection of focal cortical dysplasia so as to
evaluate the extent of resection as one might
do after a tumor resection. The authors tend
not to obtain immediate
routine postoperative MR imaging scans but rescan the patient
in a delayed fashion as an outpatient to provide correlation with the intended resection
volume.
In the case of overlap of the seizure focus
and functional cortex or in the case of cortical
dysplasia with intrinsic function, they consider a staged resection of the focus plus multiple subpial transections. Performing
a complete lesionectomy
later, if necessary, would
be an option only if the need for additional
seizure control outweighs the consequences of
potential functional loss.
THE YALE UNIVERSITY

EXPERIENCE

To better understand the experience of the

senior author in the operative management
of focal cortical dysplasia, the Yale University epilepsy database was searched for all
cases of pathologically
proven focal cortical
dysplasia between 1985 and 2000. The year
1985 was chosen as the earliest year to ensure that MR imaging was obtained in all
cases.
A total of 19 *cases were found in the
database. This excludes heterotopias, hamartomas, tubers, gangliogliomas,
and dysembryoplastic
neuroepithelial
tumors
(these
diagnoses are included in some series of cortical malformations).
Of those 19 patients, 15
had at least 12 months of follow-up. Table 1
summarizes the patient characteristics for this
subset of 15 patients. Ten patients were male
and five were female. The age at seizure onset

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& SPENCER

Table 1. PATIENT CHARACTERISTICS

(FOCAL
CORTICAL
DYSPLASIA,
YALE UNIVERSITY,
1985-2000)
Total number
of patients
Patients with > 12 months of follow-up
Male
Female
Age at seizure onset
Range
Median
Age at surgery
Range
Median
Preoperative
duration
of epilepsy
Range
Median
Seizure types
Complex
partial
Simple partial
Secondary
generalized
Tonic
Seizure frequency
per month
Range
Median
Aura
.Yes
No
Risk factors
Perinatal
injury
Significant
head injury
Family history
Central nervous system infection

19
15
10
5
-37
5
11-57
26
6-41
15
13
4
1
2
l-750
60
8
7
2
0
0

ranged from 1 to 37 years (median of 5 years),

and the age at surgery
ranged from 11 to
57 years (median of 26 years). The duration of
epilepsy between onset and resective surgery
varied from 6 to 41 years (median of 15 years).
Of the various seizure types, complex partial
seizures were by far the most common and
were present in 13 of the 15 patients. Four
patients exhibited simple partial seizures, two
had tonic seizures, and one had secondary
generalized seizures. Roughly half of the patients (8 of 15 patients) reported an aura. Most
patients had no significant risk factors for the
development of epilepsy (aside from the focal
cortical dysplasia).
Two patients had a history of perinatal difficulties,
and one had a
history of significant head injury (although the
history was of multiple head injuries during
fights after the seizures began at the age of
5 years).
Seizure frequency ranged from 1 seizure per
month to roughly 750 per month (in a pa-

tient with multiple simple partial seizures per

day), for a median of 60 seizures per month.
Despite impressive
seizure frequencies,
most
patients were quite functional.
Results of IQ
testing revealed the following
median scores:
performance
IQ of 93, verbal IQ of 89, and
full-scale IQ of 92. All patients underwent
detailed neuropsychologic
testing, the further results of which are difficult to organize for a relatively small group of patients with lesions in
disparate cortical regions.
Table 2 summarizes
the preoperative
evaluations in this group of patients. All patients
underwent
MR imaging. In most cases (13 of
15 cases), the lesion was appreciated
on MR
imaging.
In eight patients,
single-photon
emission CT was performed,
and the area
of hypoperfusion
was concordant
with the
location of the focal cortical dysplasia in four
of these patients. Similarly, hypometabolism
as revealed by PET was concordant
in four
of seven cases for which it was performed.
Although
all patients
underwent
continuous audiovisual
EEG monitoring,
seizures

Table 2. EPILEPSY
EVALUATION
(n = 15) (FOCAL
CORTICAL
DYSPLASIA,
YALE UNIVERSITY,
1985-2000)
Median
IQ
Verbal IQ
Performance
IQ
Full-scale
IQ
Magnetic
resonance
imaging
concordant
Yes
No
Single-photon
emission
computed
tomography
concordant
Yes
No
Not done
Positron emission
tomography
concordant
Yes
No
Not done
Ictal electroencephalographic
concordant
Yes
No
Seizure not captured
Intracarotid
amobarbital
procedure
Performed
Not Performed
Intracranial
electrode
study
Performed
Not Performed

89
93
92
13
2

4
4
7

4
3
8
9
4
2
11
4
7
8

SURGERY FOR FOCAL CORTICAL

were not captured in two patients. Of the

13 patients with successful ictal recordings,
the findings were concordant (in terms of correct hemisphere or better) in nine cases.Eleven
patients underwent intracarotid amobarbital
testing, and seven patients underwent placement of intracranial electrodes for further
localization.
Table 3 summarizes the operative management and outcomes. Most (14 of 15) patients
underwent cortical resection, whereas one
patient (with focal cortical dysplasia involving
the primary motor cortex) primarily underwent multiple subpial transections, with a
biopsy to confirm the diagnosis. In six cases,
the resection was considered to be a lesionectomy, whereas in eight cases, the resection
was more extensive (partial lobectomy). Two
patients underwent
awake intraoperative
mapping. The locations of resection were
distributed among all four lobes as follows:
four frontal, two temporal, four parietal, and
five occipital. In 6 of 15 cases,the resection was
within the dominant hemisphere. Three pa-

Table 3.OPERATlVE
MANAGEMENT
AND OUTCOME
(n = 15) (FOCAL
CORTICAL
DYSPLASIA,
YALE
UNIVERSITY,
1985-2000)

Location
Frontal
Temporal
Parietal
Occipital
Operation
Lesionectomy
Partial lobectomy/larger resection
Multiple subpial resections plus biopsy
Awake intraoperative mapping
Number of resective operations
1
2
New deficits/complications
Transient fourth nerve palsy,
Transient hemiparesis
Transient dysphasia
Meningitis
Follow-up duration (months)
Range
Median
Seizure outcome
Engel class I
Engel class II
Engel class III
Engel class IV

4
2
4
5
6
8
1
2
12
3
1
1
1
1
12-143
47
11
0
4
0

DYSPLASIA

97

tients required repeat resections for persistent

seizures.
Clinical follow-up ranged from 12 to 143
months (median of 47 months). Seizure outcome was graded according to the Engel
classification.3 Of the 15 patients, 11 were
seizure-free (Engel class I) and 4 had improved
but persistent seizures (Engel class III). Of
the patients with a class III outcome, two had
undergone more than one resection and one
had undergone multiple subpial transections
rather than resection. There were three transient, new, postoperative neurologic deficits
that resolved (fourth nerve palsy, hemiparesis,
dysphasia) and one infectious complication
(meningitis). The meningitis occurred in a
patient who underwent an intracranial study
and two separate resections.
Case Study
I?. K. is a 2.5-year-old boy who was diagnosed
with infantile suasmsat the ape of 1 month and
successfully treated with adre&orticotropin hormone. He did well until the age of 7 months,
when he had a generalized seizure. After this, he
developed simple partial seizures involving the
right arm and leg. His seizures frequently began with him grabbing his right hand with his
left hand and saying stop. These seizures lasted
from 5 to 10 minutes and occurred an average of
three to four times per week, although they sometimes occurred more frequently (up to three times
per day) and had recently been increasing in frequency. The patient remained interactive throughout his seizures and had had only two generalized
seizures.
The patient experienced cognitive and motor delays in addition to his epilepsy. At the age of
2.5 years, he was not yet able to walk but was able
to crawl and pull himself up to stand. His comprehension was good for his age, but he was able to
produce only 10 to 15words.
His past medical, history was unremarkable.
There was no history of head injury, central nervous system infection, perinatal injury,. or febrile
seizures and no family history of seizures.His two
older siblings were healthy. Multiple anticonvulsants, including carbamazepine, clonazepam, topiramate, tiagabine, valproate, and zonisamide, had
been tried. At the time of presentation, he was
on phenobarbital, lamotrigine, and oxcarbazepine
with intermittent lorazepam.
On neurologic examination, the patient was alert,
attentive,
and interactive. He clearly used his left
I

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& SPENCER

hand more than his right hand, using the right,only

as a helper and only if encouraged by his parents.
He was able to walk only if supported under both
arms. His reflexes were brisker on the right side.
The patient had undergone
prior MR imaging
scans that were read as normal. His PET scan
demonstrated
an area of hypometabblism
in the region of the left motor cortex. Ictal EEG recordings
localized
his seizures to the left central region.
Because of the PET and EEG findings as well as the
focality and consistent nature of his seizures, he underwent MR imaging with a phase array coil focused on the left frontal lobe (Fig. 1). This clearly
demonstrated
an area of cortical thickening
with
blurring
of the gray-white
junction that extended
posteriorly to the motor cortex, consistent with focal cortical dysplasia.
In anticipation
of resective surgery, the patient
underwent
an intracranial
electrode study with
frameless stereotactic guidance. The following electrodes were placed: a grid over the abnormal area
detected on Ml7 imaging, one depth electrode into
the motor cortex, two interhemispheric
strips, one
frontal strip, and one parieto-occipital
strip. Several
stereotypical
seizures were recorded arising from
the anterior interhemispheric
strip overlying dys-

plastic cortex corresponding

to the foot motor region and supplementary
motor area. His awake extraoperative
motor mapping
using stimulation
of
the subdural
electrodes demonstrated
a disorganized arrangement
of motor function with some
displacement
and duplication
of motor function
within the postcentral gyrus.
The patient returned
to the operating
room
4 days after the first operation
for removal of
the electrodes and resection of the epileptic focus
(Figs. 2-5). It was believed that resection of functional motor cortex was acceptable, given the patients young age and baseline contralateral
motor deficits. The fact that significant motor function
was present in the postcentral gyrus was thought
to represent either extension of functional dysplastic cortex into that region as well or a shift of function from dysplastic motor cortex into otherwise
normal sensory cortex. The area of cortical resection measured 5 cm in length, 2 cm in width, and
2.5 cm in depth. The large draining veins within the
area of resection were preserved by using the ultrasonic aspirator between and underneath
the vessels. Pathologic
examination
revealed disordered
neocortex with occasional balloon cells consistent
with focal cortical dysplasia (Fig. 6).2
Within the first few postoperative
weeks, the parents noted increased use of the patients right hand
and improved speech production.
At 8 months after surgery, his seizure frequency and severity were
significantly improved. He still had occasional partial seizures, but they occurred only on falling
asleep, involved
the hand only, and were much
shorter (lasting only 30-40 seconds).

SUMMARY

Figure 1. MR imaging of a patient with the phased-array

coil technique,
highlighting
the thickened
cortex of the left
superior frontal gyrus with blurring of the grey-white
junction. This abnormality
was not apparent
on conventional
MR images, demonstrating
the value of the phased-array
coil technique
in preoperative
planning.

Although the operative management of

focal cortical dysplasia has improved with
the ability to detect the presence and extent
of disease on imaging, surgical outcomes are
still less than satisfactory in many cases. The
causes of inadequate postoperative seizure
control are multifactorial,
including failure to detect the full extent of disease and
the presence of multifocal disease or dual
pathologic findings. Furthermore, adequate
resection is often hindered by the presence
of functional cortex within or near the lesion.
Future advances are unlikely to involve resective techniques but instead are likely to rely on
stimulation techniques or local drug-delivery
techniques that are better suited to treatment
of epileptic foci within functional cortex.

SURGERY

FOR

FOCAL

CORTICAL

Figure
2. Patient in preparation
for surgery
is supine with a roll under the left shoulder
and his head turned to the right. His head was
shaved
before the first operation.
The stitches
have been removed
from the U-shaped
scalp flap and the head has been prepped.
The
13 electrode
leads, which were tunneled
away from the incision, have
been tied together
with umbilical
tape to be pulled from underneath
the drapes during the operation
and after being cut from within the
scalp flap.

Figure
3. The patients
head is turned
to the right; the midline is down. The
scalp flap and dura have been opened,
revealing
the 8 x 8 contact grid overlying the abnormal
cortex.
The bone flap had been left out and kept frozen
after the first operation
to prevent excessive
intracranial
pressure
with the addition of the electrodes.
It was replaced
after the resection.
The 12 contact depth
electrode
in the motor cortex can be seen exiting the brain (arrow).

13YSILASIA

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& SPENCER

Figure
4. Results of the extraoperative
awake motor mapping
(performed
the
previous
day by stimulation
of the subdural
electrodes)
are designated
with
numbers
on the cortex. The numbers
denote motor functions
that were present
in the precentral
and postcentral
gyri, indicative
of abnormal
motor representation The two interhemispheric
electrode
strips and the depth electrode
are still
present. The string outlines the planned resection
site (arrow).

Figure 5. A bare brain photograph

always is taken before resection.
The depth
electrode
has been removed
and the two interhemispheric
electrode
strips
remain.
The mesial posterior
frontal cortex underlying
the anterior
interhemispheric strip was the site of the seizure focus.

SURGERY

Figure
6. Pathology
revealed
with focal cortical dysplasia.

disordered

neocortex

ACKNOWLEDGMENTS
We thank Richard
Bronen,
MD, for his expertise
with
the intraoperative
digital images taken for the case study.
We also thank Judith
Hess for her assistance
with the
database.

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WE, Cataltepe
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occasional

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balloon

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cells

(arrow),

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17. Pahnini
A, Gambardella
A, Andermann
F, et al:
Operative
strategies
for patients
with cortical
dysplastic
lesions
and it&actable
epilepsy.
Epilepsia
35(suppl):s57-s71,l994
18. Raymond
AA, Fish DR, Sisodiya
SM, et al: Abnormalities
of gyration,
heterotopias,
tuberous
sclerosis,
focal cortical
dysplasia,
microdysgenesis,
dysembryoplastic neuroepithelial
tumor, and dysgenesis
of the
archicortex
in epilepsy. Brain 118:629-660,1995
19. Sisodiya
SM: Surgery
for malformations
of cortical
development
causing
epilepsy.
Brain 123:1075-1091,
2000
20. Taylor DC, Falconer
MA, Bruton CJ, et al: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol
Neurosurg Psychiatry
34:369-387,197l
21. Wyllie E, Baumagartner
C, Prayson
R, et al: The clinical spectrum
of focal cortical
dysplasia
and epilepsy.
J Epilepsy
7:303-312,1994
Address

reprint

requests to

Dennis D. Spencer, MD
Department
of Neurosurgery
Yale University
School of Medicine
333 Cedar Street
PO Box 208082
New Haven, CT 06520-8082
e-mail:

dennis.spencer@yale.edu

CONTEMPORARY
OF CORTICAL

MANAGEMENT
DYSPLASLAS

OF MALFUNCTIONS

1042-3680/02

$15.00 + .OO

SURGERY FOR HEMISPHERIC

MALFORMATIONS
OF
CORTICAL
DEVELOPMENT
Eldad

The term malformation of cortical development

encompasses a spectrum of structural brain
abnormalities
arising during fetal development. Many reports exist of various congenital
lesions that have been categorized
under
this heading, including focal cortical dysplasia, lissencephaly,
polymicrogyria,
schizencephaly, periventricular
nodular heterotopia,
and hemimegalencephaly.
The causes, pathophysiologic findings, and treatment of these
lesions vary considerably,
and each should
be considered individually.
For the purposes
of this article, hemispheric malformations
of
cortical development,
including
hemimegalencephaly, are discussed.
Cortical dysplasia refers to disorders involving the development
and maturation
of
the cerebral cortex. These lesions may be focal
(Taylor type) or diffuse, involving
a region
or hemisphere of the brain. Neuropathologic
characteristics are well described and variably include disturbed cortical lamination,
atypical large neurons with prominent
dendritic arborization,
and ballooned astrocytes
with pleomorphic
nuclei and cytoplasmic

J. Hadar,

CLINICS

OF NORTH

VOLUME37*NUMBER1~JANUARY20O2

and William

E. Bingaman,

MD

eosinophilia.35 Despite a growing knowledge

of the histopathologic
and imaging
characteristics, an adequate classification
scheme
for malformations
of cortical development
remains elusive. When considering
hemispheric malformations,
it is adequate to use
an imaging-based
scheme. The malformation
may include severe histopathologic
changes
and gross anatomic distortion with enlargement of the ipsilateral hemisphere characteristic of hemimegalencephaly
(HM) as illustrated
in Figure 1. I7 More commonly, however, hemispheric malformations
include less severe
histopathologic
changes and subtle distortion
of the cortical architecture. This is described
as hemispheric
dysplasia (HD) and is represented in Figure 2.
The clinical features of hemispheric
malformations and the decision-making
process
preceding surgical intervention
also are presented in this article. Decisions regarding the
appropriate surgical technique and timing of
surgery remain unknown and controversial.
It is the authors opinion that each hemispheric malformation
should be considered

From the Section of Epilepsy

Surgery,
Division
of Neurosurgery,
Hill, North
Carolina
(EJH); and Section of Epilepsy
Surgery,
Foundation,
Cleveland,
Ohio WEB)

NEUROSURGERY

MD,

University
Department

of North
Carolina
of Neurosurgery,

at Chapel
Hill,
The Cleveland

Chapel
Clinic

AMERICA

103

104

HADAR

& BINGAMAN

Figure 1. Axial MR images

gray-white

matter

differentiation

demonstrating
associated

the characteristic
hemispheric
with hemimegalencephaly.

enlargement

and

blurred

individually with emphasis on obtaining resection or disconnection of dysplastic tissue

and a seizure-free outcome.

CLINICAL FEATURES

Figure 2. Axial Ml3 image demonstrating

enlarged
gyri
and an indistinct
gray-white
junction
in the right hemisphere.
These finding
imply a diffuse hemispheric
malformation
of cortical
development.
Note the absence
of
mass effect on the contralateral
hemisphere
(compared
with Figure 1).

Epilepsy is the most common presentation

of malformations of cortical development.
Hemispheric malformations typically present
early in childhood with severe epilepsy, developmental delay, and focal motor symptoms 2.IO.12 The electrographic and clinical
manifestations are rarely specific. Partial seizures can occur, but patients more typically exhibit infantile spasms and generalized
seizures., 31 Motor impairment can be difficult to assess in the infant, varying from
mild hemiparesis to severe flaccid hemiplegia. Cognitive manifestations are common,
ranging from normal intelligence to severe
mental retardation.* Similarly, hemianopsia
is present when visual pathways are involved
with dysplastic cortex. Language disturbance is variable depending on the hemisphere involved and the age of the patient.

SURGERY FOR HEMISPHERIC

MALFORMATIONS

Language development
may range from generalized delay to more severe autistic-like
behavior when the dominant
hemisphere is
involved.

PRESURGICAL

EVALUATION

Electrographic

Data

Scalp electroencephalographic
(EEG) findings in patients with hemispheric
malformations are highly variable and tend to poorly
localize ictal onset, often demonstrating
multifocal interictal spiking. 19,27*29,3o Discharges are
often evident at sites distant from those anticipated by clinical semiologic findings or imaging, including the contralateral hemisphere.
These patients may have bilateral or unilateral
EEG abnormalities.
The changes in the seemingly unaffected hemisphere
may indicate
secondary generalization
from the affected
hemisphere
or may represent independent
discharges. It is important to document these
patterns so as to prognosticate outcome after
surgical intervention. 4 It is especially important to recognize independent
contralateral
foci when they exist. These may indicate the
presence of occult areas of malformation
or
regions of secondary epileptogenesis
as a
result of seizures initially
generated from
the malformed
hemisphere.4
Such patterns
are not absolute contraindications
to surgical treatment but certainly may portend a
worse prognosis. It has been demonstrated
in such patients undergoing functional hemispherectomy that some clinical seizures may
be expected to continue even after successful
disconnection.33 Many authors, however, have
come to the conclusion that scalp EEG data do
not correlate strongly with outcome.9, XV23*27,38

Anatomic

Imaging

Magnetic resonance (MR) imaging is currently the diagnostic test of choice for structural imaging
and is capable of detecting
50% to 70% of malformations.37
MR imaging
has been shown to be superior to computed tomography in demonstrating
gray-white mat-

OF CORTICAL

DEVELOPMENT

105

ter contrast in patients with cortical malformations.5 Newer MR imaging techniques

such as fluid-attenuated
inversion
recovery (FLAIR),
diffusion-weighted
scanning,
and three-dimensional
volume
reconstructions have increased sensitivity even further.
Several series of surgically treated epilepsy
patients have been used to correlate abnormal
MR imaging findings with clinical and electrographic data, demonstrating
a concordance
rate of 84%.9-21,37 False-negative
results for
3 of 10 patients were reported with normal
MR imaging scans and histologic evidence of
cortical malformations,
demonstrating
that
subtle malformations
can exist undetected
by MR imaging. When present, MR imaging
findings
include
abnormal
gyral patterns,
shallow sulci, increased cortical thickness,
poor gray-white matter differentiation,
and
increased
subcortical
signal intensity
on
T2-weighted images (see Figs. 1 and 2). Nodular heterotopia may be seen anywhere from
the subependymal
area to the cortical surface
and appears as clusters of irregular nodules of
gray matter within the white matter.
The impact of high-resolution
multiplanar
MR imaging on the treatment outcome of cortical malformations
remains unknown. There
are few published series with outcome data
generated from current imaging techniques.
With the addition of three-dimensional
MR
imaging surface reconstruction,
subtle gyral
anomalies
are increasingly
demonstrated.
These findings are frequently associated with
intractable epilepsy, yet their significance remains unclear. Investigational
techniques such
as MR spectroscopy and functional MR imaging are heralding
the biochemical
imaging
of epilepsy at a cellular level. The challenge
remains to demonstrate improved
treatment
outcome and to define normal versus abnormal cortical anatomy.
The role of MR imaging with hemispheric
malformations
is better established.
Definition of extent of a malformation
and the
surgical anatomy remains the primary purpose. Additional
information
regarding the
absence of dysplastic cortex in the normal
hemisphere and the presence of hemimegalencephaly helps to prognosticate outcome. MR
imaging also has a role in the postoperative

106

HADAR

& BINGAMAN

assessment by demonstrating
a correIatioxi between the extent of resection and seizure-free
outcome., 24,27
Positron Emission Tomograph;
and Single-Photon
Emission
ComputedTomography
Interictal
positron emission tomography
(PET) has become more commonplace
in
the preoperative evaluation of potential candidates for epilepsy surgery. Focal metabolic
changes correlating to epileptogenic
cortex
are now widely recognized in association
with temporal lobe epilepsy, Similarly, PET
has been demonstrated
to aid in identifying metabolic defects associated with cortical
dysplasia. 7r38 Hypometabolism,
hypermeta-holism, or mixed areas of hyper- and hypometabolism
can occur, making the interpretation of these studies difficult. At the
authors institutions, PET scanning for hemispheric dysplasia serves as an adjunct to
high-resolution
Ml3 imaging, helping to confirm the absence of abnormal
metabolism
in the normal hemisphere. It has also been
reported useful in infants, because the lack of
complete myelination
in the immature brain
sometimes makes the interpretation
of MR
imaging difficult.32
Single-photon
emission computerized
tomography scanning uses an injected tracer
to demonstrate regional differences in cerebral blood flow. Typically, these studies are
obtained with ictal and interictal (baseline)
injections of radioactive tracer, and the ictal
results are compared against the baseline
results. Although the findings in patients with
mesial temporal lobe epilepsy have been well
documented,
this technique has not been
used extensively to study patients with cortical malformations.
It has been proposed that it
may be more difficult to obtain an ictal injection in extratemporal epilepsy because of the
shorter length of auras and their semiologic
variability.j2
NonetheIess,
the literature
to
date indicates a potentially useful correlation
between the results of preoperative ictal and
interictal
single-photon
emission
computerized tomography and electrographic
and

histologic data in patients undergoing surgery

for cortical malformations.32 This may be more
useful for those cases in which structural
imaging is unremarkable.
Neuropsychologic

Evaluation

The range of cognitive capacity in patients

with diffuse hemispheric malformations
varies wideIy and seems to be dependent on
the degree of involvement
of the contralatera1 hemisphere.
Some patients with early
unilateral brain injury may demonstrate normal intellectual development, although severe
retardation
is typically a feature of diffuse
bihemispheric
involvement.4
Progressive intellectual deterioration
is more characteristic
of a progressive pathologic process such as
Rasmussens encephalitis, but it may also be
seen as a result of chronic severe seizures in
patients with static pathologic processes like
cortical malformations.
Early and repeated neurupsychologic testing is important in the evaluation of potential surgical candidates so as to assess the potential prognosis as well as to help determine
the timing of surgical intervention
in patients
with progressive deterioration. Parental counseling is an important part of the preoperative
interview to ensure that postoperative cognitive expectations are realistic.
SURGICAL

TECHNIQUE

As a general rule, when clinical findings and

concordant imaging and elecfrographic
data
suggest a localized onset of seizure activity, a
limited cortical resection is desirable. Unfortunately, this is rarely the case with hemispheric
malformations,
because clinical, radiographic,
and electrugraphic data point to a diffuse or
unilateral multifocal onset. Consideration
for
surgery occurs once medical intractability
is
established and bilateral hemispheric pathologic changes are excluded. The choice of
technique depends largely on the extent of
the motor deficit and the degree to which
electrographic
abnormalities
are unilateral.28
When the hemiparesis is severe or complete,
hemispherectomy
is the preferred procedure,

SURGERY FOR HEMISPHERIC

MALFORMATIONS

producing
the highest likelihood
of seizure
control.8*28*36 When the hemiparesis is mild or
absent, a more focal resective strategy (multilobar resection) may be undertaken
to spare
motor and sensory function, although the degree of seizure control is less than that seen
after hemispherectomy?
Finally, nonresective
strategies such as callosotomy may be considered for patients with bilateral electrographic
abnormalities
and drop attacks.
Hemispherectomy
Hemispherectomy
involves
the removal
or disconnection
of a cerebral hemisphere.
The operation has evolved over the years to
include anatomic removal and disconnective
procedures. The former is characterized by
resection of all cortical gray matter in a single
cerebral hemisphere, and the latter consists
of various disconnective procedures leaving
a portion of the hemisphere
vascularized
and in situ while electrically isolating it from
remaining brain structures. The pros and cons
of anatomic versus functional disconnection
include concerns about blood loss, tissue
shifts, superficial
cerebral hemosiderosis,
hydrocephalus,
and aseptic meningitis. In addition, complete disconnection can be difficult
to assess in those patients still seizing after
disconnective functional hemispherectomy.
At the Cleveland Clinic Foundation,
analysis of hemispherectomies
for cortical malformations
reveals a worse outcome in the
group of hemimegalencephaly
patients compared with hemispheric dysplasia patients. It
remains unclear whether this is secondary to
bilateral dysplastic tissue or to an incomplete
disconnection
surgical technique.
Recently,
anatomic hemispherectomy
has yielded better results in the hemimegalencephaly
patients. These patients generally have severe
malformations
obscuring
anatomic
landmarks and white matter pathways, which
makes functional hemispherectomy
difficult.
Anatomic hemispherectomy
allows for better
visualization
of deep brain structures and
basal frontal lobe dysplastic tissue (Figs. 3
and 4). At the Cleveland Clinic Foundation,
anatomic hemispherectomy
has become the

OF CORTICAL

DEVELOPMENT

107

procedure of choice for hemimegalencephaly.

The hemispheric dysplasia group was characterized by less severe architectural disruption
without hemispheric enlargement. This group
did as well with traditional
functional hemispherectomy as the nondysplastic
hemispherectomy patients, with seizure-free outcomes
approaching
80%. When the hemimegalencephaly and hemispheric dysplasia groups are
considered together, only 56% were seizurefree at a mean follow-up interval of 25 months.
This is in agreement with the literature, where
outcomes after surgery for malformations
of
cortical dysplasia are generally worse than
those for other lesional
epilepsies.6, 28,~4,38
Prognostic variables seem to include the presence of hemimegalencephaly
and the type of
surgical procedure selected. A prospective
randomized
trial of anatomic versus functional hemispherectomy
for these difficult
patients would help to answer which operation leads to the better outcome. Because of the
rarity of the disease, a multicenter trial would
be necessary.

Multilobar

Resection

The surgical strategy for highly selected patients with diffuse hemispheric malformations
and preserved motor function should be tailored to the individual
anatomy of the malformation. When the ictal onset localizes to
noneloquent cortex, a limited function-sparing
multilobar
resection can be attempted.
This
is accomplished
with the use of stereotactic
navigation,
somatosensory
evoked potential
monitoring,
and, when appropriate,
intraoperative cortical stimulation.
The future epileptogenic potential of residual dysplastic tissue
remains unknown, and the risk of recurrent
seizures must be balanced with the benefits
of preserved hand function. This type of approach involves extensive dialogue and informed consent discussions with the patient
and parents. Preservation of preoperative motor and sensory function can be expected, but
a lesser degree of seizure control may be the
result.3 In these cases, additional surgery may
be necessary to complete the disconnection.

108

HADAR

& BINGAMAN

Figure
3. Coronal
MR images demonstrating
characteristic
cephaly:
deep basal frontal lobe dysplasia,
distorted
cortical
white matter. The ipsilateral
ventricle oflen is enlarged.

Callosotomy

When electrographic data demonstrate bilateral independent

onset of seizures, resective surgery is generally not possible. Many
of these patients suffer from epileptic drop attacks, and when these become medically intractable, consideration may be given to complete or partial ca110s0t0my.**
Kuzniecky et al reported on seven patients with congenital bilateral perisylvian
syndrome undergoing
partial or complete
callosotomy. This resulted in cessation of drop
attacks in five patients and a marked reduc-

findings
associated
with hemimegalenarchitecture,
and increased
signal in the

tion in the other two. Similar success has been

reported for patients with double cortex
syndrome and drop attacks,,h but patients
with lissencephaly or generalized pachygyria
typically obtain no benefit from surgery.2s

TIMING

OF SURGERY

In functional MR imaging studies of patients who had previously undergone hemispherectomy, the remaining intact hemisphere
had reorganized to support ipsilateral
motor and sensory functions.3-5 When similar

SURGERY

FOR

HEMISPHERIC

MALFORMATIONS

OF

CORTICAL

DEVELOPMENT

109

Figure 4. Operative
treatment
of hemimegalencephaly.
A, Preoperative
axial MR image demonstrating right hemimegalencephaly.
B, Intraoperative
photograph
displaying
anatomic
removal
of posterior
frontal, parietal,
occipital,
and temporal
lobes. The frontal pole and a strip of cortex along the sagittal
sinus are left in place. (See also Color Plate I, Fig. 28) C, Postoperative
coronal
MR image demonstrating operative
cavity at level of third ventricle.

studies were performed preoperatively

on
patients with diffuse hemispheric malformations, comparable ipsilateral activation
was seen in supplementary motor and sensory areas. This implies that some degree of
functional transfer or ipsilateral functional
development occurs in the presence of a severe cortical deformity. To what degree this
process is accelerated or inhibited by removal
or disconnection of the diseased hemisphere
is unclear. Furthermore, in patients with frequent seizures who are experiencing progressive loss of neurologic function, it is unclear

whether early surgery and initial acute loss of

such function ultimately results in a more efficient and complete transfer of function to the
intact hemisphere. Many epileptologists are
reluctant to recommend surgery until functional loss is maximal; however, this subjects
the intact hemisphere to repeated exposure
to chronic seizures, the effects of which are
unclear on cognitive development.4 Although
no good clinical literature exists to definitively
influence the timing of surgery, the competing
considerations of acute functional loss and potentially chronic cognitive impairment must

110

HADAR

& BINGAMAN

be balanced against one another to arrive at

such decisions. It is important
to consider
each case individually
with the complete
participation
of the patient and family in the
decision-making
process.
SUMMARY.

This discussion highlights

the decisionmaking process involved in a challenging clinical problem. Many patients with hemispheric
malformations
are medically intractable, yet
the surgical alternatives
typically
involve
large resections or disconnections. Even with
hemispherectomy,
seizure-free outcome
is
not guaranteed and developmental
outcome
is poor. Despite this, surgery improves the
quality of life of these difficult patients, and
with proper informed consent, realistic postoperative expectations can be met.
Over the last several years, the ability to
evaluate patients with large cortical malformations has benefited significantly
from the
rapid development
of diagnostic tools, especially with regard to structural and functional
neuroimaging.
As such technologic progress
continues, this may help us to understand the
natural history of this process and to more effectively select patients who are appropriate
candidates for surgical intervention.
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Whiting S, Duchowny M: Clinical spectrum of cortical dysplasia in childhood: Diagnosis and treatment
issues. J Child Neurol14:759-771,1999
Wyllie E, Comair YG, Kotagal P, et al: Epilepsy
surgery in infants. Epilepsia 37:625-637,1996
Address reprint requests to
William E. Bingaman, MD
Department of Neuros&gery-SSO
The Cleveland Clinic Foundation
9500 Euclid Avenue
Cleveland, OH 44195
e-mail: bmgamb@ccf.org

CONTEMPORARY MANAGEMENT
OF CORTICAL DYSPLASIAS

OF MALFUNCTIONS

1042-3680/02

HEMISPHERECTOMY

$15.00 + .OO

TECHNIQUES
Johannes Schramm, MD

There has been an amazing degree of development

in the technique of hemispherectomy over the last 25 years, particularly
during the last 6 to 8 years. The development
went from larger brain excisions to smaller
and smaller excisions and more hemispheric
disconnection. This has led to the coexistence
of various surgical techniques, making the direct comparison of different series difficult and
a review of techniques useful.
The term hemispherecfomy means the removal of a brain hemisphere, usually leaving
the basal ganglia block behind. A functional
hemispherectomy
is an operative
procedure
functionally
equivalent
to the
removal of a hemisphere, but anatomically
significant parts of the hemisphere may be
left behind disconnected
from deep and
contralateral structures. The term hemispherofomy means a disconnection
of the cortical
layer around one hemisphere
and may be
associated with a small resection of parts
of the hemisphere such as the insular cortex or anterior hippocampus.
A functional
hemispherectomy
comprises the functional
hemispherectomy
technique
as developed
by Rasmussen, 33 but it also includes the later
described techniques from Bonn, Montreal,
and Paris, 35-37,49 and their variants.% They all
This work was supported by grant SFB 400, TP Bl from
the German Research Council (Deutsche Forschungsgemeinschaft).

have in common the fact that only some parts

of the brain are removed and the rest of the
cortical tissue is disconnected from the other
hemisphere and the deeper lying basal ganglia block. Because the cortical layer is disconnected from the deeper structures, it has also
been called a hemispheric deafferentation36 or
hemispherotomy.3*42
Other techniques that have been used include cerebral hemicorticectomf
and hemidecortication.
These involve the removal
of the cortex of one hemisphere;
more precisely, the term would be hemispheric decorficafion. The term hemispherofomy avoids the suggestion that the hemisphere is actually taken
out, although
parts may have been taken
out. The use of the term hemispherotomy or
hemispheric deafferentation would also have
the added advantage that nonneurosurgeons
would not be led to the wrong impression of
a large resective type of surgery In clinical
practice, however, the term functional hemispherectomy is just as frequently
used and
seems to be the prevailing terminology.
Some
details are handled quite differently in the
various types of surgeries such as removal of
the insular cortex, removal of the mesiotemporal structures, or avoidance of entry into the
ventricular system.
Concerning the purpose, it is not irnportant whether parts of the hemisphere or the
whole hemisphere
is removed or whether

From the Department of Neurosurgery, BOM University Medical School, BOM, Germany
NEUROSURGERY CLINICS OF NORTH AMERICA
VOLUM!Z37.NUMBERl*JANUARY2002

113

114

SCHRAh4M

the cortex is removed or only disconnected;

seizure results should be similar provided that
the procedure is technically well done. The
decision as to what type of surgery to choose
should primarily be based on the, experience
of the surgeon, his familiarity
with the individual steps of the procedure, and the specifics
of the individual
case. Only recently, more
publications have become available that allow
the surgeon to base the decision regarding
a specific type of functional
hemispherectomy on useful and comparable data. Here,
intraoperative
events, early complications,
late complications,
and seizure outcome are
relevant 9,14.19.22,31.36-3641.44
The main impetus to move away from the
original anatomic resection came from a number of frequently serious late complications.
Hemispherectomy
is the most likely epilepsy
surgery technique that still carries a mortality risk. 9*3,37,44The more recent changes in
surgical technique were also influenced by
the desire to shorten the operation; to minimize blood loss, exposure, and operation time;
and, finally, to make better use of the principles of modern microsurgery, This article reviews techniques, including their advantages
and disadvantages, and describes techniques
applicable to the various forms of dysplasia.

DEVELOPMENT
OF
HEMISPHERECTOMY

TECHNIQUES

After DandyI described hemispherectomy

for infiltrative glioma in 1923, McKenzie26 suggested the procedure for untreatable epilepsy
in 1938, and KrynauwU did the first resection
for infantile hemiplegia
with drug-resistant
epilepsy in 1950.
The use of the procedure increased, but
in the 1960s and 197Os, the first reports on
late complications appeared, which consisted
of superficial cerebral hemosiderosis, progressive development
of neurologic disturbances,
development
of hydrocephalus,
and mortality from repeated hemorrhages and complications of hydrocephalus.6, 8*2g*34 Several approaches were developed to overcome the
problem of the empty cavity and the tendency
to develop hemosiderosis and hydrocephalus.

Adams1*7 developed the technique of obliterating the subdural space by folding down
the dura onto the residual brain after having
plugged the foramen of Monro. Peacock et a13
implanted
a shunt system into the subdural cavity as a routine measure. Rasmussen33
developed a new resection technique termed
fu~zctional hemispherectomy. The procedure was
a large central resection plus temporal lobectomy combined with callosotomy
and disconnection of the frontal and parieto-occipital
residual brain, which was left in place. Another approach was the development
of different procedures removing only the cortex,
termed hemidecortication or hemicorticectomy,
first by Ignelzi and Bucy20 and then modified
by Winston et a147and Kanev et a1.2
More recently developed functional hemispherectomy procedures include techniques
such as the perisylvian transcortical transventricular deafferentation
procedure with temporal lobectomy,35,36 the perisylvian window
technique,42 and the dorsal transcortical subinsular central hemispherotomy
and callosotomy by Delalande and his colleagues.3*44
Shimizu and Maehara38 later described another variation
that combines elements of
Villemures
techniques and Delalandes subinsular transection.
The most recent addition to this development
is the transsylvian, transcortical, transventricular
keyhole
hemispherotomy.37
The latter development,
governed by less resection and more disconnection, was driven by the wish to further
reduce the length of the operation, extent of
exposure, necessity for blood transfusion, and
occurrence of significant intraoperative
problems such as hemodynamic
instabilities8,15,28
and postoperative
problems such as a high
infection rate and a high hydrocephalus
rate.
The recent literature,37*38 on the modern
methods is able to demonstrate that the need
for blood transfusion is really reduced. Comparing hemidecortication
with peri-insular
hemispherotomy,
Kestle et al= showed a reduction in blood loss from a mean of 1300 to
452 mL. In their series containing mainly dysplastic cases, Shimizu and Maehara3* found
a mean intraoperative
blood replacement
volume of 224 mL with a range of 60 to
650 mL, similar to the blood replacement

HEMISPHERECTOMY

requirements
in our perisylvian
deafferentation group, with a mean of 31.5 mL (range:
150-600 mL). In the authors
own recently
reported series,37 mean intraoperative
blood
replacement
went down from 835 mL for
Rasmussens
resection
to 315 mL for the
perisylvian
deafferentation
to 266 mL for the
trans-sylvian
keyhole technique. The percentage of patients with blood replacement
in
our series was 100% for Rasmussens
resection, 58% for the perisylvian
deafferentation
group, and only 15% for the trans-sylvian
keyhole group. Because many cystic lesions
are included in the perisylvian
group and the
trans-sylvian
keyhole group, the numbers are
expected to be lower compared with Shimizu

TECHNIQUES

115

and Maeharas
group, in which 79% of cases
needed blood replacement, with many of their
cases being cortical dysplasias (CD).

PREVIOUS EXPERIENCE
WITH HEMISPHERECTOMY
IN CORTICAL
DYSPLASIA
There are well-known
types of CD that
may easily affect a whole hemisphere
and are
typically associated with chronic epilepsy.3,4,6
These are good indications
provided
that
hemiparesis
and severe drug-resistant
or catastrophic epilepsy are present (Figs. 1 and 2).
The classic diagnoses
to be considered
are

Figure 1. Sturge-Weber disease in a 16-month-old boy. Axial (left) and coronal (right) MR images with contrast (upper) show the pathologic vascularization and the enlarged insular cistern and atrophy of single gyri and the whole
hemisphere. White lines indicate the short distances between circular sulcus
and ventricle. The case was done with the trans-sylvian keyhole functional hemispherectomy technique.

116

SCHRAt 4M

Figure 2. Hemimegalencephaly

in a Syear-old
boy. Coronal
(upper row) and axial
(bottom row) MR images demonstrate
that despite enlargement
of the hemisphere,
ventricles
still can be wider than normal. Orientation
nevertheless
may be difficult in
the ventricle
because of malformed
structures
(e.g., the frontal horn) and thickening
of normal structures
(e.g., subcallosal
area). Arrows point out areas in which parts
of the malformed
side cross the midline and are in close but irregular
contact to the
healthy side, making orientation
about the midline difficult.

HEMISPHERECTOMY

hemimegalencephaly
(HME),
Surge-Weber
disease (SWD), hemispheric maturation disorders, extensive hamartias or multiple hamartomas, and disorders of gyration such as
widespread
microgyria
or polymicrogyria.
Hemispherectomy
is considered separately in
general and in relation to CD.

Experience with
Hemispherectomy

in General

In the extensive collection of Holthausen

et al, a few facts that are of great interest
concerning the use of hemispherectomy
are as
follows:
1. Five hemispherectomy
techniques were
used with different frequencies. Anatomic resection was the least frequently
used (13%1, the most frequently used was
functional hemispherectomy
(31%>, and
the hemispherotomy
procedures (17%)
were used less frequently than the modification of Adams and hemidecortication procedures (19%).
2. Seizure-free rates for all causes vary from
center to center, ranging from the mid50% to the mid-80% range.
3. The percentage of seizure-free patients
was different for the five main surgical
techniques. The hemispherotomy
group
had 85.7% seizure-free patients,
the
Adams modification
group had 78.3%,
functional
and anatomic hemispherectomy group had 66.1% and 64.3%, and
the hemidecortication
group was lowest
with 60.7%.
4. The percentage of seizure-free patients
varies with different causes. Patients with
CD fared worse than the other main
groups.19
It should be noted that there are marked differences from center to center in the type of patients for whom this procedure is performed.
Patient influx is obviously different from center to center, with some centers specializing
in pediatric cases and others including more
adolescents and adult cases. Because the local
preference for various resection types can also

TECHNIQUES

117

be marked, one must be careful when looking at results of the different centers not to
come to the wrong conclusions regarding the
efficiency of a certain operation for a specific
disease.
Previous
reviews
on hemispherectomy
techniques,30, 40,41,43 results of hemispherectomy,5 history with many details, and neuropathologic findings* are available.
Hemispherectomy
in Cortical Dysplasia
The various types of CD constitute a considerable number of cases in the published
hemispherectomy
series: 26% (18 of 69) in the
Bonn series, 31% (103 of 333) in the international review series, 40% (23 of 52) in
the Baltimore series, and 57% (33 of 58) in
Peacock et als series. 3 Di Rocco and Iannelli14
published a series comprising
15 HME cases,
and Maehara et alz published
a series of
13 children with HME. Kestle et al published
a series comprising
eight CD cases in a series of 16 pediatric hemispherectomies,
and
Villemure et aI4 published a series of 20 of
53 cases of CD or HME. Some authors include
SWD in their CD series. Nobody includes perinatal infarct or porencephalic cases in the CD
series, although it has repeatedly been shown
that dysplastic features are frequently found
in the cortex close to the old cystic lesions
or infarcted areas.30,32 This may occur during the time of early hemispheric
damage,
when the maturation process has not yet been
concluded. In a large review of the results
from 11 centers, Holthausen
et ali9 described
the experience with 333 hemispherectomies,
from which 328 patients could be followed
after five perioperative
deaths (giving
a
mortality
of 1.5%). In this case collection,
dysplasia in 103 of 333 cases was the most
common indication, followed by Rasmussens
encephalitis,m vascular cause,46 hemiatrophy,44
SWD I28 and others.28 For these 103 dysplasia cases, the following
procedures
were
used: hemidecortication
(23%1, functional
hemispherectomy
(38%), hemispherotomy
(18%), anatomic hemispherectomy
(12%), and
Adams modification
(9%).

118

SCHRAMM

In summary, CD constitutes a large proportion of the hemispherectomy series. Outcome

seems to be worse for CD, and HME shows
even lower seizure-free rates than the nonHME dysplasias.

If seizure outcome was analyzed in that

according
to cause, the perlarge seriesI
centage of seizure-free
patients was lowest
in the dysplasia
cases, excluding
SWD, at
56.6%. Outcome was best in SWD, with 82%
seizure-free cases. Most interestingly,
the poor
outcome with dysplasia
was the same regardless of the surgical technique used. If the
dysplasia group was broken down into those
with and without HME, those with HME had
a poorer outcome (53% seizure-free
patients)
compared
with
other dysplasia
diagnoses
without
HME (68 [6%1 seizure-free
patients).
Only a few reports include easily recognizable
data on outcome
after hemispherectomies
for CD. Maehara et alZ published a series on
13 children 2 years old or younger. Followup was available in 11 children; 38% were
seizure-free plus four who showed over a 90%
reduction in seizures. Wyllie et a14 had a 68%
seizure-free rate in their 16 hemispherectomy
cases. In their series of 15 HME cases, Di Rocco
and IanneIli14 used anatomic hemispherectomy in 11, Rasmussens
technique in two,
and Winstons
hemicorticectomy
procedure
in two, and they achieved a class I outcome
in 66% of these cases. A breakdown
in outcome for CD cases was not performed in two
large series. 22,38 In the authors
own series,
50% of 12 CD cases (excluding
SWD) were
seizure-free and 63% of 16 CD cases (including
SWD) were seizure-free
(Table 1). The 23 CD
cases in Carson et als series9 had immediate
follow-up
available in 20 cases, and of these,
50% were seizure-free. Long-term follow-up
in
10 CD cases (including SWD) showed a 70%
seizure-free rate.
Table 1. OUTCOME

FOR

CAUSAL

OUR OWN PATIENTS

The foIlowing box shows the authors own
diagnoses, with the most common disorder
being HME. SWD was included because not
only the vasculature but the structure of the
cortical layers is dysplastic.

Our Own Cases

8 hemimegalencephaly
2 hemisphericdysplasia
3 hemisphericmaturation disorder
1 polymicrogyria
Total 14
4 Sturge-Weber disease
Total 18

Fourteen cases belonged to classic CD,

including HME, gyration and maturation
disorders, and others. The mean age in the
group was 4.2 years (range: 0.3-13 years). The
youngest patient was operated on at 4 months
of age, and a total of 8 patients were 1 year
old or younger at the time of surgery. There
were 7 female and 11 male patients. Nine
procedures were performed on the left side.
The youngest patients either had catastrophic
epilepsy or severe drug-resistant epilepsy.

GROUPS

Outcome
Group
HME*
Non-I-ME
Non-HME

SWD

All cases

CD+
+ I-ME

CD

II

III

IV

Number of
Patients

7
5
12
4
16

3
3
6
4
10

43
60
50
100
63

1
1

20
8

4
1
5

57
20
42

31

One postoperative
death excluded.
t One intentional incomplete hemispherotomy
case excluded.
CD = cortical dysplasia, Hh4E = hemimegalencephaly,
SWD = Storge-Weber
l

disease.

HEMISPHERECTOMY

The older patients had long-standing

drugresistant epilepsy The workup included the
usual neurologic, neurophysiologic,
and neuroradiologic
tests and, to the extent possible,
neuropsychologic
evaluation. If necessary and
possible, an intracarotid amobarbital
test was
performed. 36,37The indications and the presurgical workup and imaging for hemispherectomy are described elsewhere in this issue.
Three Rasmussen-type hemispherectomies,
five perisylvian
transcortical
hemispherectomies, and nine trans-sylvian-transventricular hemispherectomies
were performed,
which were associated with resection of the
operculum
in three cases because of HME.
In one case with missing transfer of motor
function, subtotal disconnection
sparing the
central motor sensory area was done. The
mean follow-up
was 25.6 months (range:
6-86 months). The outcome is shown separately for HME cases, non-HME
dysplasias,
SWD cases, and all cases combined in Table 1.
ANATOMIC

HEMISPHERECTOMY

The classic anatomic hemispherectomy

cludes the following main features:

in-

1. Large T-shaped skin incision along the

midline and down to the temporal base
2. Large craniotomy from the frontal pole to
the occipital pole and from close to the
midline down to the temporal base
3. Occlusion of the anterior and middle
cerebral artery and of the parasagittal
veins
4. Interhemispheric
callosotomy and frontobasal disconnection
of the insular cortex to5. Disconnection
gether with the temporal
stem from
the ventricle down to the mediotemporal base, including
the occipitomesial
disconnection (Fig. 3B)
6. Removal of the hemisphere en bloc or in
larger parts such as the frontal lobe and
occipital lobe
With the patient placed in a lateral position
with the head in a Mayfield frame or on a soft
silicone ring, the head is positioned horizon-

TECHNIQUES

119

tally, a fronto-occipital
skin incision is made
from the hairline down to the occiput, and
a second incision is made from the bregma
down toward the temporal base in front of
the ear. Large craniotomies
approaching
the
size of a hemicraniotomy
and reaching the
midline
have been recommended.30
It may
be much better to cut the bone about 15 mm
away from the sinus, avoiding the bridging
veins in the case of accidental opening of the
dura and avoiding severe blood loss from
the superior sagittal sinus and granulations.
The dura must be opened using several
flaps. The middle cerebral artery is clipped
and divided
shortly before its bifurcation,
leaving the perforating branches to the basal
ganglia intact. The anterior cerebral artery
is divided,
leaving the perforators
intact
(i.e., before and after the division into the
communicating
and A2 branches). The interhemispheric
fissure can be entered by
retracting the brain, having cut some bridging
veins and, later, all veins on the mesial aspect,
exposing the corpus callosum. The residual
connections of the anterior cerebral artery
are divided, and the callosotomy can be performed entering the ventricle. The frontobasal
matter can be divided from the anterior aspect
of the frontal horn. In the original description,
a transection underneath
the insular cortex
down to the mesial border of the temporal
lobe was performed from within the lateral
ventricle,
sectioning
the temporal
stem.12
Here, the vascular supply to the mesial temporal lobe needs to be disconnected from the
anterior choroidal
and posterior communicating arteries. The posterior cerebral artery
is divided in its P3 segment. Depending
on
personal preference,
the classic anatomic
hemispherectomy
can be done in two or three
different steps such as removing the temporal
lobe and the frontal lobe separately from the
rest. Today, the basal ganglia block is usually
left behind, and the insular cortex is either
removed or left behind., 24.47 Early on, the
basal ganglia block could be removed partially
in an extrathalamocaudate
fashion or on an
interthalamocaudate
line.
It is useful to leave a few bridging veins
intact until the last step of the resection. The

120

SCHRAMM

Figure 3. Scheme of disconnection lines shown in the coronal plane for anatomic hemispherectomy, hemidecortication, and trans-sylvian keyhole hemispherotomy. A, Anatomic hemispherectomy
including basal ganglia. B, Anatomic hemispherectomy and preservation of basal ganglia medial to
putamen. C, Hemidecortication including the lateral putaminal part of the basal ganglia block. D,
Hemidecortication with preservation of basal ganglia but including removal of insular cortex. E, Transsylvian keyhole approach with trans-sulcal transcortical transventricular disconnection (note similarity
to 0).

HEMISPHERJXTOMY

now empty space needs to be irrigated repeatedly. After dura closure and replacement
of the bone flap, subgaleal drainage should
be used. Various modifications
concerning
the degree of removal of parts of the basal
ganglia exist (see Fig. 3A and B). It seems
advisable to remove the cortex from the insula.
If the hemispheres are slightly atrophic, access
to all three basal vessels is relatively good, but
in HME cases, it seems useful not to go for en
bloc removal but to do it in several pieces if
one believes that classic anatomic removal is
to be done. Most authors recommend removing the hemisphere in a few large fragments,
but a few recommend that it be removed in
several smaller segments.~41
Total anatomic hemispherectomy
proved
to be associated with early and late complications, which finally led to a significant decline
in its use. The early series described problems
related to the huge exposure, with severe
intraoperative
bleeding,
hypotension,
rare
intraoperative
cardiac arrest, need for large
transfusions, and even occasional death on
the table.8,g,31 More important
was the rate
of early and late hydrocephalus,
which was
sometimes
associated with brain shift and
frequently
associated with death.b8r24,33*46
In the 196Os, a specific complication
associated with anatomic removal of the whole
hemisphere was described, I882g,34: superficial
cerebral hemosiderosis, classically developing
after 8 to 15 years and leading to increased intracranial pressure, mental deterioration,
and
neurologic problems and resuhing in an unacceptable frequency of death. Many patients
needed a shunt (overall, 52% in the Montreal
series) and suffered from shunt-related problems. Brain stem shift to the resection side was
observed.g*3g Wroe et al& observed ballistic
movements bilaterally as a late complication.
Di Rocco and IanneU4 have used a band of
lyophilized
dura to retain the basal ganglia
block in position and prevent its dislocation
as a result of head positioning. This was introduced after a report in the literature that if the
patients head was positioned on the operated
side, he or she developed neurologic disturbances thought to arise from gravity-induced
dislocation.g

TECHNIQUES

121

Modern series of anatomic hemispherectomy rarely describe dramatic intraoperative

events,8,g,3 but the infection rate is definitely
higher, possibly as a result of the large bone
flap sizes and long operation times., 7.-14*
z 31,41

ADAMS HEMISPHERECTOMY
MODIFICATION
This is an attempt to avoid the complication of hemosiderosis
and hydrocephalus.
The classic anatomic hemispherectomy
is supplemented by a muscle plug in the foramen
of Monro on the resection side and by folding down the stripped dura of the convexity
bone onto the falx and basal ganglia block and
into the temporal cavity. The subdural space
is occluded to a large extent, and outflow
of cerebrospinal
fluid (CSF) from the good
side is prevented. Because of the large extension of the craniotomy
and brain resection,
blood transfusions usually are needed.2 There
seems to be a higher rate of infection, but the
rate of hydrocephalus
seems to be reduced2f4*
compared with the classic anatomic resection.

HEMIDECORTICATION
Decortication
of one hemisphere is based
on the principle that only the ictogenic cortex
needs to be removed. The idea was introduced
in 1968 by Ignelzi and Bucy. The integrity of
the lateral ventricle is largely preserved, except at the temporal lobe, where removal of
the hippocampus
necessitates opening of the
temporal horn (see Fig. 3C and D). This technique has been used for HME and SWD in several series 9*14f21,22,45,47
Hemicorticectomy
or hernidecortication
includes the following:
1. Large craniotomy
2. Removal of all cortex without callosotomy
3. No ependymal
opening into the lateral
ventricle, except at the tip of the temporal
lobe

122

SCHRAMM

The cortex can be removed using bipolar

coagulation and suction, a spatula or dissector,
or a combination
of an ultrasound aspirator
and dissector. There are several primary weaknesses of this technique:
I
1. Although the main aim is to avoid opening the ventricular system, removal of the
hippocampus makes opening the temporal horn unavoidable.
2. A large wound surface is created, and
at the same time, the CSF resorption
through the granulations at the midline
has disappeared.
3. In cases of HME where dysplastic ictogenie tissue may be located deeper inside the white matter, orientation can be
difficult.
In HME, the increased volume of the hemisphere with the reported occasional tendency
for increased bleeding makes the amount of
dissection large and can induce the same intraoperative
problems as seen with classic
anatomic hemispherectomy.
Because a similarly large exposure is needed
as for classic anatomic removal of the hemisphere, similar intraoperative
problems have
been reportedsp22,3 as well as, unfortunately,
a relatively high rate of hydrocephalus
(20%
in one reportg3 and 33% in anotherg5). It also
seems that the risk for incomplete deafferentation is higher in HME. Blood loss is also high
(mean loss of 1300 mL).
RASMUSSENS
FUNCTIONAL

HEMISPHERECTOMY

Rasmussen introduced this variant of hemispherectomy in response to the problems with

classic anatomic removal of the whole hemisphere. The hemispheric removal is subtotal,
with two large parts of the hemisphere left in
situ but disconnected from the basal ganglia
and the contralateral hemisphere.
The main principles of this procedure are as
follows:
1. Large craniotomy (smaller than for classic anatomic hemispherectomy)
2. Temporal lobectomy

Removal of the central hemispheric area,

including the dorsal frontal lobe and anterior parts of the parietal lobe
Callosotomy
and disconnection
of the
frontal lobe
Disconnection
of the residual parietal
and occipital lobe
The rationale
behind this development
was the belief that a smaller resection cavity,
preserved parasagittal granulations and corticoarachnoidosinus
association, and bridging
veins help to avoid hemosiderosis
and hydrocephalus. The hydrocephalus
rate could
be reduced to around 7% in a series of 54
functional hemispherectomies.4
TRANS-SY LVIAN,
TRANSVENTRICULAR,
FUNCTIONAL
HEMISPHERECTOMY

This approach was developed as refined

version of the perisylvian
technique
and
briefly described in the original publication as
modification
2.36 A detailed description with
results from 20 cases has appeared out of a
total series of 38 cases.37
Key features of this approach are:
1. Small craniotomy
and trans-sylvian exposure of the insular cortex
2. Anterior mesial temporal lobe resection
(amygdalouncohippocampectomy)
3. Transcortical
access to the ventricular
system through the circular sulcus of the
insula from the tip of the temporal horn
to the tip of the frontal horn
4. Frontobasal disconnection anterior to the
anterior cerebral artery
5. Mesial disconnection following the anterior cerebral artery through the corpus
callosum to the splenium
6. Posteromedial
disconnection
in the
trigone following the outline of the falcotentorial border to the temporal mesial
resection cavity
This procedure is especially suited for cases
with enlarged ventricles, porencephalic cysts,
and marked atrophy of the insula-basal ganglia block or for cases with generally enlarged
cisterns and sulci (see Fig. 1).

HEMISPHERECTOMY

With the patient placed in a lateral position, the head is slightly

pointed downward in a horizontal
position. A small craniotomy through
a linear slightly
anteriorly
curved frontotemporal
incision is positioned
over the frontal operculum so that the sylvian
fissure is just exposed in the lowest part of the
craniotomy. The size of the craniotomy
is chosen guided by the length of the corpus callosum, the anteroposterior
diameter of the basal
ganglia-insula
block (limen insulae to pulvinar), and the degree of ventricular
enlargement. The craniotomy varies between 4 x 4 cm
up to 5 x 6 cm (Fig. 4), but using the keyhole principle may be shorter than the dis-

TECHNIQUES

123

tance from the limen insulae to pulvinar. Neuronavigation

technique may be used for ideal
placement of the craniotomy.
The Sylvian fissure is then opened, and the circular sulcus is
exposed, taking advantage of the fact that the
temporal operculum
is overlying
the inferior
limb of the central sulcus only about 0.5 to
1 cm, whereas the frontal operculum can overlie the frontal limb of the circular sulcus up to
3 cm. Access to the temporal horn is gained
through the inferior circular sulcus approach
(Fig. 5). The uncus and the lateral parts of the
amygdalum
are removed, and the hippocampus also is taken out either by suction or en
bloc. Sparing the major branches of the middle

Figure
4. Plain lateral radiographs
showing
range of craniotomies
for Vans-sylvian
approach.
A, A craniotomy
size sufficient
for resection of frontal operculum
as used in hemimegalencephaly
cases is
shown. B, A typical craniotomy
as in cases with ventricular
enlargement and atrophy
of the brain with easy access through
enlarged
insular cistern.

124

SCHRAMM

Figure 5. Parasagittal
MR imaging slice reconstructed
from a threedimensional
data set of a healthy
hemisphere.
The cut is slightly
lateral to the insular cortex (i.e., approximately
through
the circular sulcus of the insular cistern).
The white circle indicates
the position of the Ml ascending
parallel to the limen insulae. The three
segments
of the white line show the inferior limb of the circular sulcus, the bend around the posterior
limit of the basal ganglia block,
and pulvinar
and the superior
limb of the circular sulcus leading to
the tip of the frontal horn. These three parts are roughly equivalent
to the steps of transection
of the cortex between
the insular cistern
and the ventricular
system. The inferior limb usually is opened
as
part one of this transection,
giving access to the unco-amygdalohippocampectomy.

cerebral artery, the ventricular system is then

opened all around the insular cortex right
to the frontal horn, retracting the opercula
(Figs. 6 and 7) At this stage, looking into the
tip of the frontal horn, the basal frontal lobe
and the middle cerebral artery arising from the
depth can be seen. A transection line is now
created by suction and bipolar coagulation
from the frontal horn down to the basal arachnoidal layer just anterior to the middle and
anterior cerebral artery, finally reaching the
arachnoid of the interhemispheric fissure and
exposing the anterior cerebral artery (Fig. 8).
The mesial disconnection can now be continued around the corpus callosum following the
anterior cerebral artery but leaving the arachnoid intact (see Fig. 8, middle row). In this
way, a callosotomy is done from within the
ventricle back to the area of the spleniurn. It is

important not to go too deep and lose the way

in the splenium; thus, in the posterior part, it is
better to follow the anterior falcotentorial rim
crossing the calcar avis, sparing the posterior
cerebral artery, and then to cross through the
hippocampal tail to the resection area at the
choroidal fissure of the temporomesial resection cavity.
Along the disconnection line, some Surgicel
(Johnson and Johnson, Brussels, Belgium) may
be used for hemostasis. The ventricular system
is irrigated repeatedly. The middle cerebral
artery branches may be mobilized, and the insular cortex can be removed by suction or the
ultrasound aspirator. In dysplasia cases, the
cortex may be harder and not easy to remove.
The trans-sylvian-transventricular
hemispherectomy with only a minimal mesial
temporal lobe resection should not be used for

HEMISPHERECTOMY

TECHNIQUES

Figure
6. Modified
functional
hemispherectomy
techniques.
A, Trans-sylvian
trans-sulcal
keyhole approach
to ventricle. 37 6, Second
part in trans-sylvian
keyhole
approach:
temporomesial resection,
mesial
disconnection,
and insular
cortex
removal.
C, Peri-insular
window
technique.43
13, Variant of peri-insular
window
technique.
3s f, Dorsal transcortical
subinsular
hemispherotomy.3,
44

125

126

SCHRAMM

Figure
anterior
sylvian

7. Three axial and one sagittal

transection
is closely following
functional
hemispherectomy.

HME cases,even if the ventricles are enlarged,

for two reasons: the insular cistern may be
atypically configurated, and the trans-sylvian
approach can be more difficult with the enlarged hemisphere; and a resection cavity
with room for postoperative swelling may be
advantageous.
In HME cases, the trans-sylvian-transventricular hemispherectomy should be combined with resection of the entire temporal
lobe or with resection of the frontal operculum
to the level of the insular cortex. This resection
facilitates the transcortical access from the circular sulcus to the lateral ventricle and creates
room for postoperative swelling (see section
on specific considerations in HME).

MR imaging
the anterior

slices demonstrate
cerebral
artery

how the
in a trans-

In the authors recent seriesj7 of 20 transsylvian cases, including a large number of

porencephalic or atrophic brains, operation
times varied from 2.1 to 5 hours, with a
mean of 3.6 hours, and only 3 of 20 patients
needed intraoperative
blood replacement,
corresponding to 15% compared with 58%
in their former perisylvian series.6 Possible disadvantages of this procedure include
problems stemming from limited exposure
of anatomic landmarks such as incomplete
disconnection. Hydrocephalus, possibly induced by the large wound surface and the
transventricular approach, was not seen in the
trans-sylvian keyhole hemispherectomies for
all causes so far. No case of incomplete

HEMISPHERECTOMY

TECHNIQUES

127

Figure
8. Postoperative
MR images in hemimegalencephaly
in an 8-month-old
girl. Axial (upper row), sagittal
(middle row), and coronal
(lower row) slices are shown.
The trans-sylvian
approach
combined
with resection
of frontal operculum
and mesial temporal
lobe was used.
The cavity of the temporo-mesial
resection
and the cavity of the frontal opercular
resection
are
clearly demonstrated.
The fronto-basal
disconnection
and the disconnection
following
the outline of the pericallosal
artery can be seen. On the axial and coronal
slices, the removal
of the
insular cortex is visible.

disconnection
toward the midline
was detected,37 but too anteriorly placed disconnection lines were seen (Fig. 9). There was one
death in the series, where a 5-year-old boy was
found dead in his bed on the fifth postoperative day, with the cause remaining unknown.
There was one deep infection with revision
and a second operation for the resection of
a cyst membrane in the temporal horn, producing a reoperation rate of 10% for surgical
complications
without neurologic
sequelae.

True long-term complications

cannot be ruled
out yet. The longest follow-up for the first
transcortical procedure is only 8 years, and the
longest follow-up for the trans-sylvian technique is only 7 years.

PERI-INSULAR

HEMISPHEROTOMY

This is the second of the four functional

hemispherectomy
techniques published after

128

SCHRAh4M

the difference
between
a corFigure 9. Two sagittal MR imaging slices to demonstrate
rectly placed fronto-basal
disconnection
immediately
anterior
to the anterior
cerebral
artery
(A), and a more anteriorly
placed disconnection
(s), which leaves the dorsal
fronto-basal
cortex connected
to the basal ganglia as a possible source for postoperative
persistent
seizures.

Rasmussens technique. With the previously

described technique, it shares the transventricular mesial disconnection. Main features of
this approach are as follows:
1. Medium-sized craniotomy exposing the
frontal and temporal operculum in the
whole length of the sylvian fissure
2. Creation of two peri-insular windows
by resection of the frontal operculum
and underlying white matter, opening
the whole lateral ventricle
3. Resection of the temporal operculum
(Tl gyrus and underlying white matter),
exposing the temporal horn
4. Disconnection of the frontobasal white
matter
5. Mesial disconnection through the corpus
callosum to the splenium
6. Temporomesial disconnection with only
anterior limited resection of the lateral
amygdaloid body and most anterior
aspect of the hippocampus (completing disconnection from chorioid fissure
to mesial arachnoid of the uncus) (see
Fig. 60
This procedure is best suited for caseswith
enlarged ventricles and some degree of atro-

phy, but because of the more extensive resection of the operculum and underlying white
matter, it also can be applied for HME cases.
The craniotomy needs to be larger than that
for the keyhole trans-sylvian approach, but
compared with Rasmussens technique, it offers definite advantages in reduction of operation time and, most likely, blood loss, although figures are not available. Kestle et al
used this technique in 11 of their 16 cases.
Estimated blood loss was 462 mL compared
with 1300 mL for decortication, 73% of their
patients needed a transfusion, and there was
no necessity for a shunt. In the former series42
as well as the later series, no perioperative
complications caused by hypovolemia were
observed. In a summary of functional hemispherectomies that included a larger number
of the perisylvian window cases, five shunts
were needed in 63 patients. There were three
deaths in the series.&

CENTRAL
VERTICAL

HEMISPHEROTOMY

This is the third variation of the functional

hemispherectomy technique; it was presented

HEMISPHERECTOMY

in an abstract in 199213 and recently described

in more detail.& It includes the following
features:
1. Small parasagittal craniotomy
2. Complete
callosotomy
and opening of
roof of lateral ventricle (see Fig. 6E)
3. Anterior disconnection of the hemisphere
through frontobasal white matter
4. Disconnection
of the insular cortex and
hemispheric
white matter by dissection
from the lateral ventricle through the lateral parts of the basal ganglia block to the
mesial aspect of the temporal lobe
5. Dorsomesial
disconnection
connecting
the callosotomy
with the subinsular
temporomesial
disconnection line
The results in 53 cases, including 20 CD or
HME cases and six SWD cases, were recently
reported. There was one death in the series.
Ten patients (all HME cases) needed a shunt.
In general, results were excellent, with 80% of
patients seizure-free, but half of the 10 patients
who were not seizure-free had HME, pointing
out the significance of cause.

JAPANESE MODIFIED
PERI-INSULAR
HEMISPHERECTOMY
This technique38 is the fourth modification and is thought of as a replacement for
Rasmussens technique (see Fig. 6D). It combines elements of the peri-insular
window
technique (see Fig. 6C) with subcortical access
to the mesial temporal lobe as described by
Delalande et al (see Fig. 6E).13The following
main steps are included:
1. Medium-sized
craniotomy
over the
whole length of the lateral ventricle,
including the trigone
2. Resection of the frontal operculum and
upper half of the insular cortex
3. Transection of subinsular white matter to
the lateral ventricle and transventricular
callosotomy
4. Subcortical disconnection
of the insula
with access to the mesial temporal lobe

TECHNIQUES

129

5. Temporomesial
disconnection
by resection of the hippocampal
head and amygdalum and cutting the tail of the hippocampus dorsally
Shin-&u and Maehara38 reported on a large
series, including
many cases with CD. The
series included 14 CD cases and 12 HME
cases. Intraoperative
blood transfusion was
performed
in 79% of these cases, with a
mean volume of 225 mL. There were three
incomplete
disconnections
requiring reoperation. Five shunts were inserted, and all were
needed in pediatric patients with HME.

SPECIAL ASPECTS OF THE

PEDIATRIC
POPULATION
The physiologic
and pathophysiologic
profiles in children are well known to be
quite different; as a result, pediatric hemispherectomy
requires
special precautions
because of the differences in body fat, body
surface-to-body
volume ratio, metabolism,
and, most importantly,
blood volume. Special
care needs to be taken to prevent hypothermia,
to start blood replacement early, and to correct disturbed serum parameters quickly.8, l5
Because hemispherectomies
may be necessary even in small babies, the utmost care
and precision are necessary to manage loss
of blood components
to avoid coagulation
disorders or hypotensive
periods. It should
not be forgotten that in the few reports on neuroanesthesia for HME and pediatric epilepsy
surgery, the particularly
dangerous aspects
of hemispherectomies
have been mentioned,
including
episodes of severe hypotension,
hemodynamic
instability, metabolic acidosis,
hypothermia,
and even episodes of cardiac
ar-est 8,9.15.22.30
The modem warming methods (e.g., Bair
Hugger [Augustine
Medical,
Eden Prairie,
MN]), frequent analysis of serum parameters, surgical technique
that avoids blood
loss and long duration of surgery, and meticulous replacement
of blood components
and coagulation
factors help to avoid most
of these problems. It is obvious that a surgical technique that helps to avoid significant

130

scHRAh4M

disturbances of homeostasis is better than

even the most refined and up-to-date anesthesiologic management
of them. If seizure
outcome is equivalent, a surgical technique
that minimizes
severe negative effects on
homeostasis seems preferable.
SPECIFli= CONSIDERATIONS
IN HEMIMEGALENCEPHALY
Hemimegalencephaly
poses specific challenges for, the surgeon. The increase in brain
volume increases the amount of work, the
depth of the field, and the expected blood
loss. The voluminous and partly hamartomatous structures around the ventricle make orientation more difficult, particularly because a
clear-cut border between superficial gray substance or the deeper indentations of the cortical gray substance and the white matter is
frequently obscured by ectopic gray matter
(see Fig. 2). Some authors also report higher
blood loss from increased vascularization and
a greater tendency to bleed in surgery for
ljME.3t4.14

Voluminous and dysplastic gyri of the diseased hemisphere may bulge beyond the midline in an irregular fashion and make orientation about the midline difficult (see Fig. 2). The
sagittal sinus may be displaced to the good
side, rendering the midline craniotomy for a
hemidecortication
or anatomic removal more
dangerous. Despite the increase in volume,
the ventricle is frequently enlarged but may
be malformed
(see Fig. 2). The handling of
the vessels depends on the type of surgery intended. In anatomic resections, it would be
useful to clip the middle cerebral artery and
anterior cerebral artery early during the procedure, leaving some veins open. In the smaller
disconnection
procedures combined with a
smaller degree of resection,37,B,Q it would be
unwise to clip middle cerebral artery branches
or veins as described, because postoperative
swelling in an HME patient can lead to a dangerous situation. The large brain volume, the
tendency to an already displaced midline, and
the smaller resections used in the disconnection procedures should enhance the awareness
of some degree of postoperative swelling in

the face of less rese,rve space and should lead

to a well-planned degree of volume resection,
leaving enough space for some postoperative
swelling.
The recommended
procedure
in HME
should include adequate exposure of brain
landmarks (limen insulae, frontal opercuhun,
anterior tip of the frontal horn, trigone, and
anterior tip of the temporal horn), an adequate
degree of tissue resection, and well-visualized
total disconnection
of the remaining
hemisphere. A minimalistic
procedure such as
the trans-sylvian, transventricular,
functional
hemispherectomy
with only amygdalohippocampectomy
is not ideal for HME cases,
although the authors have performed
this
creprocedure. 37 They would recommend
ating some room either by performing
a
standard anterior temporal
lobectomy
or
by resecting the frontal operculum,
which
makes the approach to the lateral ventricle
easier. This corresponds to modification
2
from their first hemispherectomy
procedure36
and is similar to the two other techniques
that involve frontal opercular resection3 or
resection of frontal and temporal operculum
plus white matter down to the ventricle.42 If
the opercular resection is chosen, the temporal resection can be restricted to the mesial
part of the temporal lobe just like in selective amygdalohippocampectomy
(see Fig.
6B). Alternatively,
mesiotemporal
disconnection is performed with minimal
resection
(see Fig. 6C).
Hemispherectomy
for HME can be achieved
by several functional hemispherectomy
techniques. It is not of importance which of the
functional
hemispherectomy
techniques
is
used: Rasmussens, trans-sylvian with modification,37 perisylvian
window
technique,
or the variation of Shin&u
and Maehara38
or Delalande et a1.13The authors believe that
the anatomic resections (including
Adams
modification)
and the hemidecortication
procedures may be chosen but are certainly
associated with much longer operation times,
extensive exposures, higher infection rates,
more blood loss, less security concerning completeness, and, according to Holthausen et als
review, less success. The Rasmussen type of

HEMISPHERECTOMY

functional hemispherectomy
is, of course, a
good alternative, although it involves much
more work, a larger exposure, and a longer
operating time.

POSTOPERATIVE

MANAGEMENT

Patients should be brought to the intensive

care unit (KU) and extubated when fully
awake and at a normal temperature,
which
usually takes place between 2 and 8 hours
after surgery. The classic parameters
are
monitored,
including
state of wakefulness,
motor reaction, pupillary reaction, and verbal
response as well as pulse frequency, temperature, and blood pressure. Some blood
replacement
is sometimes necessary in the
early postoperative
period. Except for HME
cases, the ICU stay can be restricted to the
next morning after surgery. In small infants
less than 6 months of age, the ICU stay may
be prolonged.
The preoperative
medication
is continued in the authors service without
interruption
(usually for at least 2 years). If
adjustment
in the postoperative
anticonvulsant regimen is necessary, the pretreating
epileptologist
would be the ideal partner.
Classically, hemispherectomy
patients run a
mild to moderate temperature for 7 to 12 days,
usually without positive CSF culture, which
all authors ascribe to contamination
of the CSF
by detritus and blood. If postoperative
early
seizures occur, their semiologic
characteristics should be carefully noted to be able to
discriminate
between the older well-known
seizures and possibly a new type coming from
the good hemisphere. The significance of
early postoperative seizures in other types of
epilepsy surgery is considered to be low; in
hemispherectomy,
it seems unclear.

REOPERATIONS
POSTOPERATIVE

AND
SEIZURES

Reoperations have been described for most

functional
resection types. Reoperation
is
meant to complete an incomplete
disconnection in the Rasmussen type procedure,

TEC?lNIQUES

131

to remove residual cortex in the decortication procedures, to complete a disconnection

in the hemispherotomy
procedures,
or to
place a disconnection
line more ideally and
thus disconnect some residual cortex. The
need to consider reoperation
after a functional hemispherectomy
arises after it has
been determined
whether persistent seizures
come from the operated or good hemisphere.
Reoperations
in this context are not meant
to be those for the various complications
that may occur with any type of cerebral
surgery such as subdural effusions, infections,
membrane
resections, or shunt insertions.
Reoperations for complications
are of interest,
however, if one wants to have a general assessment of a specific type of surgery. A good way
to keep the number of reoperation cases with
persisting seizures low is to avoid stretches of
disconnected cortex. One way to do this seems
to be always to opt for removal of insular
cortex during the first surgery. The value of
this maneuver remained unproved in the review by Holthausen et aP9 as well as for some
other authors,*47 but in persisting seizures,
it eliminates the need for a second operation
just to make sure and to exclude this possible
cause. In trans-sylvian-transventricular
and
perisylvian
disconnection
procedures,36*37
the authors have occasionally
noted some
spared cortex lying frontobasally
posteriorly
(see Fig. 9). This can be avoided if the frontobasal disconnection
is done right in front of
the anterior cerebral artery. Another way to
achieve sec&e knowledge about the degree
of deafferentation
is to do early postoperative MR imaging (within 72 hours), in which
the blood-tinged
Surgicel perfectly outlines
the disconnections
right down to the arachnoid on the basal and mesial hemispheric
surface (see Figs. 6 and 8).
Persisting seizures are not infrequent in CD
(see seizure-free rates in section on previous
experience with hemispherectomy
in CD). Incomplete disconnection
has been mentioned
by many authors as the reason.*4,9*30*38*41Reoperation to complete disconnection has been
done in these cases. Another reason may be
the radiologic presence of dysplastic features
in the good hemisphereN,3
or contralate&

132

SCHRAMM

electroencephalographic
abnormalities.
In an
analysis of six publications with postmortem
findings in 10 children with unilateral megalencephaly, only 3 cases had contralateral
abnormal findings. The significance of contralateral spikes over the good hemisphere
is discussed, but even in a large review of
over 300 cases, this question could obviously
not be settled. In a series of 38 cases from
Oxford, England, five of six patients with
active bilaterally independent
spiking developed recurrent seizures within 6 months of
surgery?
Persisting seizures seem to be more dependent on cause than on surgical technique. In
one report, it was stressed that the development of disconnection
techniques (for all
causes) has not led to poorer seizure outcome figures in general.
In particular, it
was noted that patients with dysplasias did
less well compared with patients with other
causes with all surgical techniques. In cases
with dysplasia, the functional hemispherectomy techniques even had a lower success rate
than the hemispherotomy
techniques. Still, at
the present time, the question as to whether
cause or surgical technique is more important for outcome in CD has not been settled
definitely.

SUMMARY
Hemispherectomy
techniques are reviewed
with reference to various forms of CD. The
history of the development of these techniques
and previous experiences with hemispherectomies in CD are summarized.
The authors
own CD cases are briefly described. The
anatomic hemispherectomy
techniques and
the reasons for their less frequent use are
described. Several functional
hemispherectomy techniques
are reviewed, including
their advantages and disadvantages.
Three
special aspects are covered: special pediatric
considerations, specific aspects of HME, and
reoperation in postoperative seizures. It can be
summarized that CD poses a particular challenge for the surgeon. A thorough knowledge

of the available techniques is of particular interest for any neurosurgeon who wants to take
up this type of surgery. Evidence is increasing
that the outcome for CD is worse than for
other causes treated by hemispherectomy.
HME has the worst prognosis of all subgroups
and a higher shunt rate. Several hemispherectomy techniques
involving
less and less
resection of the brain and a greater degree of
disconnection are available. Because the more
recent hemispherotomy
techniques seem to
have fewer intraoperative
and postoperative
problems but comparable results, this trend to
modern hemispherotomy
techniques seems
justified.

AC!KNOWLEDGMENTS
Erika Heunemann
and GerIinde
Walther
manuscript
preparation;
Thomas
Kral, MD,
patient
data; Gerard
Rao, MD, helped with
and Jens Krahe helped with figure preparation.

helped with
helped with
referencing;

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CB:
Hemispherectomy-a
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1997
22. Kestle J, Connolly M, Cochrane D: Pediatric periinsular hemispherotomy. Pediatr Neurosurg 3244-47,
2000
23. Krynauw RA: Infantile hemiplegia treated by removing one cerebral hemisphere. J Neurol Neurosurg
Psychiatry 13:243-267,195O
24. Laine E, Pruvot P, Osson D: Resuhats eloignes de
Ih&nispherectornie
dans les cas dhemiatrophie
cerebrale infantile generatrice depilepsie.
Neurochirurgie 5507-5221964
25. Maehara T, Shimizu H, Shigetomo R, et al: Functional
hemispherectomy for children aged 2 years or less
for the treatment of intractable epilepsy caused by
cortical dysgenesis (in Japanese). No To Hattatsu 32:
395-400,2000
26. McKenzie KG: The present status of a patient who
had the right cerebral hemisphere removed. JAMA
111:168-183,1938
27. Meagher-VilIemure
K: Neuropathological
findings in paediatric functional hemispherectomies.
In Tuxhom I, Holthausen H, Boenigk H feds):
Paediatric Epilepsy Syndromes and Their Surgical Management.
London, John Libbey, 1997,
pp 713-721

TECHNIQUES

133

28. Moyes PD, Jenkins LC, Doll WA: Hemispherectomies

with particular reference to the anaesthetic management. British College of Medicine Journal 13241-243,
1971
29. Oppenheimer
DR, Griffith HB Persistent intracranial bleeding as a complication
of hemispherectomy. J Neurol Neurosurg Psychiatry 29229-240,
1966
30. Peacock WJ: Hemispherectomy for the treatment of
intractable seizures in childhood. Neurosurg CIin
North Am 6:549-563,199s
31. Peacock WJ, Wehby-Grant MC, Shields WD, et al:
Hemispherectomy for intractable seizures in children:
A report of 58 cases. ChiIds Nerv Syst 12376-384,
1996
32. Prayson RA, Bingaman W, Frater JL, et al: Histopathologic findings in 37 cases of functional hemispherectomy. Annals of Diagnostic Pathology 3:205212,1999
33. Rasmussen T Hemispherectomy for seizures revisited. Can J Neural Sci 10:71-78,1983
34. Rasmussen T Postoperative superficial hemosiderosis of the brain, its diagnosis, treatment and
prevention. Transactions of the American Neurologic Association 9813~137,1973
35. Schramm J, Behrens E, Entzian W: Hemispherical
deafferentation: A modified functional hemispherectomy technique [abstract]. Epilepsia 33fsuppl 3):71,
1992
36. Schramm J, Behrens E, Entzian W: Hemispherical
deafferentation: An alternative to functional hemispherectomy. Neurosurgery 36:509-516,1995
37. Schramm J, Kral T, Clusmann H: Transsylvian keyhole functional hemispherectomy. Neurosurgery 49:
891-901,200l
38. Shirnizu H, Maehara T Modification of peri-insular
hemispherotomy and surgical results. Neurosurgery
47:367-3722000
39. Verity CM, Strauss EH, Moyes ID, et al: Long-term
follow-up after cerebral hemispherectomy: Neurophysiologic, radiologic, and psychological findings.
Neurology 32:629-639,1982
40. Villemure JG: Hemispherectomy:
Techniques and
complications. In Wyllie E fed): The Treatment of
Epilepsy: Principles and Practice. Philadelphia, Lea &
Febiger, 1993, pp 1116-1119
41. Viiemure JG: Hemispherectomy techniques: A critical review. In Tuxhom I, Holthausen H, Boenigk H
feds): Paediatric Epilepsy Syndromes and Their Surgical Treatment. London, John Libbey, 1997, pp 729738
42. Viiemure JG, Mascott CR: Peri-insular hemispherotomy: Surgical principles and anatomy. Neurosurgery
37:975-981,199s
43. Villemure
JG, Adams CB, Hoffman HJ, et al:
Hemispherectomy. In Engel J fed): Surgical Treatment of the Epilepsies. New York, Raven Press,
1993, pp 511-518
44. ViIIemure JG, Vemet 0, Delalande
0: Hemispheric disconnection:
Callosotomy
and hemispherotomy. Adv Tech Stand Neurosurg 2625-78,
2000
45. Vining EI?, Freeman JM, Brandt J, et al: Progressive
unilateral enceohalooathv of childhood (Rasmussens
syndrome): A reapprajsal. EpiIepsia 34639-650,
1993

134

scHRAMM

46. Wilson PJ: More second

thoughts
on hemispherectomy in infantile
hemiplegia.
Dev Med Child Neurol
12:799-800,1970
47. Winston
KR, Welch K, Adler JR, et al: Cerebral
hemicorticectomy
for epilepsy.
J Neurosurg
77889-895,
I
1992
48, Wroe S, Richens A, Compston
A: Bilateral
ballistic
movements
occurring
as a late complication
of hemi-

spherectomy
and responding
to sulpiride.
J Neurol
233:3X5-316,1986
49. Wyllie
E, Comair
YG, Kotagal
P, et al: Seizure
outco-me after epilepsy
surgery-in
children
and adolescents. Ann Neurol44:740-748.1998
50. Zaiwalla
Z, Adams
CBT, .Oxbury
JM: Seizurespost
hemispherectomy
[abstract].
Seizure
3958,
1996
Address

reprint

requests

to

Johannes Schramm,
MD
Neurochirurgische
Universitltsklinik
Sigmund-Freud-Strasse
25
53105 Bonn
Germany
e-mail:

johannes.schrammQukb.uni-bonnde

CONTEMPORARY
OF CORTICAL

MANAGEMENT
DYSPLASIA!3

OF MALFUNCTIONS

1042-3680/02

$15.00 + .OO

OUTCOME AFTER
SURGICAL TREATMENT
Katherine

D. Holland,

Although hippocampal
sclerosis is the most
common cause of surgically treated epilepsy
in adults, malformation(s)
of cortical development (MCD) are increasingly recognized as
an important
cause of medically
intractable
epilepsy MCD is the cause in up to one quarter of adults and at least 50% of infants and
childreng*23.34 referred for surgery to treat intractable epilepsy. Additionally,
microscopic
evidence of MCD can be seen as a dual pathologic finding with hippocampal
sclerosis or
developmental
low-grade tumors.
MCD comprises a range of developmental abnormalities,
including focal microscopic
cortical dysplasia, abnormalities
of gyration
(macrogyria, microgyria, and agyria), schizencephaly, hemimegalencephaly,
subependymal
heterotopia, and subcortical laminar heterotopia. These malformations
may be seen with
either generalized or focal epilepsy Patients
are usually considered candidates for epilepsy
surgery if there is evidence of a localized or
regional epileptic process. The determination
that a patient is a candidate for surgery is
based on evidence from interictal and ictal
electroencephalography
(EEG), seizure semiology, magnetic resonance (MR) imaging of
the brain, and positron emission tomography (PET). Additional
information
from ictal
From

the Section

of Pediatric

NEUROSURGERY
VOLIJMJZ

37 - NUMBER

CLINICS

Epilepsy,

OF NORTH

1 l JANUARY

2002

Department

of Neurology,

MD,

PhD, and Elaine

Wyllie,

MD

single-photon
emission tomography
and MR
spectroscopy can be helpful in some cases.
Surgical approaches for MCD include focal
resection, multilobar
resection, and anatomic
or functional hemispherectomy.
Patient age
and the extent of resection are not independent. For example, most hemispherectomies
and multilobar
resections are performed
in
infants and young children. Also, the goals of
epilepsy surgery in infants and young children are often different from those in adolescents and adults. In infants with multiple daily
seizures, the goals for surgery are reduction
in seizure burden and improvement
in behavior and development.
In contrast, the goals
for surgery in adolescents and adults usually
include independence,
ability to drive, and
improved employment,
which require seizure
freedom. .
Before the 199Os, limitations
of the available imaging
modalities
meant that MCD
was often not identified before surgery. The
abnormality
was identified
by histopathologic examination
after epilepsy surgery. As a
result, the extent of the malformation
may not
have been appreciated at the time of surgery.
Early outcome series do not reflect current
experience. This discussion is restricted to
experience that includes the use of modem era
The Cleveland

Clinic

Foundation,

Cleveland,

Ohio

AMERICA

135

136

HOLLAND

& WYLLIE

MI? imaging techniques. Probably as a result

of improvements
in neuroimaging
in recent
years, the surgical outcome for MCD has
improved. Overall, seizure-free outcome after
surgery for focal epilepsy caused by MCD is
approximately
50% in most series (Table 1).
Although this frequency of postoperative freedom from seizures is lower than that seen in
hippocampal
sclerosis or tumor,*1,35 a substantial number of people with intractable focal
epilepsy from MCD are effectively treated
with surgery
The results from surgical treatment far surpass those achieved during controlled trials of
new antiepileptic
drugs for patients with intractable focal epilepsy.7*8- Patients who do
not become seizure-free during treatment with
their initial antiepileptic drug because of lack
of efficacy have less than a 15% chance of
becoming seizure-free with a second or third
drug. I7 Drug combinations are also rarely effective in refractory patients. When the initial
treatment fails because of intolerable side effects or idiosyncratic reactions, the response
to a subsequent medication is better. Response
to the third medication is again poor, however. When patients with focal MCD fail to
respond to medical therapy after several medication trials, the potential for surgical treatment should be evaluated, because surgical
management affords a better chance of seizure
control.
The greater effectiveness of surgery compared with medical management
in patients
with refractory temporal lobe epilepsy has
been demonstrated
in a controlled study.32
Candidates for resective surgery were randomized to immediate
surgery or to contin-

Table l.A COMPARISON

(EXCLUDING
OUTCOME

Article
Edwards
Paolicchi
Sugimoto
Duchowny
Wyllie et
Chugani

et aP
et al=+
et aP
et alg+
al%
et al6

OF SURGICAL
FOLLOWING

Age Range
3 months-47
years
6 months-12
years
3-34 months
6-32 months
3 months-12
years
5 months-4
years

OUTCOMES
FOR
HEMISPHERECTOMY)

uation of medical therapy After 1 year, 58%

of the surgically treated patients were seizurefree compared with 8% of the medically managed patients (P < 0.001). Although the study
included adults and most patients (70%) had
mesial temporal sclerosis, results may be relevant to patients with different causes, including MCD.
In appropriate cases, surgery also seems to
offer more advantages than vagus nerve stimulation (VNS) and the ketogenic diet. Freedom from seizures is obtained for less than 5%
of patients treated with VNS and for 3% of
patients treated with the ketogenic diet.12 Direct comparisons between VNS, the ketogenic
diet, and surgery are not available, however.
Moreover, VNS and the ketogenic diet are typically not used in patients who are good candidates for focal resection.
SURGICAL

OUTCOME

Factors Affecting Postsurgical

Outcome for Focal
or Lobar Malformation(s)
of
Cortical Development
Results from surgical series of patients with
MCD have been variable, with 11% to 70% of
patients becoming seizure-free.6* g,lo*21*~3,35 The
reason for this variability is unclear; however,
the results of studies based on patients selected for surgery after 1990 are more uniform.
Variability may be influenced by patient selection factors such as imaging, by surgical differences such as the extent or location of resection, or by differences in the histopathologic
profile of the MCD.

MALFORMATIONS

Mean Follow-Up

(years)

3.4
5.0
2.8
z-1.0
3.7
2.5

; Series from same center (Cleveland Clinic) may include some overlapping
patients.
Series from same center (Miami Childrens Hospital) may include some overlapping

OF CORTICAL

Seizure-Free
17135
22/42
2/B
4/10
16/31
7/10
patients.

(49%j
(52%)
(25%)
(40%)
(52%)
(70%)

(%)

DEVELOPMENT

Rare Seizures (%)

8/35
11/42
2/B
2/10
6/31
2/10

(23%)
(26%)
(25%)
(20%)
(19%)
(20%)

OUTCOME

Seizure Outcome and the Role of

Magnetic Resonance Imaging
MR imaging plays an important role in the
presurgical evaluation of patients with MCD
and intractable epilepsy. In a study of infants
with intractable seizures, the presence of a
discrete lesion on preoperative neuroimaging
correlated with favorable outcome.
Fifteen
(83%) of 18 infants with discrete lesions became seizure-free compared with 4 (36%) of
11 infants with normal or nonspecific abnormalities on MR imaging (16 patients) or CT
(two patients) (P < 0.01). Although this study
included
infants with pathologic
findings
other than MCD, over two thirds of the infants
had cortical dysplasia.
The extent of the MR-imaged
abnormality
also seemed to have prognostic importance
in another study in adults and children.
Of
21 patients with MCD localized by means of
MR imaging to one lobe or region, 10 (48%)
were free of seizures after surgery and seven
(33%) had rare seizures. In contrast, of four patients with hemispheric or multilobar
MCD,
only one (25%) was free of seizures after
surgery and 1(25%) had rare seizures.
Seizure Outcome and the Role of
Positron Emission Tomography Scans
Chugani and colleague& demonstrated that
infants with catastrophic epilepsy as a result of
MCD with focal dysfunction of glucose use as
determined by fluorodeoxyglucose
PET scanning could be successfully treated surgically
even in the absence of MR-imaged
abnormalities. In a series of 23 infants who underwent
focal cortical resection or hemispherectomy
for infantile spasms or seizures with a prior
history of infantile spasms, MCD was identified as the cause of spasms in 15 patients. Of
this group, only seven had their MCD identified preoperatively
on MR imaging or CT
scanning, although all 15 patients had localized abnormalities
on PET scans. Ten of these
patients had lobar or multilobar
resections of
the PET-defined
abnormal region, and five
had hemispherectomies.
Electrocorticography
(ECoG) was used to aid in determining
the extent of resection in the focal resection group.

AFTER SURGICAL

TREATMENT

137

Seven infants (70%) became seizure-free, and

another two had a significant
reduction in
seizures after lobar or multilobar
resection. In
the hemispherectomy
group, two of five patients became free of seizures, and another patient had only occasional seizures.
The use of PET was also suggested by the
Cleveland Clinic report on surgical outcome
for MCD.O Nine (75%) of 12 patients who had
interictal PET hypometabolism
in the region
or lobe that was resected became seizure-free.
In contrast, of the 10 patients whose PET findings did not correspond to the region resected, only three (30%) became seizure-free. The
numbers were small, however, and this difference did not reach statistical significance.

Seizure Outcome by Completeness

of Resection
Complete
resection of the MR imagingdefined region with MCD may correlate with
favorable surgical outcome.0,23 In one series
based on pre- and postoperative MR imaging
findings, 58% of the adolescents and adults
with complete resection of malformations
were seizure-free and 33% had rare seizures
compared with 27% of patients who were
seizure-free and 36% with rare seizures in
the group with incomplete
resections; this
difference was not statistically
significant,
however.O Although outcome was improved
when the MCD was co-mpletely resected, 3 of
11 patients had a favorable outcome even with
partial resection. All three of the patients with
bilateral MCD continued to have persistent
seizures.
Other measures quantifying
the extent of
resection have, also been shown to predict
surgical outcome. Palmini
and, colleagues**
evaluated the electrographic
patterns seen in
intractable epilepsy associated with cortical
dysplasia. Patients with ictal or continuous
epileptogenic
discharges during intraoperative ECoG had a more favorable outcome
if this activity could be completely
excised.
Nine of the 12 patients with complete resection of cortical regions exhibiting
this pattern became seizure-free or had only infrequent seizures compared with none of the

138

HOLLAND

& WYLLE

6 patients with incomplete resection of this

(P < 0.01). Cortical regions with ictal
or continuous epileptogenic
discharges often
colocalized to imaging evident? of the cortical dysplasia. Not all the patients in this study
had MR unaging scans, and the MR imaging scanners used at the time of the study
were less powerful than those currently available. As a result, the relative importance of
MR imaging and ECoG cannot be determined
from this study
Another study looking at the predictors of
outcome for epilepsy surgery in infants and
children also identified
complete resection
of the MR-imaged
extent .of the lesion and
an electrographically
abnormal
region as
the most significant
predictors of surgical
outcome.23 For the purp oses of the study, complete resections were defined as those with
total removal of any MR-imaged lesion and of
the region with a significant ictal or interictal
abnormality on extra- or intraoperative ECoG.
Freedom from seizures was seen in 76% of
49 children who had a complete resection and
in 27% of 26 children who had an incomplete
resection. For statistical analysis, the authors
defined good outcome as rare or no seizures.
This was seen in 92% of children who had
a complete resection and in 50% of children
with an incomplete
resection (P < 0.001).
Forty-two of the 75 patients (56%) in this series
had MCD.
Another study compared the surgical outcome of patients with malformations
(n = 20)
in the temporal lobe with that of patients with
isolated mesial temporal sclerosis (n = 36).16
Interestingly,
dual pathologic findings were
often present, with unilateral
or bilateral
hippocampal
atrophy seen in 16 (80%) of
the 20 patients with temporal lobe MCD.
In this study, the surgical outcome was not
significantly
different between the patients
who had a temporal lobectomy for MCD or
hippocampal
sclerosis, with a greater than
90% reduction in seizure frequency noted for
71% of patients with MCD and 91% of patients
with hippocampal
sclerosis. Complete resection of potentially epileptogenic brain regions
affected outcome, however. Patients with
bilateral hippocampal
atrophy were more
likely to have an unfavorable outcome than
pattern

those with unilateral atrophy irrespective

the presence or absence of coexistent MCD.

of

Seizure Outcome and Type of Resection

Studies in infants, children, and adults with
MCD do not show a significant difference in
surgical outcome of temporal and extratemporal resections.g*0,23,35 For example, in one series of patients with MCD,O 53% of patients
became seizure-free and 18% had only rare
seizures after extratemporal
resection compared with 33% seizure-free patients and 50%
with rare seizures after temporal resection. Although the numbers were small, outcome after multilobar resections was generally not different than when resections were confined to
one lobe. In another pediatric series, children with multilobar
resections had a lower
frequency of a seizure-free outcome (22%)
than did those with focal resections (59%)
(P = 0.05). The overall numbers were small,
however, and for this part of the analysis, the
authors did not provide separate results for
patients with cortical dysplasia and those with
other pathologic findings.
Seizure Outcome and Age at Surgery
The percentage of patients who are seizurefree after surgery does not seem to be dependent on age. Throughout
all age ranges,
approximately
50% of patients who have
surgically treatable MCD become seizure-free
and another 25% have only rare seizures
(Table 1). In one study, however, there was
a tendency toward seizure freedom with
younger age at surgery. Surgical outcome is
also not dependent on preoperative
seizure
frequency.
Seizure Outcome and Invasive
Electroencephalographic
Monitoring
The effect of the use of subdural grids on
seizure outcome is controversial.
Although
Palmini and colleagues showed that ECoG
may be important to surgical planning, other
studieslo have not demonstrated
that the use
of subdural grids improves seizure outcome.

OUTCOME

AFTER SURGICAL

139

TREATMXNT

In an MR imaging-based
series, seizure outcome was not different between patients who
underwent
subdural
grid evaluation
and
those who did not. The cases selected for
study with subdural electrodes were usually
more complicated than those that progressed
to surgery based on noninvasive tests; thus,
a selection bias was operant. Invasive monitoring
with subdural
electrodes may be
especially helpful to define seizure onset in
relation to functional areas of cortex.

with abnormal cellular elements that contain

neuronal and glial properties.
Nevertheless,
detailed reports of studies on outcome for
MCD based on histopathologic
findings of
surgical specimens have not been published
since the current neuroimaging
technology
has become widely available.

Seizure Outcome and Pathologic

Findings of Lesions

The surgical procedure of choice in cases

with extensive hemispheric malformation
and
preexisting hemiparesis
is usually anatomic
or functional
hemispherectomy.
These procedures remove or disconnect all potentially
epileptogenic
tissue in the affected hemisphere. Although
the available literature is
limited, it seems that the surgical outcome of
hemispherectomy
for MCD is similar to that
for lobar and multilobar
resections for more
limited MCD. The results of several recent
studies are summarized
in Table 2. Seizures
are completely
controlled in one half of the
patients and are significantly
reduced in another one quarter. The factors that influence
the outcome are discussed next.

In adult series, differences have been noted

based on cause with hippocampal
sclerosis
portending
a better prognosis than MCD
for postoperative
freedom
from seizures.
Some adult surgical outcome series35 have
also shown that seizure-free outcome is less
frequent for patients with MCD than for patients with tumors or vascular lesions. In one
pediatric surgical outcome study,35 seizurefree outcome was less frequent in patients
with cortical dysplasia (52%) than in patients
with tumors (82%). In contrast,
in another
pediatric study,23 pathologic
diagnosis did
not correlate with outcome. In both pediatric
studies,23*35 the number of children with hippocampal sclerosis was too small to permit
this comparison.
Within
MCD,
there may be certain
features that are associhistopathologic
ated with a poor outcome. MCD with only
dyslamination
of cellular elements and that
with a mild degree of dysplastic neurons may
have a better surgical outcome than MCD

Table 2. A COMPARISON
OF CORTICAL

OF SURGICAL
DEVELOPMENT

Article
Carreiio et al4
Sugimoto et aP+
Duchowny et al9
Viig
et aP
Chugani et al6

Age Range
2 months-12
4-54 months

years

1-36 months
3 months-18 years
5-10 months

OUTCOMES

Factors Affecting Outcome

Hemispheric
Malformations
Cortical Development

Surgical Outcome and Magnetic

Resonance Imaging Extent of the
Pa thoiogic Findings
The surgical
spherectomy
the extent of
cent study of

outcome after functional hemifor MCD may be dependent on

the cortical malformation.
A reseizure outcome after functional

OF HEMISPHERECTOMY

Hemispherectomy
We
Functional
Anatomic

Functional
Anatomic
Not stated

FOR

Seizure-Free
6/12
314
6/9
B/21
2/5

(%)

(50%)
(75%)
(67%)
(38%)
(40%)

Patients who died from complications of surgery were not included in seizure outcome data.
Three of the patients in this series had hemispherectomies after more limited pro~&~s failed,
l

for
of

MALFORMATlONS

Rare
Seizures (%)
4/12 (33%)
o/4 (0%)
l/9 (11%)
6/21(21%)
l/5 (20%)

Perioperative
Mortality*
0
0
2

,140

HOLLAND

& WYLLE

hemispherectomy
for hemispheric
MCD in
12 -patients (infants and children)
examined surgical outcome based on Ml&imaged
features.4 Three MR imaging patterns were
identified.
Six patients had hemimegalencephaly defined as a diffuse hemispheric
malformation
of cortical development
with
increased hemispheric size; four l-tad extensive
hemispheric MCD with relative preservation
of cortical architecture in part of one lobe; and
three had hemispheric MCD with atrophy. The
patients who had hemimegalencephaly
usually had abnormalities
in the white matter in
the affected hemisphere, a dysplastic appearance of basal ganglia, and a small contralateral
hemisphere. These abnormalities
were absent
or less pronounced in patients with hemispheric MCD with partial preservation of one
lobe or hemispheric MCD M;ith hemispheric
atrophy. After functional
hemispherectomy,
five of the six patients with hemimegalencephaly (83%) continued to have seizures. In
contrast, five of the six patients with partial
preservation
of one lobe or atrophy were
seizure-free after surgery
Even patients with persistent seizures benefited from surgery. 4 Preoperatively,
these
patients all had severe epilepsy and developmental delay, with many seizures every
day After functional hemispherectomy,
five
of seven patients with persistent seizures had
marked improvement
in the seizure frequency
and severity The caregivers also reported
increased alertness and social interaction
even in patients who were not completely
seizure-free.

Surgical Outcome and lnterictal and

lctal Electroencephalography
Compared with neuroimaging,
EEG features may be a weaker predictor of seizurefree outcome in patients with hemispheric
MCD. In the aforementioned
series,4 bilateral independent epileptiform
discharges and
generalized ictal EEG patterns were seen in
some patients who became free of seizures
after functional hemispherectomy.
All the patients had focal seizures arising from the malformed hemisphere, with or without addi-

tional generalized electrodecrements

during
infantile spasms, however, and none of the
patients had focal EEG seizures arising independently from the contralateral hemisphere.
Doring and colleagues8 noted that bilateral
EEG abnormalities
were common in children
with extensive unilateral MCD. In a follow-up
study, 47% of these children became seizurefree after hemispherectomy.

Functidnal Versus
Anatomic Hemispherectomy
It is unclear whether functional or anatomic
hemispherectomy
is the more effective procedure. There are no studies that directly
compare these two procedures. In the largest
series of patients treated with anatomic hemispherectomy for MCD, the surgical outcome
is similar to that for functional hemispherectomy (Table 2). The group at John Hopkins3
reviewed their experience with anatomic
hemispherectomy
in infants and children.
Of 21 patients with cortical dysplasia, eight
(38%) were seizure-free and an additional
six (29%) had mild seizures after surgery
In contrast, surgical series after functional
hemispherectomy
for MCD report 50% to
67% of patients seizure-free with an additional 11% to 33% having only rare seizures
(Table 2). Although numbers are small in all
these studies and the radiologic involvement
of MCD is not well outlined in some of these
reports, these results suggest that functional
hemispherectomy
is at least as effective as
anatomic hemispherectomy.
The frequency
of complications
may also be lower after
functional hemispherectomyF9
Nevertheless,
of five patients with hemimegalencephaly
who continued to have seizures after functional hemispherectomy,
three had seizures
that arose from the operated hemisphere and
two had seizures arising from the contralatera1 hemisphere .4 These results suggest that
anatomic hemispherectomy
may be more effective in patients with hemimegalencephaly
and that functional
hemispherectomy
may
be appropriate
for patients with more restricted hemispheric MCD. This is an area that
requires more study

OUTCOME AFTERSURGICALTREATh4ENT

NEUROLOGIC

OUTCOME

Complications
and Postoperative
Neurologic
Deficits
After Focal Resection
The most frequent complication
of temporal
lobe resection is an asymptomatic
homonymous superior quadrantanopia.5
This occurs
in up to approximately
50% of patients.32
Memory and language problems have been
reported after temporal
lobe resection in
adults, with risk factors that include higher
preoperative
functioning
or left resection.5
Few systematic data are available from preadolescent children because of the difficulties in
performing neuropsychologic
tests in this age
group, the lag in development
of appropriate
testing instruments
for use at young ages,
and the low numbers of children who have
undergone the operation. Preliminary
results
suggest that the neurocognitive
risks of temporal lobe resection may be similar in children
and adults, with IQ remaining
stable and a
possible decrease in memory function., I302s
For extratemporal
resections, chronically
implanted subdural electrodes can be used to
define the epileptogenic region and to permit
functional mapping of language, motor, and
sensory cortex. This information
is used to
limit complications
of extratemporal
resection
in the frontal lobe, central region, and posterior portion of the temporal lobe. Visual field
deficits are associated with posterior parietal
and occipital resections.
After Hemispherectomy
In the Johns Hopkins series?r 2 of 24 children who had an anatomic hemispherectomy
for cortical dysplasia died within several
hours of completing the procedure. Ventriculoperitoneal
shunting was required almost
in half of the patients in one series after
anatomic
hemispherectomy.31
Late postoperative complications
of hemispherectomy
include hemorrhage
into the hemispherectomy cavity, which is predominantly
seen
after anatomic
hemispherectomy.2s
Superficial cerebral hemosiderosis
is a long-term

141

complication
of anatomic hemispherectomy
that can occur years after the surgery and
is associated with neurologic
deterioration
and death.29 The mortality
and long-term
complications
associated with anatomic hemispherectomy have led to the development
of
the functional
hemispherectomy
procedure.
In a series of 12 patients who had a functional
hemispherectomy,
surgical
complications
included a bone flap infection in one patient
and obstructive hydrocephalus
in three patients. No deaths were reported in this small
series,* although operative mortality has been
reported after functional
hemispherectomy
in other surgical series.6*9,23 Mortality
may
be higher in infants because of their smaller
blood volumes and greater problems with perioperative bleeding and fluid management.
Patients who are candidates
for hemispherectomy
typically
have a preoperative
hemiparesis. Motor impairment
is unchanged
or improved after hemispherectomy
in most
hemiof these patients. 29 If the preoperative
paresis is mild, the deficit may be more
pronounced
after hemispherectomy.
After
hemispherectomy
in the setting of congenital
hemispheric MCD, patients develop language
commensurate
with their global cognitive
leve1.6
Hemispherectomy
candidates may have a
preexisting homonymous
hemianopia.
In patients without this deficit, however, the hemianopia that follows functional hemispherectomy typically does not result in functional
deterioration
or affect activities of daily living,
except for driving.29 In the presence of some
other preexisting visual abnormality
(e.g., amblyopia or retinopathy of prematurity),
the effect of a postoperative
homonymous
hemianopia may be more serious.

SPECIAL
Catastrophic

ISSUES

IN INFANCY

Epilepsy

Epilepsy in infancy can be associated with

severe and frequent seizures. The high seizure
burden can significantly
affect the quality
of life of the infant and family and may also

142

HOLLAND

& WYLLIE

adversely affect the infants development.

As a result, even if the infant does not become seizure-free after surgery, a reduction
in seizure frequency can have a significant
positive impact.
Effect of Surgery

on Development

There is limited information

available regarding
the postoperative
developmental
outcome in infants undergoing
surgery for
extensive MCD. Preliminary
observations
suggest that early relief from catastrophic
infantile epilepsy may allow resumption
of
developmental
progression
during
critical
stages of brain maturation. One study examined developmental
outcome in 24 children
with infantile
spasms who had resective
surgery at a mean age of 21 months; 17 of
these children had MCD. The authors found
a significant increase in developmental
assessment scores at 2 years after surgery compared
with preoperative levels, although only 4 of
the 24 children had a normal rate of development.
Another
report noted favorable
intellectual
development
and improvement
in developmental
delay in 12 of 21 patients
who had an anatomic hemispherectomy
for
MCD, with six patients having normal intelligence or only mild retardation.31 Others
have also noted improved
and catch-up
development in infants after surgery for MCD,
although many of the children continue to
exhibit some degree of delay.6 The team at
the University of California at Los Angeles
reported a cautionary case.26 A 25-month-old
patient with several seizures per week caused
by mild right hemimegalencephaly
had nearly
complete remission of seizures and good developmental progression after craniotomy and
ECoG without cortical resection. The authors
pointed out that a localized developmental
brain abnormality
in a child with intractable
seizures should not necessarily lead to cortical
resection, especially if the child is meeting
developmental
milestones.
There is more information
available about
the effects of epilepsy surgery on development
than is available for the effects of the newer
antiepileptic
drugs on infant development.

Because most antiepileptic

medications are associated with cognitive side effects in adults,is
it is possible that these medications
could
have adverse effects on intellectual
development, especially because the cognitive effects
of medication
may be more insidious in a
nonverbal patient (e.g., an infant). Prospective
studies to further clarify the developmental
effects of epilepsy surgery and anticonvulsant
medications in infancy are needed before the
relative risks and benefits of surgical or medical management can be fully assessed.

Plasticity
Surgery in infancy may lead to less severe
neurologic deficits than occurs with surgery
later in life. If left hemisphere damage and
hemiparesis occur during the first 4 or 5 years
of life (before language development),
functional hemispherectomy
produces little or no
change in language function.3* 13,i9*33 Nevertheless, the language that is transferred to
the nondominant
hemisphere is typically not
completely normal even if language shifted at
an early age.7, 2s

Infantile

Spasms

and Hypsarrhythmia

In most cases, this seizure type and its

diffuse EEG pattern are associated with diffuse brain abnormalities.
In some cases, however, they can be the result of a focal process. Chugani and colleague9 were the first
to report successful surgical treatment of patients with infantile spasms and hypsarrhythmia caused by focal MCD. PET and MR imaging were used to identify the malformation
and location of cortical dysfunction.
Other
clues to a localized process included a history
of partial seizures before the onset of spasms,
focal abnormalities
on neurologic
examination, and some focal EEG feature in addition
to diffuse hypsarrhythmia.
In a series of 15 infants and children who originally
presented
with infantile spasms caused by MCD, nine
became seizure-free after focal resection or
hemispherectomy.6

OUTCOME

AFTER SURGICAL

TREATMENT

143

Complications

References

Infants with catastrophic

focal epilepsy
caused by MCD often require extensive multilobar resection or hemispherectomy,
and
in these patients, anesthesia management
is
complicated by small blood volume. Perioperative mortality
may be higher in infancy
than later in life. One or two deaths have been
reported in most series of epilepsy surgery
in infants.6*9,23,31*41 Perioperative
mortality
may be reduced by a team of pediatric surgeons, anesthesiologists, and intensivists with
experience in epilepsy surgery in infants. In
contrast to perioperative mortality, the risk for
postoperative neurologic deficits after surgery
in infancy may be reduced as a result of developmental plasticity and greater potential for
neurologic recovery

1. Adams CBT, Beardsworth ED, Oxbury SM, et al:

Temporal lobectomy in 44 children: Outcome and
neuropsychological
follow-up. J Epilepsy 3157-168,
1990
2. Asamow RF, LoPresti C, Gutherie D, et al: Developmental outcomes in children receiving resection
surgery for medically intractable infantile spasms.
Dev Med Child Neurol39:430440,1997
3. Basser LS: Hemiplegia of early onset and the faculty
of speech with special reference to the effects of hemispherectomy. Brain 85:427-460,1962
4. Carreiio M, Wyllie E, Bingaman W, et al: Seizure
outcome after functional hemispherectomy for malformations of cortical development. Neurology 57:
331-333,200l
5. Chelune GJ, Naugle RI, Liiders HO, et al: Predication of cognitive function as preoperative ability
status among temporal lobe epilepsy patients seen at
6-month follow-ma. Neurolow 41:399404.1991
6. Chugani HT, Siewmon
l%, Shields WD, et al:
Surgery for intractable infantile spasms: Neuroimaging perspectives. Epilepsia 34:764-771,1993
7. Dennis M: Capacity and strategy for syntactic comprehension after right or left hemidecortication. Brain
Lang l&287-317,198O
8. Doring S, Cross H, Boyd S, et al: The significance
of bilateral EEG abnormalities before and after hemispherectomy in children with unilateral hemispheric
lesions. Euileusv Res 3465-73.1999
9. Duchowny M, jayakar P, Resnick T, et al: Epilepsy
surgery in the first three years of life. Epilepsia
39:737-743,1998
10. Edwards JC, Wyllie E, Rugger PM: Seizures outcome
after surgery for epilepsy due to malformation of cortical development. Neurology 55:1110-1114,200O
11. Engel J Jr: Surgery for seizures. N Engl J Med 334:
647-652,1996
12. Freeman JM, Vining El, Pillas DJ, et al: The efficacy
of the ketogenic diet: A prospective evaluation of
the intervention in 150 children. Pediatrics 1021358
1363,1998
13. Harbord MG, Manson JI: Temporal lobe epilepsy in
childhood: Reaouraisal of etiolow and outcome. Pediatr Neurol3:%..268,1987
,
14. Hirabayashi S, Binnie CO, Janot I, et al: Surgical treatment of epilepsy due to cortical dysplasia: Clinical
and EEG findings. J Neurol Neurosurg Psychiatry
56:765770,1993
15. Katz A, Awad IA, Kong AK, et al: Extent of resection in temporal lobectomy for epilepsy. II. Memory
changes and neurologic - comphca&ons. Epilepsia
30:76X71,1989
16. Kuzniecky R, Ho SS, Martin R, et al: Temporal lobe
developmental malformations and hippocampal sclerosis. Neurology 52:479-484,1999
17. Kwan P, Brod& MJ: Early identification of refractory
euileosv. N Enal I Med 3423314319.2000
18. Mars& AG, I?ahir ZA, Chadwick DW: New antiepileptic drugs: A systematic review of their efficacy
and tolerability. BMJ 313:1169-1174,1996
19. McFie J: The effects of hemispherectomy
on intellectual functioning in cases of infantile hemiplegia. J Neurol Neurosurg Psychiatry 24240-249,
1961

SUMMARY
Outcomes from surgery for epilepsy caused
by MCD in pediatric and adult series are similar. Overall, approximately
50% of patients
with cortical dysplasia become seizure-free after resection and another 20% have significant
improvement
in seizure frequency The outcome seems to be improved when the cortical dysplasia is completely resected. Some patients have significant improvement
in seizure
frequency even with partial resection of the
dysplasia, however. MR imaging, EEG, and
PET scans are useful in determining
the extent
of the dysplasia. Invasive monitoring
with
subdural electrodes can help to determine
the extent of resection, especially by defining
seizure onset in relation to functional areas
of cortex. The results of surgical treatment
in this group of medically refractory epilepsy
patients far surpass those achieved during
controlled
trials of new antiepileptic
drugs
for patients with intractable focal epilepsy.
Surgery for catastrophic epilepsy caused by
MCD in infancy may afford the potential for
greater neurologic recovery because of developmental plasticity, but it also entails a higher
risk of mortality
than does surgery later in
childhood.

l&t

HOLLAND

& WYLLIE

20. Morris
GL, Mueller
WM: Long-term
treatment
with
vagus nerve stimulation
in patients
with refractory
epilepsy. The Vagus Nerve Stimulation
Study Group
EOl-E05. Neurology
53:1731-1735,1999
21. Palmini
A, Gambardella
A, Andermann
F, et al: Intrinsic epileptogenicity
of human dysplastic
cortex as
suggested
by corticography
and surgical
results. Ann
Neurol37:476-487,1995
22. Palmini
A, Gambardella
A, Andermann
F, et al: Operative
strategies
of patients
with cortical
dysplastic
lesions and intractable
epilepsy.
Epilepsia
35fsuppl
6):S57S71,1994
23. Paolicchi
JM, Jayakar
I, Dean P, et al: Predictors
of
outcome
in pediatric
epilepsy
surgery.
Neurology
54:642-647,2000
24. Peacock WJ, Comair
Y, Chugani
HT, et al: Epilepsy
surgery
in childhood.
In Liiders
HO fed): Epilepsy
Surgery.
Philadelphia,
Lippincott-Raven,
1991,
pp 589-598
25. Rankin
JM, Aram
DM, Horwitz
SJ: Language
ability in right and left hemiplegic
children.
Brain Lang
14:292-306,198l
26. Shields
DW, Shewmon
AD, Peacock
WJ, et al:
Surgery
for the treatment
of medically
intractable
infantile
spasms:
A cautionary
case. Epilepsia
40:
1305-1308,1999
27. Sugimoto
T, Otsubo H, Hwang
PA, et al: Outcome
of
epilepsy surgery
in the first three years of life. Epilepsia 40:560-565,1999

28. Szabb
CA, Wyllie
E, Stanford
LD,
et al: Neuropsychological
outcome
of temporal
lobe resection in children
with epilepsy
Epilepsia
39:814-819,
1998
29. Tmuper
P, Andermann
F, Villemure
JG, et al: Functional
hemispherectomy
for treatment
of epilepsy
associated
with hemiplegia:
Rationale,
indications,
results, and comparison
with callosotomy.
Ann Neurol24:27-34,1988
30. Villemure
JG: Hemispherectomy:
Techniques
and
complications.
In Wyllie
E fed): The Treatment
of
Epilepsy:
Principles
-and Practice,
ed 2. Baltimore,
Williams
& Wilkins,
1997, DD 1081-1086
31 Vining
El, Freeman
JM,.l%las
DJ, et al: Why would
you remove
half a brain? The outcome
of 58 children
after hemispherectomy:
The Johns Hopkins
experience
1968 to 1996. Pediatrics
100:16~171,
1997
32. Wiebe S, Blume WT, Girvin
JR, et al: A randomized
controlled
trial of surgery
for temporal-lobe
epilepsy.
N Enel T Med 345:311-318.2001
hernispherectomy
for infantile
33. W&so\ *PJE: Cerebral
hemiplegia:
A report
of 50 cases. Brain 93:147-180,
1970
34. Wyllie
E, Comair
YG, Kotagal
P, et al: Epilepsy
surgery
in infants. Epilepsia
37:625-637,
1996
35. Wyllie
E, Comair
YG, Kotagal
P, et al: Seizure
outcome after epilepsy
surgery
in children
and adolescents. Ann Neurol44:740-748,1998
Address
Katherine
The Cleveland
Clinic

reprint

requests to

D. Holland,
MD, PhD
Foundation,
Desk S51
9500 Euclid Avenue
Cleveland,
OH 44195

e-mail:

hollankl@ccf.org

CONTEMPORARY

MANAGEMENT

OF MALFUNCTIONS

OF CORTICAL DYSPLASIA5

INDEX

Note: Page numbers of article titles are in bold face type.

Adams hemispherectomy modification, 121
Agyria, pathology of, 17-18
Amino-3-hydroxy-S-methyl-4-isoxazol
acid (AMPA)
receptors, epilepsy and, 29

Balloon cells, in cortical dysplasia, 3,5-7,22,43,72

Band heterotopia, radiologic-pathologic
correlations in,
51-52
Behavioral disorders, in cortical dysplasias, 36
Blood oxygen level-dependent (BOLD) functional
magnetic resonance imaging. See Magnetic
resonance imaging, functional.

CaBosotomy, in cortical dysplasia, 108

Central vertical hemispherectomy, 128-129
Cobblestone lissencephaly, radiologic-pathologic
correlations in, 51,53
Cognitive function, in cortical dysplasias, hemispheric,
106
Cortical dysplasias
abnormal cell proliferation in, 41-50
agyria, pathology of, 17-18
balloon cells in, 3,5-7,22,43,72
bilateral opercular, 57-58
cellular migration disorders, 51-56
classification of, 1-16
clinical features of, 35-36
coactivation in, functional magnetic resonance imaging
of, 65
conditions associated with, 22-23,72-73
cortical disorganization, 56-61
deep infolding in, 54,56
dysmorphic neurons in, 3-46-8
electroencephalography
in, 36-39,87-88,105,
138-140
embryology of, 41,51,56
epileptogenicity of, 27-33,73-74
familial diffuse, electroencephalography in, 38
focal, P-10,87-92
clinical relevance of, V-10
diagnosis of, 88
epileptogenicity of, 27-33,73-74
imaging of, 9,88-89
pathology of, 71-72
radiologic-pathologic
correlations in, 43,45-46

subdural electrode studies of, 89-91

surgical treatment of, 93-102
age considerations in, 138
case study of, 97-98
functional mapping before, 94-95
invasive monitoring before, 94-95
outcome of, 136-139,141
postoperative concerns in, 95
preoperative evaluation for, 9%94
techniques for, 95
Yale University experience in, 95-98
Taylor type, 6,35
types of, 9
four-layered, 51
functional magnetic resonance imaging in, 6369,137,
139-140
functionality of, 74
giant neurons in, 5-6
hemimegalencephaly. See Hemimegalencephaly
hemispheric malformations in, 103-111
clinical features of, 104-105
surgical treatment of
evaluation before, 105-106
outcome of, 139-141
techniques for, 106-108
timing of, 108-110
heterotopias. See Heterotopias.
histopathology of, 6-8
imaging in, 36. See also specific techniques.
immature neurons in, 5-6
lissencephaly, 17-18,37-38,5I, 53
magnetic resonance imaging in. See Magnetic
resonance imaging.
microcephaly, 42
microdysgenesis, 3,61
microscopic patterns of, 20-22
mild, 8-P
neuropsychology of, 36
pachygyria, 17-18 1
pathogenesis of, 1
pathology of, 17-25,71-73
agyria, 17-18
focal, 71-72
heterotopias, 18-20
lissencephaly, 17-18
pachygyria, 17-18
surgical outcome and, 139
versus surgical outcome, 139-140
polymicrogyria, 11-12

145

146

INDEX

Cortical dysplasias
(Continued)
positron emission
tomography
in, 77-82
in infantile
spasms, 79-82
in localization-related
epilepsies,
77-79
methodology
of, 77
surgical outcome and, 137
preoperative
evaluation
of, 35-39
radiologic-pathologic
correlations
in, 41-62
focal, 43,45-46
1
in abnormal
cell proliferation,
41-50
in cellular migration
disorders,
51-56
in cortical disorganization,
56-61
schizencephaly,
12,57-60
single photon emission
computed
tomography
74-77
clinical applications
of, 75-77
methodology
of, 74-75
surgical treatment
of, 93-102
hemispherectomy
in, 113-134
in hemisphefic
malformations,
103-111
outcome
of, 13.5-144
in focal malformations,
136-139,141
in hemispheric
malformations,
139-141
in infantile
spasms, 142
in infants, 141-143
in lobar malformations,
136-139
neurologic,
141
versus medical treatment,
136
terminology
of, 2-6
treatment
of, subdural
grids in, 87-92
tumors in, N-11,22-23,43,48-50
without
balloon cells, 58,61

Gamma-aminobutyric
acid receptors
and circuits,
epilepsy
and, 29-30
Gangliogliomas,
N-11,48,50
Giant neurons,
in cortical dysplasia,
5-6
Glutamate
receptors,
ionotropic,
epilepsy
and, 28-29
Grids, subdural
electrodes
in, in focal cortical dysplasia,
89-91

in,

Developmental
delay
cortical dysplasia
surgery effects on, 142
in cortical dysplasias,
35
Double cortex syndrome,
electroencephalography
in, 38
Dysembryoplastic
neuroepithelial
tumors,
lO-11,23,43,
48-49
Dyslamination,
in cortical dysplasias,
6
Dysmorphic
neurons, 3-4,6-8
Dysplasias,
cortical. See Cortical dysplasias.
Dysplastic
tumors,
U&11,22-23
radiologic-pathologic
correlations
in, 43,48-50

Electrodes,
subdural,
in focal cortical dysplasia,
89-91
Electroencephalography,
in cortical dysplasias,
36-39
focal, 87-88
hemispheric,
105
surgical outcome and, 139-140
versus functional
magnetic
resonance
imaging,
66
Eloquent
cortical regions, localization
of
functional
magnetic
resonance
imaging in, 65-66
subdural
electrodes
in, 90
Epilepsia
partialis
continua,
electroencephalography
in,
38
Epilepsy, in cortical dysplasias.
See Cortical dysplasias.
Epileptogenic
zone concept, in cortical dysplasia,
64-65

Familial
diffuse cortical dysplasia,
electroencephalography
in, 38
Functional
mapping,
for cortical dysplasia

surgery,

94-95

Hemianopia,
homonymous,
after hemispherectomy,
141
Hemidecortication,
in cortical dysplasia,
114,121-122
Hemimegalencephaly,
11
electroencephalography
in, 38
hemispherectomy
in, 116-118,130-131
Hemiparesis,
after hemispherectomy,
141
Hemispherectomy,
107,113-134
definition
of, 113
outcome
of, 139-141
persistent
seizures after, 131-132
postoperative
management
in, 131
repeated,
131-132
techniques
for
Adams modification
of, 121
anatomic,
119-121,140
central vertical,
128-129
development
of, 114-115
functional,
140
hemidecortication
in, 114,121-W
in hemimegalencephaly,
116-118,130-131
in pediatric
patients,
129-130
Japanese per&insular,
129
peri-insular,
127-129
previous
experience
with, 115-118
Rasmussens
functional,
122
transsylvian,
transventricular
functional,
122-127
types of, 118-119
terminology
of, 113
Hemispheric
malformations,
of cortical development,

103-m
clinical features of, 104-105
surgical
treatment
of, 108-110
evaluation
before, 105-106
outcome
of, 139-141
techniques
for, 106-108. See R/SO Hemispherectomy.
timing of, 108-110
Hemispherotomy,
in cortical dysplasia,
113
Hemosiderosis,
after hemispherectomy,
141
Heterotopias,
5-6,12-13
band, 51-52
laminar,
19
marginal,
21
pathology
of, 18-20
periventricular
nodular,
51,54
radiologic-pathologic
correlations
in, 51-56
subcortical
gray matter, 54-55
subependymal,
54,56
Holoprosencephaly,
electroencephalography
in, 37
Homonymous
hemianopia,
after hemispherectomy,
141
Homonymous
quadrantanopia,
after focal cortical
dysplasia
resection,
141
Hypomelanosis
of Ito, electroencephalography
in, 38
Hypsarrhythmia,
surgical
treatment
of, 142

Imaging.
Immature

See also specific modalities.

neurons,
in cortical dysplasia,

5-6

INDEX

Infantile spasms, surgical treatment of, 142

Intellectual impairment, in cortical dysplasias, 36
Ionotropic glutamate receptors, epilepsy and, 28-29

Japanese per&insular hemispherectomy,

129

Language, cortical regions for

functional magnetic resonance imaging of,
65-66
subdural electrode localization of, 90
Lissencephaly
cobblestone, radiologic-pathologic
correlations
51,53
electroencephalography
in, 37-38
pathology of, 17-18

in,

Magnetic resonance imaging, in cortical dysplasias,

36,137
functional, 63-69
advantages of, 64
electroencephalographic-correlated,
66
epileptic zone concept in, 64-65
language sites in, 65-66
principles of, 63-64
task-related, 65-66
hemispheric, 105-106,139-140
Malformations, of cortical development. See Cortical
dysplasias.
N-Methyl-D-aspartate
receptors, epilepsy and,
28-29
Microdysgenesis
definition of, 3
radiologic-pathologic
correlations in, 61
Micropolygyria, pathology of, 18
Migration, neuronal, disordered, to cortex,
- radiologic-pathologic
correlations in, 51-56
Miller-Dieker syndrome, lissencephaly in, 53
Multilobar resection, in cortical dysplasia, 107

Neuroepithelial tumors, dysembryoplastic, W-11,23,43,

48-49
Neuron(s)
disordered migration of, to cortex,
radiologic-pathologic
correlations in, 51-56
dysmorphic, 3-4,6-B
giant, in cortical dysplasia, 5-6
immature, in cortical dysplasia, 5-6
Neuronal heterotopias, 5-6,12-13
Neuropsychologic testing, in cortical dysplasias,
hemispheric, 106
NMDA (N-methyl-D-aspartate) receptors, epilepsy and,
28-29
Noonan syndrome, electroencephalography in, 38

147

Pachygyria, pathology of, 17-18

Pediatric patients
cortical dysplasias in, surgical treatment of, outcome
of, 141-143
hemispherectomy in, 129-130
Per&insular hemispherectomy, 127-129
Perisylvian syndrome, 57-58
PET. See Positron emission tomography.
Polymicrogyria, 11-12
radiologic-pathologic
correlations in, 57-58
Positron emission tomography, in cortical dysplasias,
77-82
hemispheric, 106
in infantile spasms, 79-82
in localization-related
epilepsies, 77-79
methodology of, 77
surgical outcome and, 137
Psychiatric disorders, in cortical dysplasias, 36

Quadrantanopia, homonymous,
dysplasia resection, 141

after focal cortical

Rasmussens functional hemispherectomy,

122

Schizencephaly, 12,57-60
Seizures, in cortical dysplasias. See Cortical dysplasias.
Single photon emission computed tomography, in
cortical dysplasias, 74-77
clinical applications of, 75-77
hemispheric, 106
methodology of, 74-75
Spasms,
infantile
- in cortical dysplasias, positron emission tomography
in. 79-82
surgical treatment of, 142
SPECT (single photon emission computed tomography),
in cortical dysplasias, 74-77,106
Stereoencephalography, in focal cortical dysplasia, 87-88
Strips, subdural electrodes in, in focal cortical dysplasia,
89-91
Subcortical gray matter heterotopias, 54-55
Subdural electrodes, in focal cortical dysplasia, 89-91
Subependymal heterotopias, radiologic-pathologic
correlations in, 54,56
Sylvian fissures, primitive, 57-58

Taylor type focal cortical dysplasia, 6,35

Transsylvian, transventricular functional
hemispherectomy, 122-127
Tumor(s)
dysembryoplastic neuroepithelial, lO-11,23,43,48-49
dysplastic, U&11,22-23,43,48-50
gangliogliomas, lO-11,48,50