Epileptic Disorders
MENUA critical review of the different conceptual hypotheses framing human focal epilepsy Volume 6, numéro 2, June 2004
Illustrations
Auteur(s) : Dileep R. Nair1, Armin Mohamed2, Richard Burgess1, Hans Lders1
1. Department of Neurology, The Cleveland Clinic
Foundation, Cleveland Ohio
2. Institute of Clinical Neuroscience, Royal Prince Alfred
Hospital, Camperdown, Australia
Different concepts have been used to explain the generation and
propagation of focal seizures. The notion posited by the regional
conceptualization of epileptogencity is that there exits a
theoretical “epileptogenic zone” which, if removed, would result in
cessation of the seizure generation. Opinions differ as to the
regions of importance that should be included in this
“epileptogenic zone”. To estimate the epileptogenic zone, Penfield
and Jasper [1], hypothesized that only the initial ictal-onset
zones, as defined by neurophysiology, is important. On the other
hand, Tailarach and Bancaud [2], conceptualized a slightly more
extended epileptogenic zone that included the initial ictal-zone
and the regions of immediate seizure propagation. In contrast, the
“large network” hypothesis, recently described by S. Spencer [3],
holds that focal epilepsy is based on an organization of a neural
network in which the epileptogencity is distributed throughout the
entire network. This concept of a network is a significant
departure from the regional concept. The “large network” model
would suggests that the entire system is equally important in not
only initiating, but also propagating and maintaining the
seizure.
It has always been appealing to look for a new and alternative
conceptual framework for epilepsy, especially in light of the
recent advances in molecular biology and genetics. Shifting from
old to new paradigms has often led to a better scientific
understanding of disease processes. However, for a new paradigm to
be successful, it must not only explain all of the observations
already understood within the old conceptual framework, but must
also be useful to explain, and even to predict, new
observations.
The more restricted Penfield and Jasper’s view of the
epileptogenic-zone postulates that a specific region of the
cerebral cortex gives rise to seizures [1], and different [4]
regions of the brain have different degrees of importance. The
salient consequence of the Penfield/Jasper epileptogenic-zone
concept is that seizure-freedom can be achieved by resection of the
area of cortex generating the seizure, namely the actual (or
potential) ictal-onset zones (figure 1). It also follows
that other regions involved in the early or late seizure-spread
patterns are not a part of the Penfield/Jasper epileptogenic zone
(figure 2). An
important therapeutic corollary of this concept therefore, is that
surgical resection of brain regions outside the epileptogenic zone,
(i.e. including those involved in early seizure propagation) will
only modify the seizure spread (i.e. the seizure semiologic
expression), but will not prevent the generation of seizures.
Another concept, an expansion of the idea of regional
epileptogenicity put forth by Tailarach and Bancaud, incorporates
not only the “epileptogenic zone” but also the areas of cortex
involved in early seizure-spread. Their conclusion from this
hypothesis is that to achieve seizure-freedom the surgical
resection must be expanded to include those cortical areas
responsible for “early” propagation of seizures [2] (figure 3).
The large network hypothesis on the other hand suggests that all
the parts of the neural network are equally important for the
generation of seizures. It suggests that seizure-freedom can be
achieved by the interruption of the network at any level (figure 4). The concept
of a neural network organization in epilepsy and the suggestion
that epileptogenicity requires an intact network is not new [5],
and has been described by other authors [2]. Although networks are
clearly involved during seizure propagation, it does not
necessarily follow that all parts of the network are equally
important in the generation of seizures. The large network
hypothesis makes no distinction between the importance of local and
distant regions of a neural network for the generation of epileptic
seizures.
The cornerstones of the large network hypothesis include the
following: 1) seizures are a disease of large neural networks
and not of discrete cortical regions; 2) interference with any
part of the network will alter or stop seizure generation i.e. all
regions of the network are potential sites of treatment;
3) seizures may propagate through the network or outside the
network. While the Penfield/Jasper and Tailarch/Bancaud
epileptogenic zone hypothesis certainly supports the third point,
it does not support the first two (figure 2).
Networks of neurons in the central nervous system have been
conceptualized for the most part using various computational
models, and there are analogies between the biological and
biomathematical models of neural networks. While a branch of
biomathematical techniques known formally as “Artificial Neural
Networks” shares several, very simple properties with its namesake
in clinical neuroscience, it is important not to let the semantic
similarities prompt unwarranted conclusions. There do exist
specialized mathematical network configurations optimized for
efficient computer processing, but the majority of configurations
employ quite different “connection weights” at each input and
intermediate “neuron”, thereby imparting very different
significances to activities in various parts of the network [6]. In
this sense, there is a clear differentiation between parts of a
network in which particular components carry more importance in the
operation of the network function than others. Similarly, the
epileptogenic zone (as defined in the Penfield/Jasper and
Tailarch/Bancaud model), which has a more crucial role in the
generation of seizures, would carry higher “connection weights”
than other parts of the network, such as the “irritative zone” or
the “symptomatogenic zone”. Although each of these zones is able to
sustain epileptic activity, only the “epileptogenic zone” can
initiate seizures.
An example of the workings of these zones is shown in figure 5. This is a case
study of a patient with peri-rolandic epilepsy in whom the
“symptomatogenic zone” included not only the post-rolandic primary
sensory region of the hand (somatosensory aura), but also the
ipsilateral supplementary motor area (asymmetric tonic seizures) as
well. The patient had a somatosensory aura in the 2nd
through 4th digits of the left hand followed, within
seconds, by a asymmetric tonic seizure. Invasive recordings with
subdural grids helped to identify a very small seizure onset zone
in the primary sensory cortex, which was confirmed when the patient
became seizure-free following resection of this small area of
cortex. In this figure, we also make the distinction between the
Penfield/Jasper epileptogenic zone, the Tailarch/Bancaud
epileptogenic zone and the large network. All of the different
parts of the network are important to produce the clinical
symptomatology of the seizures, but the seizure-freedom after
resection of the very limited Penfield/Jasper epileptogenic zone
indicates that only that area of the cortex is essential for the
generation of seizures.
This diagram shows the Penfield/Jasper epileptogenic zone, the
symptomatogenic zone and “large networks” in a patient with
epileptic seizures consisting of a somatosensory aura followed
within seconds by a generalized asymmetric tonic seizure. The
seizure onset zone was in the primary somatosensory area which
represents the Penfield/Jasper epileptogenic zone. The
Tailarch/Bancaud epileptogenic zone would also include the early
spread of the seizure into the supplementary motor area. The limits
of the large network hypothesis are more poorly defined but could
include connections of the primary somatosensory area(a),
supplementary motor area(b), thalamus(c), adjacent cortex(d), and
even the contralateral cortex(e).
The first line of evidence in support of the large network
hypothesis comes from intracranial recordings of stereotypical
seizures [3]. It is argued that the electrographic variability of
the seizures, recorded with intracranial electrodes in a patient
with stereotypical clinical seizures, is due to a variation in the
location of the seizure onset within a large network. We believe
that the more likely explanation is that the “epileptogenic zone”
consists of multiple, independent, small and potentially
overlapping “seizure-onset zones” (figure 6). Seizures,
therefore, can start from any of the different small “seizure-onset
zones”, which may be closely connected. The propagation pathways
may differ depending on which of the seizure onset zones start the
seizure. Therefore, the notion that the pathways of seizure-spread
vary, is highly consistent with the Penfield/Jasper epileptogenic
zone hypothesis. It is important to remember here that even a large
number of intracranial electrodes will usually cover only a
fraction of the total surface area of cortex. If recording comes
from only part of the ictal-onset zone, seizure propagation from
different, but closely spaced epileptogenic zones, may have a
variable electrographic appearance (figure 6). The variable
appearance or the implication of separate epileptogenic zones may
be due to a) an absence of electrode coverage of the true
epileptogenic zone, b) seizures generated from the depths of a
sulcus, or c) other differences in the propagation patterns. In
addition, electrical seizures can only avail themselves of a
limited number of clinical manifestations since most parts of the
cerebral cortex are “silent”, i.e. cause no clinical changes as the
electrical seizures propagate through them. Seizures arising from
different, but closely situated epileptogenic zones, may extend to
a common symptomatogenic zone, despite variability in the
electrical spread of each seizure.
It is also argued that widespread interictal hypometabolism on FDG
PET is evidence for the large network hypothesis of epilepsy at
work [3]. However, this is contradicted by extensive evidence in
the literature showing that resection of an epileptogenic zone much
more restricted than the large region of PET hypometabolism, is
frequently sufficient to eliminate seizures [7-9]. Moreover, after
resection of a limited “epileptogenic zone”, there is normalization
of the more extensive PET hypometabolism area that had been
observed before surgery [10], again validating [11-13] the
“epileptogenic zone” concept that there are local regions of
relatively greater importance in the neural network. Ictal PET
scans can show a discrete focus of marked glucose hypermetabolism,
as shown by the example in figure 7. This
30 year-old woman with temporal lobe seizures had undergone
lateral temporal neocortical resection prior to presentation to our
institution. The surgery had failed to alter her seizure frequency
or semiology. The ictal FDG PET scan showed a discrete area of
marked hypermetabolism in the remaining hippocampus. A second
procedure removing only the relatively limited area of FDG PET
hypermetabolism rendered the patient seizure-free. This suggests
that there are important differences between local and distant
areas of the network.
It is also unclear how the large network hypothesis in epilepsy
would explain the results of lesionectomies that included only a
limited resection of cerebral cortex and resulted in
seizure-freedom [14-17]. Extensive experience with limited
lesionectomies have established that the epileptogenic zone is
frequently at or in the immediate environs of lesions recognizable
on MRI. These observations also contradict the Tailarch/Bancaud
hypothesis that “early” seizure spread pathways should be included
in the surgical resection to obtain seizure-freedom. The case
illustrated in figure
5 illustrates a case in which an extremely limited
resection rendered the patient seizure-free, even though EEG
recordings showed that the seizure was spreading to the
supplementary motor area immediately after seizure onset. Another
example comes from experience with hypothalamic hamartomas where,
if the resection includes only the recorded cortical ictal onsets
zone, and the lesion is left behind, the seizure outcome is poor
[18]. The large network hypothesis makes no clear distinction
between local and distant regions of the network, suggesting that
modification “in any part of the network will alter seizure
expression or occurrence” [3]. It is true that both EEG seizures
and seizure semiology can be altered by resection of areas outside
of the epileptogenic zone, but this is simply a modification of
seizure propagation and rarely achieves seizure-freedom [19, 20],
therefore, in the example shown in figure 5, resection of the
primary somatosensory cortex or of the somatosensory motor cortex
should have been effective in modifying the seizures. It is
universally recognized, for example, that patients with mesial
temporal sclerosis who have lateral temporal neocortical or
incomplete mesial temporal resections only, frequently continue to
have seizures and often require further surgery. The variety of
novel therapies that have been developed to affect outcome by
interruption of the neural network, such as electrical stimulation
(see figure 1),
provide additional examples. To date, these modalities, including
vagal nerve stimulation, have almost never achieved complete
seizure-freedom [21]. In experiments with another therapeutic
modality, animal research showed that the seizure termination
effect of focal cooling of the cortex disappeared if the cortical
area being cooled was moved just a few millimeters away from the
epileptogenic zone [22]. In summary, treatment of seizures by an
“interruption” of network pathways is frequently unsuccessful in
controlling seizures, whereas lesionectomies have a 70-90 %
chance of post-surgical seizure-freedom [23]. Indeed, even the
removal of a tumor in cases showing a “mirror focus” of epileptic
activity has resulted in good seizure outcomes [24].
In conclusion, there is no question of the importance of networks
in epilepsy for determining patterns of seizure propagation, or
that the alteration of these networks can modify seizures. However,
we feel that the large network hypothesis offers little in exchange
for the Penfield/Jasper epileptogenic zone hypothesis. There is no
convincing neurophysiological evidence to suggest that all regions
of a neural network have equal importance for the generation and
maintenance of seizures. Nor is there any neurophysiological
evidence to suggest that networks are required to sustain seizure
activity via re-entrant or “circus movements” akin to cardiac
neurophysiology. On the other hand, there is evidence that
selective resection of the “initial” seizure-generating neurons is
sufficient to produce seizure-freedom in patients with restricted
epileptogenic zones. Even though detailed neurophysiological
evaluations often reveal “early” seizure spread to widespread
areas, there is no evidence that these “early” seizure spread
regions (included in the Tailarch/Bancaud “epileptogenic zone”)
must be resected for successful epilepsy surgery.
Explorations based on the “epileptogenic zone” hypothesis continue
to make significant contributions to development of new research
insights and treatment paradigms. The Tailarch/Bancaud concept of
an expanded “epileptogenic zone”, and the “large network”
hypothesis as it has been recently presented, do not stand as
stable and consistent platforms for further
investigations. n