ARTICLE
Auteur(s) : Aileen
McGonigal1,2,3, Martine Gavaret1,2,3,
Agnès Trébuchon Da Fonseca1,2,3, Maxime
Guye1,2,3, Didier Scavarda1,2,4, Nathalie
Villeneuve1,2,5, Jean Régis1,2,4, Fabrice
Bartolomei1,2,3, Patrick Chauvel1,2,3
1INSERM, U 751, Laboratoire de neurophysiologie et
neuropsychologie
2Aix-Marseille Université, Faculté de Médecine
3Service de neurophysiologie clinique, Hôpital La
Timone, Marseille
4Service de neurochirurgie, Hôpital La Timone,
Marseille
5Service de neuropédiatrie, Hôpital La Timone,
Marseille, France
Article reçu le 1 Mai 2008, accepté le 1 Septembre 2008
Clinical history
The patient first presented to our service at the age of eight
years. The product of a normal pregnancy, he had presented a
single, uncomplicated febrile seizure at the age of one year in the
context of a throat infection. His mother and sister also had a
history of febrile convulsions, but there was no family history of
epilepsy. His psycho-motor development was entirely normal until
the age of 18 months, when he presented with a first diurnal
seizure. This was described as an episode of staring with loss of
contact lasting several seconds, associated with rubefaction,
chewing and bilateral hand tapping movements. Further similar
events followed (occurring in the daytime or while falling asleep)
and paediatric neurology assessment resulted in a diagnosis of
probable frontal lobe epilepsy. Clinical examination was
unremarkable and he was right-handed. Initial surface EEG showed
rare, right rhythmic anterior spikes (FP2, F4, F8) as well as
bilateral polyspike wave discharges (predominant on the right side,
activated by sleep). Videotelemetry at the age of two years allowed
recording of two frontal seizures, one of which had apparent
left-sided and one right-sided onset. Cerebral MRI was normal.
Treatment with carbamazepine was commenced, resulting in a one year
period of complete remission. However, seizures then recommenced at
the age of three years, this time in the form of nocturnal attacks
(“night terrors”), characterised by vocalisation and agitation with
elevation of both upper limbs; a change in his daytime behaviour
was also noted, with a tendency to hyperkinetic activity and
attentional difficulty. It was noted that he seemed to remain aware
or partially aware, and could ask following a seizure “why am I
laughing?” Subsequent trials of various anti-epileptic drug
combinations including carbamazepine, valproate, vigabatrin,
clonazepam, phenytoin, topiramate and lamotrigine were unsuccessful
in controlling the seizures and he was eventually referred to our
centre for pre-surgical assessment. At this time, seizures often
occurred in clusters of many per day, several times a month with
negative consequences for his schooling.
A preliminary phase of comprehensive, non-invasive presurgical
investigation was performed in our unit, the results of which are
summarised below.
Non-invasive investigation
Interictal surface EEG showed bilateral frontal spikes and
spike-wave discharges, predominantly right-sided; associated rapid
discharges in the same region were also subsequently demonstrated
using high resolution EEG (EEG-HR) (figure 1). No independent
left-sided abnormality was seen. Three habitual seizures were
recorded on videotelemetry, with semiology that can be summarised
as follows: sudden onset of bilateral lower limb movements with
asymmetric extension and/or flexion; sometimes “beating time” to
the tune as he sang; less obvious bilateral upper limb movements
sometimes with extension. He also presented humming or frank
singing, sometimes preceded by a cry, occurring close to
seizure-onset. He would then present verbal automatisms
characterised by echolalia (sometimes in a sing-song style), with
either comprehensible or incomprehensible words. The duration was
around 20 seconds and in the post-ictal period no deficit was
noted, but he would often seem euphoric or cheerful. Ictal EEG of
these seizures showed a pattern of flattening in right anterior
frontal regions and the anterior vertex, followed by a localised,
rapid spike discharge 3-5 seconds later, in right frontal
electrodes (FP2, F8, FZ) (see video sequence 1). High resolution
EEG (EEG-HR) revealed that surface interictal spikes had two
separate components, which, when examined sequentially and analysed
using source localisation tools (MUSIC), showed antero-posterior
propagation from the right medial fronto-polar region to the right
superior frontal sulcus (SFS) (figure 2). Cerebral MRI,
including careful review following the results of other
investigations, was normal. The MR protocol used consisted of
transverse diffusion images, transverse T2-weighted images, coronal
T1-weighted inversion recovery images, coronal FLAIR
(fluid-attenuated inversion recovery) images and a
three-dimensional T1-weighted acquisition. Acquisition plans were
referred to the bi-hippocampal plane for the transverse
acquisitions and to the AC-PC plane for the coronal and axial
acquisition. Reconstructions of the 3D T1 images were adapted to
the type of epilepsy. MRI examinations were performed on a
1.5-Tesla Symphony machine (Siemens Medical Systems, Erlangen,
Germany), with a 4-channel head coil being used. Interictal SPECT
on two previous occasions had shown right fronto-temporal
hypoperfusion (during initial paediatric assessment); at the time
of pre-surgical work-up, bilateral anterior mesial frontal and
right anterior temporal hypoperfusion were noted. PET and ictal
SPECT were not performed. As part of a research protocol, a
computerised analysis of sulcal anatomy was performed using raw MRI
data, and this suggested a possibly unusual appearance of the right
superior frontal sulcus. This method remains however, an as yet
unvalidated research tool (Mangin et al. 2004) and the significance
of this finding is therefore unclear.
Neuropsychological assessment showed intellectual capacities
within the normal range, with no visuo-verbal dissociation.
Although a relative preservation of executive functions was
demonstrated, a deficit in visuo-spatial programming (deficit in
visual exploration strategies) was present as was some mild, verbal
dysfunction in terms of impaired narrative ability and difficulty
in problem-solving tasks.
Stereroelectroencephalographic (SEEG) exploration
Following this non-invasive assessment, the decision was taken to
perform SEEG. The main hypothesis based on electroclinical features
was that of a single localised epileptogenic zone in the right
prefrontal region, with the relative contribution of mesial,
dorsolateral and orbitofrontal structures to be determined. The
exploration also aimed at excluding a more widespread epileptogenic
zone, with electrodes therefore being placed in premotor and
temporal lobe structures. The EEG-HR was strongly suggestive of
focal right prefrontal interictal activity, and ictal EEG was also
in keeping with right prefrontal onset, such that bilateral
exploration was not considered necessary.
SEEG recordings were performed using intracerebral multiple
contact electrodes (10 to 15 contacts, length: 2 mm, diameter:
0.8 mm, 1.5 mm apart), placed intracranially according to
Talairach’s stereotactic method as previously described (Talairach
et al. 1992). Nine right-sided depth electrodes were placed as
follows (figure
3): electrode FP exploring medial and lateral parts of the
fronto-polar region with medial and lateral contacts respectively;
electrode CR exploring the anterior cingulate region (Brodmann area
32) with medial contacts and the dorsolateral prefrontal cortex
(Brodmann area 9/46) with lateral contacts; electrode PS exploring
the pre-supplementary motor area (SMA) with medial contacts and
frontal eye fields (Brodmann area 8) with lateral contacts;
electrode S exploring the SMA with medial electrodes and lateral
premotor cortex (Brodmann area 6) with lateral contacts; electrode
CC exploring the anterior cingulate gyrus (Brodmann area 24) with
medial contacts and lateral premotor cortex (Brodmann area 6) with
lateral contacts; electrode OF exploring the caudate nucleus with
medial contacts and the frontal operculum with lateral contacts,
passing through the insula; electrode O exploring medial and
lateral orbitofrontal cortex with medial and lateral contacts
respectively; electrode T exploring the medial temporal lobe with
medial contacts and the superior temporal gyrus with lateral
contacts; electrode TP exploring medial and lateral aspects of the
temporal pole with medial and lateral contacts respectively.
Interictal SEEG (figure 4) was
characterised by continuous spikes, polyspike and spike-wave
activity as well as rapid discharges (35 Hz) recorded
synchronously from the electrodes exploring the anterior cingulate,
dorsolateral prefrontal and fronto-polar regions (contacts CR 2-3
and 3-4, spreading to CR1-2 and CR 5-7) and FP (1-6). These spikes
could spread to involve premotor regions (electrodes PS and S). The
middle contacts of electrodes O, OF and TP showed interictal slow
wave activity.
During SEEG, one spontaneous seizure was recorded and four
seizures were provoked by electrical stimulation of selected
electrode contracts. The semiology of all five seizures was
comparable to those described above.
In terms of ictal SEEG, for the single spontaneous seizure, a
modification of background activity was noted 2 min 30 before
seizure-onset, in the form of rhythmic spikes in the middle
contacts of electrodes CR and FP (dorsolateral prefrontal region).
This pre-ictal spiking then stopped abruptly, giving way to a fast
tonic discharge (20 Hz) (CR 2-7 and FP 1-7), lasting eight
seconds (figure
5). This was followed by a second, faster tonic discharge
(80 Hz) in the same region, corresponding to the moment when
the first clinical signs occurred. Following this, a clonic spike
discharge was seen in the same electrodes, subsequently spreading
to more lateral contacts of CR, FP then towards orbital and
premotor regions (intermediary contacts of O and S).
The provoked seizures were induced by stimulation of electrodes
CR 1-2, CR 5-6 and FP 1-2, 3-4 (see video sequence 2); in other
words, in the same contacts as in the initial rapid discharge of
the spontaneous seizure.
Conclusion following SEEG and subsequent surgical outcome
From analysis of all available data, including detailed analysis of
the exact position of SEEG electrodes using 3D MRI, it was
concluded that the irritative zone and epileptogenic zone were
practically superimposed, involving a localised region within the
right superior frontal sulcus. The preferential propagation pathway
involved the orbito-frontal region. The EEG features and the
localisation to the base of a sulcus raised the question of
underlying dysplasia, despite the lack of any imaging abnormality.
The patient subsequently underwent right, prefrontal cortectomy
including the right SFS and intermediate frontal sulcus, extending
posteriorly to the anterior pre-cingulate region (figure 6). Histopathology
of the resected section confirmed focal cortical dysplasia type IIB
(Taylor-type with balloon cells). The dysplastic lesion was
relatively voluminous, being present in the bases of several
adjacent sulci of the superior prefrontal cortex, particularly in
their mesial aspect. The patient has been followed up in our
service for four years post-operatively and has remained
seizure-free since surgery. Neuropsychology assessment shows an
improvement in the visuo-spatial and verbal tasks that were
slightly abnormal prior to surgery. He has taken no anti-epileptic
medication for the past two years and his school progress is
entirely normal for his age. He is psycho-socially well-integrated
within his family and school activities.
Discussion
This patient falls within the group of those presenting for
surgical evaluation with normal structural imaging, but with other
features indicating a likely localised region of seizure
production. Frontal lobe epilepsy surgery is the second most common
resective surgery performed for drug resistant epilepsy after
temporal lobe resection, and the group of frontal epilepsies with
normal imaging is considered to be one of the most challenging,
with relatively poorer surgical outcomes reported in the literature
(Jeha et al. 2007). While some authors have argued that such
patients should be automatically excluded from pre-surgical
assessment because of the low chance of success, it is however,
well-recognised that selected patients can have very good surgical
outcomes, dependant upon correct localisation, which usually
requires intra-cranial recording. The method of SEEG, differing in
many key respects from other techniques such as subdural grids, may
afford certain advantages as illustrated in the current case. For
example, recording from deep as well as superficial structures
permits recording from buried cortex or the base of sulci
(crucially, in this case, from the base of the SFS where the
dysplasia was situated). In addition, simultaneous recordings from
both medial and lateral structures allows a temporo-spatial pattern
of activity to be characterised (here, confirming the pattern of
spike propagation suggested by HR-EEG). Indeed, the current case
was previously included in a reported series of 100 SEEG
explorations from the Marseille group, which demonstrated no
difference in localisation rates or eventual surgical outcome
between those with MRI lesions and those with normal imaging
(McGonigal et al. 2007).
In terms of formulating a set of hypotheses to determine a
strategy for intracranial exploration in this case, a number of
elements contributed. The semiology was not, in itself, clearly
localising or lateralising, other than suggesting frontal and in
particular prefrontal involvement. The semiology of prefrontal
seizures is complex, variable and certainly remains incompletely
characterised (Jobst et al. 2000, Chauvel 2003). However, some
semiological elements here, namely the singing, echolalia and
distal hand tapping movements, can be viewed as a form of “forced
acting” or pseudo-compulsive behaviour, which has previously been
described as a feature of dorsolateral prefrontal seizures (Bancaud
and Talairach 1992, Chauvel and Bancaud 1994). Indeed, it has been
noted that the pattern of distally driven, semi-purposeful
movements seen in certain prefrontal seizures is very different
from the proximal, purposeless, often violent movements that
correspond to what has also been called “hypermotor seizures”, this
second pattern being rather associated with prefrontal
mesio-ventral cortex involvement; the difference in semiological
pattern may ultimately present a means of classifying pre-frontal
seizures (Chauvel 2003). The association of ictal emotional
modification with stereotyped motor behaviours has been identified
as a feature of epileptic activity involving the anterior cingulate
region (Bancaud and Talairach 1992). Singing during seizures is
rare, but in previous series has been associated with involvement
of frontal, particularly right prefrontal regions (Bartolomei et
al. 2007).The retained consciousness during this patient’s seizures
argued against widespread seizure propagation to bilateral frontal
or temporal lobe regions. The absence of significant postural
features or forced eye deviation indicated a lack of involvement of
frontal pre-motor areas or frontal eye fields, and no secondary
generalisation occurred. In addition, there was no ictal language
dysfunction or post-ictal deficit, arguing against significant
involvement of dominant hemisphere language structures.
Surface EEG showed rhythmic abnormalities associated with fast
activity in bilateral anterior regions, predominantly right-sided.
The morphology of such abnormalities was quite evocative of
underlying dysplasia (Gambardella et al. 1996), whilst HR-EEG not
only confirmed a clear, right pre-frontal pattern but also
indicated a probable antero-posterior propagation of interictal
activity. The HR-EEG was therefore an important argument for
proceeding to intracranial exploration, with the main hypothesis
being a right, pre-frontal localisation. This technique, when used
in association with source localisation tools, has been previously
validated in frontal lobe epilepsy by corroboration with depth EEG
studies (Gavaret et al. 2006), being particularly useful in
determining lateral and mesial, but not basal frontal
localisations. As has been previously noted in other cases of
lateral frontal epilepsy (Foldvary et al. 2001), the ictal surface
EEG in this case demonstrated a likely localised onset.
In terms of SEEG data, very focal interictal spikes, combined
with consistently localised seizure-onsets characterised by a rapid
discharge in the same region, were recorded. In addition,
stimulation of the middle contacts of the principal electrodes
involved reproduced habitual seizures and showed the preferential
propagation pathway involving the orbitofrontal region. These data,
together with the ensemble of other elements, therefore allowed
confident estimation of primary seizure organisation within a
limited region centred on the right SFS. The lack of involvement of
premotor or temporal regions in seizure production was also
confirmed. The recording of seizure-onsets, with a clear temporal
relation between rapid discharge and production of clinical signs,
indicated that the choice of electrode placement appeared to have
been satisfactory. Indeed, the characteristic pattern of SEEG
abnormalities (Chassoux et al. 2000), including the presence of
interictal and preictal rhythmic spike discharges on SEEG and the
occurrence of very fast ictal discharge within the same localised
region, indicated the probability of an underlying dysplastic
lesion despite the normal MRI. These rhythmic discharges recorded
with depth electrodes correspond to the rhythmic spiking and fast
activities seen on interictal surface EEG.
This patient proved to have a type IIB focal cortical dysplasia
(Taylor-type, with balloon cells) in resected tissue. Despite
ongoing, rapid advances in MR techniques, an unknown proportion of
all dysplasias remain undetected by magnetic resonance imaging, and
it is acknowledged that even lesions visible on MRI may only be the
“tip of the iceberg” (Luders and Schuele 2006); in addition, the
epileptogenic zone is often greater than the lesion itself
(Chassoux et al. 2000). The usefulness of SEEG in assessing
dysplastic lesions has been previously confirmed (Chassoux et al.
2000), particularly with regards to permitting direct
intra-lesional recording as in the present case. The presence of
localised surface EEG interictal abnormalities has been associated
with better prognosis in MRI-negative cases, including dysplasias
(Lee et al. 2005). Despite some studies reporting poor surgical
prognosis in malformations of cortical development without visible
MRI abnormalities (Jeha et al. 2007), excellent outcomes in such
patients have been demonstrated by others (Nobili et al. 2007), and
experience in our own centre is also positive in this respect
(McGonigal et al. 2007). Outcome in children appears to be better
than that reported for adults and it is argued that improved
cerebral plasticity may contribute to this effect (Fauser et al.
2008). Early surgical intervention in such cases is therefore
desirable. In this case, not only has the patient become and
remained seizure-free, but medication has been withdrawn and his
educational and neuropsychological progress is entirely normal.
Disclosures
No financial assistance was received for this work and no conflict
of interest is declared.
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