revisiting the role of the insula in refractory partial epilepsy
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Revisiting the role of the insula in refractory partial
epilepsy∗Dang Khoa Nguyen, ∗Dong Bach Nguyen, yRamez Malak, zJean-Maxime Leroux,∗xLionel Carmant, ∗Jean-Marc Saint-Hilaire, ∗Normand Giard, ∗Patrick Cossette,
and yAlain Bouthillier
∗Service de Neurologie, yService de Neurochirurgie, and zDepartement de Radiologie, Hopital Notre-Dame du
CHUM, Universite de Montreal, Montreal, Quebec, Canada; and xService de Neurologie, Hopital Sainte-Justine,
Universite de Montreal, Montreal, Quebec, Canada
SUMMARY
Purpose: Recent evidence suggesting that some
epilepsy surgery failures could be related to unrec-
ognized insular epilepsy have led us to lower our
threshold to sample the insula with intracerebral
electrodes. In this study, we report our experience
resulting from this change in strategy.
Methods: During the period extending from
October 2004 to June 2007, 18 patients had an intra-
cranial study including 10 with insular coverage.
The decision to sample the insula with intracere-
bral electrodes was made in the context of (1) non-
lesional parietal lobe-like epilepsy; (2) nonlesional
frontal lobe-like epilepsy; (3) nonlesional temporal
lobe-like epilepsy; and (4) atypical temporal lobe-
like epilepsy.
Results: Intracerebral recordings confirmed the
presence of insular lobe seizures in four patients.
Cortical stimulation performed in 9 of 10 patients
with insular electrodes elicited, in decreasing
order of frequency, somatosensory, viscerosen-
sory, motor, auditory, vestibular, and speech
symptoms.
Discussion: Our results suggest that insular cor-
tex epilepsy may mimic temporal, frontal, and
parietal lobe epilepsies and that a nonnegligeable
proportion of surgical candidates with drug-resis-
tant epilepsy have an epileptogenic zone that
involves the insula.
KEY WORDS: Insular cortex epilepsy, Refractory
epilepsy, Intracranial study, Cortical stimulation,
Epilepsy surgery.
Recent evidence suggest that failure to recognize theinsula as the epileptogenic zone may be responsible forsome surgical failures in patients diagnosed with temporallobe (TL), parietal lobe (PL), and frontal lobe (FL) epilep-sies (Ryvlin & Kahane, 2005; Ryvlin, 2006). Using intra-cerebral electrodes, insular seizures were demontrated infive patients with TL-like epilepsy (Isnard et al., 2000,2004) and four patients with FL-like epilepsy (Ryvlinet al., 2006; Dobesberger et al., 2008). Furthermore,Aghakhani et al. (2004) suspected the contribution of theinsula in six patients with PL- and/or TL-like epilepsieswho failed TL and PL surgeries. These insightful reports
have led us to modify our presurgical approach of refrac-tory epileptics in 2004, particularly those requiring an inva-sive study, as our threshold to sample the insula withintracranial electrodes is now much lower. For example,most patients with nonlesional refractory epilepsy withsemiological features suggestive of FL, TL, or PL epilepsynow have the insular region covered by depth electrodes.We report here our experience resulting from this changein strategy. The data shown here support the view that theinsula is a great mimicker and plays a nonnegligeable rolein the rate of failure currently encountered in epilepsysurgery.
Methods
Cohort of patientsDuring the period extending from October 2004 and
June 2007, 18 patients had an intracranial study in ourepilepsy service. Among this cohort of 18 patients, 10 had
Accepted June 10, 2008; Early View publication August 20, 2008.Address correspondence to Dang K. Nguyen, Service de Neurologie,
H�pital Notre-Dame du CHUM, 1560 rue Sherbrooke Est, Montr�al,Qu�bec, Canada. E-mail: d.nguyen@umontreal.ca
Wiley Periodicals, Inc.ª 2008 International League Against Epilepsy
Epilepsia, 50(3):510–520, 2009doi: 10.1111/j.1528-1167.2008.01758.x
FULL-LENGTH ORIGINAL RESEARCH
510
an intracranial study that included electrodes sampling theinsular region (among other regions). Cortical structures tobe explored by intracerebral electrodes were chosen basedon findings from a typical presurgical evaluation andagreed upon by members attending the epilepsy surgeryconference. This presurgical evaluation included a detailedquestionnaire and physical examination, a neuropsycho-logical evaluation, high-resolution cerebral magnetic reso-nance imaging (MRI), video electroencephalography(EEG) recording of seizures, ictal single-photon emissioncomputed tomography (SPECT), and 18F fluorodeoxyglu-cose positron emission tomography (PET).
Electrode implantation and intracerebral recordingsIn general, the decision to sample the insula with intrace-
rebral electrodes was made in the context of (1) nonlesionalPL-like epilepsy; (2) nonlesional FL-like epilepsy; (3) non-lesional TL-like epilepsy; and (4) atypical TL-like epilepsyas suggested by early occurrence of laryngeal discomfortwith thoracic oppression or dyspnea, unpleasant paresthe-sia, or warmth sensation focused on the perioral region orextended to a large somatic territory (as suggested byIsnard et al., 2000). In order to maximize the yield of eachspecific intracranial study, a different combination of sub-dural grid, strip, and/or depth electrodes were used for eachpatient capitalizing on the singular advantages of each typeof electrodes. The insular cortex was investigated by meansof depth electrodes placed under direct vision after micro-surgical opening the Sylvian fissure. In short, a frontotem-poral craniotomy was performed. After opening the duramatter, the Sylvian fissure was identified with the help ofneuronavigation and dissected using microsurgical tech-niques. Care was taken to spare most of the veins crossingthe Sylvian fissure. The fissure was opened to expose theinsular cortical area of interest: Anterior, posterior, or both.This was determined by the noninvasive preoperativeinvestigation. Once exposed, the surface of the insula wasinspected to localize the insular arteries (the M2 branchesof the middle cerebral artery). Safe areas between the arter-ies were then chosen for electrode placement. This wasdone after a small incision of the pia matter with a micro-scalpel. The depth electrode was then inserted under directvision. The depth electrodes used (Spencer depth elec-trodes; Ad-Tech Medical Instrument Corporation, Racine,WI, U.S.A.) had four contacts, each of 1.1 mm length, sepa-rated by 2.3 mm. In most cases, two contacts were insertedin the insular cortex. Each electrode was sutured to sub-dural electrodes placed on the lateral surface of the hemi-sphere and to the dura matter. At least two depth electrodeswere implanted in each patient. We also took advantage ofthe craniotomy to place other depth and subdural elec-trodes, depending on the preoperative investigation. Thescheme of implantation and explored areas for each patientare listed in Table 1. Postimplantation MRI was always per-formed to determine the exact position of the electrodes.
One hundred twenty-eight channels of simultaneous EEGrecordings were available for adequate display and inter-pretation of the information.
Cortical stimulation protocolIntracerebral electrical stimulation was performed to test
the excitability and functionality of the investigated brainregions. The parameters for extraoperative cortical map-ping using the Grass S88 Stimulator (Grass Instruments,W. Warwick, RI, U.S.A.) were as follows: Stimulus fre-quency of 50 Hz with a pulse width of 100 ms, a stimulusintensity of 1–10 mA, and a stimulus train duration of 5 s.Stimuli were administered with an intervening rest intervalof at least 1 min. Afterdischarges (ADs) were assessed ateach stimulation. For language mapping, our procedureincluded object naming, sentence completion, reading, andverbal commands tasks.
Insular site locationIn order to create a cartography of implanted insular
contacts, the patients’ postimplantation MRI files wereretrieved. Using SPM99 software package (WellcomeDepartment of Cognitive Neurology, London, U.K.),dicom files were converted with our Matlab toolbox(MathWorks, Natick, MA, U.S.A.) into analyze format(*.img, *.hdr) files to be opened with MRIcro. The ninepatients’ brains were normalized to fit the spatially normal-ized single-subject high-resolution T1 volume provided bythe Montreal Neurological Institute (Collins et al., 1998).Once normalized to fit the standardized brain, eachpatient’s contacts were manually detected and placed onthe template according to their MNI coordinates. Contactsthat were found not be in the insula area were removed.
Results
The clinical and paraclinical features of all 10 patientswho had insular electrodes are summarized in Table 1.There were four men and six women. Age varied between19 and 41 years of age. Apart from case 1, none hadobvious seizure risk factors. None had experienced febrileseizures except possibly patient 5. MRI was reportednormal except for two patients: Patient 1 had a right hemi-spheric atrophy with right hippocampal sclerosis followingmeningitis in childhood, and patient 10 had a noncongruentmild left hippocampal atrophy contralateral to suspectedepileptogenic zone. Intracerebral recordings confirmed thepresence of insular lobe seizures in four patients (patients1, 2, 5, and 6). There were no clear distinguishing featuresbetween the four patients with insular seizures and the sixpatients without (demographics, age of onset, scalp EEG,functional studies). We report below two sets of data help-ful in determining the role of the insula in refractoryepilepsy: First, the clinical and intracranial EEG presenta-tion of four patients with insular cortex seizures and
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Intracerebral Study of Refractory Insular Cortex Epilepsy
Epilepsia, 50(3):510–520, 2009doi: 10.1111/j.1528-1167.2008.01758.x
Tab
le1.
Pre
surg
icalevalu
ati
on
,su
rgic
altr
eatm
en
t,an
dsu
rgic
alo
utc
om
e
Seiz
ure
Outc
om
eFU
Cas
eA
geSe
xEtiolo
gySe
mio
logy
MR
IFD
GPET
SISC
OM
ICele
ctro
des
Ispik
es
Idis
char
ges
focu
sC
ort
ect
om
y(E
nge
l)(m
onth
s)Pat
holo
gy
123
FM
enin
gitis
Lhan
dplu
sth
roat
par
est
hesi
as,r
isin
g
epig
astr
ic
sensa
tion,f
eelin
g
ofs
tran
gula
tion,
±al
tere
dcs
c
Rhem
ispheri
c
atro
phy
incl
u-
din
gR
HS
Notdone
RT
,RT
-I>
LF
1G
rid
(RF-
P-T
);
2st
rips
(RT
);
3dep
ths
(RA
,
RH
,RI)
+rd
sor
lvfa
RT
-IR
T-I
Ia38
Glio
sis
(HS)
236
MU
nkn
ow
nR
han
dfi
Rlim
b
par
est
hesi
as/p
ain
fiR
arm
ele
vation
Norm
alN
orm
alL
F-P,I
,cin
g1
Gri
d(L
P);
2
dep
ths
(LI)
;
5st
rips
(LT
,LF,
inte
rhem
ispheri
c)
+lv
faL
IL
post
IIII(
Iapost
-
GK
S)
35
n.a
.
325
FU
nkn
ow
nA
rousa
lfi
thora
cic
and
thro
at
oppre
ssio
nfi
tras
hin
g,pedal
ing
Norm
alN
otdone
Multip
leN
-L1
Gri
d(R
F);2
dep
ths
(RI)
;5st
rips
(Rorb
ito-F
,lat
F)
))
Rm
esi
o-F
Rm
esi
o-F
IVb
26
Norm
al
419
FU
nkn
ow
nA
rousa
lfi
min
imal
low
er
limb
mvm
ts
±m
ildpedal
ing
±al
tere
dcs
c
Norm
alfl
RF
Multip
leN
-L1
Gri
d(R
latF)
;1
dep
th(R
I);1
1
stri
ps
(LF,
LT
,
Lpar
asag
,
Lin
terh
em
ispheri
c,
Roperc
ulo
-F,
Rorb
ito-F
,RT
)
))
Rm
esi
o-F
Lm
esi
o-F
Ia22
Glio
sis
537
FU
nkn
ow
nA
rousa
lfi
asym
tonic
post
uri
ng,
grim
acin
g,
voca
lizat
ion,
pedal
ing,
kic
kin
g,ro
ckin
g;
diu
rnal
lipan
d
Rhan
dpar
esth
esi
as
Norm
al(n
on-
speci
fic
LIm
illi-
metr
icsi
gnal
)
flL
IM
ultip
leN
-L2
Depth
s(L
I);1
1
stri
ps
(Lorb
ito-F
,
Lla
tF,
LT
,
Lin
terh
em
ispheri
c,
LP)
+lv
faL
IPen
din
gn.a
.n.a
.n.a
.
626
FU
nkn
ow
nT
hora
cic
plu
sth
roat
plu
slo
wer
jaw
swelli
ng
sensa
tion
fife
ar,a
nxie
ty
±deja
vu±
alte
red
csc
plu
s
auto
mat
ism
splu
s
spitting
Norm
alfl
RT
RT
>R
P5
Depth
s(L
I,L
A,
LH
),4
stri
ps
(LT
)
)rd
sor
lvfa
RT
-IR
T-I
Ia17
Glio
sis
(CA
4);
ect
opic
gian
t
neuro
ns
Continued.
512
D. K. Nguyen et al.
Epilepsia, 50(3):510–520, 2009doi: 10.1111/j.1528-1167.2008.01758.x
Tab
le1.
Co
nti
nu
ed
Seiz
ure
Outc
om
eFU
Cas
eA
geSe
xEtiolo
gySe
mio
logy
MR
IFD
GPET
SISC
OM
ICele
ctro
des
Ispik
es
Idis
char
ges
focu
sC
ort
ecto
my
(Enge
l)(m
onth
s)Pat
holo
gy
741
MU
nknow
nEpig
astr
icbuzz
,
nau
sea,
oeso
phag
eal
heat
,
bac
kch
illfi
alte
red
csc
Norm
alfl
Rhem
isphere
RT
,F,P
5D
epth
s(R
A,
RH
,RI)
,9
stri
ps
(RT
,
Rorb
ito-F
,
Rin
terh
em
i-
spher
ic
))
Rm
esi
o-T
RA
ITL
Ia16
Glio
sis
(HS)
825
MU
nknow
nA
rousa
lfi
fear
,
pedal
ing,
kic
kin
g,
tras
hin
g;ra
re
diu
rnal
cephal
icau
ra
Norm
alN
orm
alM
ultip
le
N-L
3D
epth
s(R
A,
RH
,RI)
,11
stri
ps
(Rin
ter-
hem
ispheri
c,
Rorb
ito-F
,
Rla
tF,
2T
)
))
Rm
esi
o-F
Rm
esi
o-F
n.a
.n.a
.n.a
.
919
FU
nknow
nR
arm
par
est
hesi
as/p
ain
Norm
al(s
usp
ici-
ous
Lfr
onta
l
sulc
us)
Norm
alM
ultip
le
N-L
2G
rids
(LF,
L
FP),
2depth
s
(LF2
,LI)
+)
LF
dors
o-lat
era
lL
F2Ia
11
Cort
ical
dys
pla
sia
10
24
MU
nknow
nH
otflas
h,d
izzy
fial
tere
dcs
cfi
±
frequentG
TC
Lm
ildhip
po-
cam
pal
atro
phy
flR
TM
ultip
le
N-L
1G
rid
(LF-
T),
4depth
s(R
I,R
H),
8st
rips
(LT
subd,R
T,
Rorb
ito-F
))
Rm
esi
o-T
RA
ITL
Ia9
n.a
.
Tab
lesu
mm
ariz
ing
dem
ogr
aphic
s,pre
surg
ical
findin
gs,i
ntr
acra
nia
lEEG
resu
lts,
and
surg
ical
outc
om
eofth
e10
pat
ients
with
insu
lar
intr
acere
bra
lele
ctro
des.
Pat
ients
with
dem
-
onst
rate
din
sula
rse
izure
sar
ehig
hlig
hte
din
gray
.L,l
eft
;R,ri
ght;
csc,
consc
iousn
ess
;H
S,hip
poca
mpal
scle
rosi
s;F,
fronta
l;T
,te
mpora
l;I,
insu
lar;
P,p
arie
tal;
A,a
myg
dal
a;H
,hip
po-
cam
pus;
N-L
,nonlo
caliz
ing;
par
asag
,par
asag
itta
l;rd
s,re
cruitin
grh
ythm
icsp
ikes
or
spik
ean
dsl
ow
wav
es;
lvfa
,lo
wvo
ltag
efa
stac
tivi
ty;C
ort
ect
om
y:T
,te
mpora
llo
bect
om
y;I,
insu
lect
om
y;A
ITL,an
teri
or
inte
rnal
tem
pora
llo
bect
om
y;F2
,re
sect
ion
ofF2
sulc
us;
mesi
o-F
,re
sect
ion
ofci
ngu
late
gyru
s,F1
±F2
±su
pple
menta
rym
oto
rar
ea;
GK
S,c-
knife
sur-
gery
;FU
,follo
w-u
p;n
.a.,
notap
plic
able
.
513
Intracerebral Study of Refractory Insular Cortex Epilepsy
Epilepsia, 50(3):510–520, 2009doi: 10.1111/j.1528-1167.2008.01758.x
second, the behavioral responses to electrical stimulationof the insula.
Clinical and intracranial EEG presentation of seizuresoriginating in the insula
Case 1, with a past history of meningitis, suffered fromdaily to weekly seizures characterized by left hand andthroat paresthesias, followed by a rising epigastric sensa-tion and a feeling of strangulation with or without alteredconsciousness. Evaluation disclosed right hemisphericatrophy on MRI, right mesiotemporal activation on a firstictal SPECT and right temporoinsular activation on a sec-ond, and right hemispheric rhythmic h ictal activity onscalp EEG. The invasive study included a grid over theright frontoparietotemporal carrefour, depth electrodes in
the right insula, amygdala, and hippocampus, and subduralstrips for the right lateral and inferior temporal regions(Fig. 1). Several episodes of left hand paresthesias wereassociated with rhythmic spiking involving synchronouslytwo contacts in the insula and two contacts in the superiortemporal gyrus. In addition, one complex partial seizureoriginating from mesiotemporal structures and spreadingto the insula was recorded. The patient underwent a righttemporal lobectomy plus insulectomy and has remainedseizure-free since (follow-up 38 months).
Case 2 developed seizures at age 30 characterized by anintermittent burning, swelling, wave-like sensation overthe right hand for a few seconds, recurring multiple times aday in a crescendo fashion and building up to a brief(10–20 s) but intense pain over the right arm/groin/leg
Figure 1.
The first row shows the three-dimensional (3D) visualization of each patient’s brain along with the intracranial
electrodes used. Point of entrance of depth electrodes or interhemispheric strips are represented by an asterisk.
The second and third rows show, on axial and sagittal planes, respectively, the location of insular contacts that were
involved at seizure onset or considered to belong to the epileptogenic zone for all four patients with insular cortex
epilepsy.
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Epilepsia, 50(3):510–520, 2009doi: 10.1111/j.1528-1167.2008.01758.x
areas up to 20 times a day. Evaluation revealed discrete in-terictal EEG irregularities over the left frontocentrotempo-ral regions, no ictal EEG changes during briefdysesthesias, but late semirhythmic h slow waves over thesame regions during longer spells, multiple small areas ofhyperperfusion on ictal SPECT, including the cingulategyrus and left insula, no hypometabolism on PET, and nolesion on MRI. The invasive study comprised a grid overthe left parietal region, depth electrodes into the left insula,and subdural strips reaching the cingulate gyrus (Fig. 1).Interictal spikes were noted over insular contacts. Dyses-thetic spells correlated with low voltage fast activity in theinsula evolving into rhythmic spiking (Fig. 2). A left pos-terior insulectomy was performed that led to a 7-week sei-zure-free period prior recurrence. The following year,complementary c-knife surgery targeting the insular areaanterior to the resection led 18 months later to seizure free-dom for the last 4 months.
Case 5 suffered since age 3 years from daily/weeklynocturnal seizures characterized by sudden arousal, asym-
metric tonic posturing, facial grimacing, vocalization, andhypermotor features. Rare daily spells were identical, butsometimes preceded by dizziness and lip paresthesiasmigrating to the right arm or bilaterally. Evaluationdisclosed left frontal and rare temporal interictal spikes,muscle artifacts on ictal EEG recordings, multiple activa-tion sites on two ictal SPECT, including bilateral insularregions, and no PET abnormality. A nonspecific millimet-ric hyperintense signal on fluid-attenuated inversion recov-ery (FLAIR) over the posterior left subinsular region wasnoted on a 1.5 tesla MRI, but not seen on a 3.0 tesla MRI.Depth electrodes were used to sample the left insula, andmultiple subdural strips were glided over inferior, lateral,and mesial portions of the left frontal lobe as well as partsof the lateral temporal and parietal cortices (Fig. 1).Implantation was complicated by dysphasia from a contu-sion of Wernicke’s area with full recovery over 1 week.Ten seizures were recorded, all associated with low-voltage fast activity originating in the left insula spreadingto temporal, parietal, and frontal regions. Because of the
Figure 2.
Intracerebral recording of interictal insular spikes and insular seizures in patient 2. (A) Preictal stage consisting of
periodic spikes or sharp waves (arrow) occurring in a rhythmic fashion confined to the insula. (B) Transition from a
preictal stage to an ictal pattern characterized by a low-voltage fast activity over the same electrode contacts (arrow)
and ending with rhythmic spike and slow waves. (C) Longer seizure showing the same transition from preictal spiking
to an ictal low-voltage fast activity (arrow) increasing in amplitude and decreasing in frequency. Parietal, electrode
contacts from the subdural grid overlying the parietal lobe; insula, electrode contacts from the insular depth
electrodes; temp, electrode contacts from the subdural strips covering the temporal lobe; front, electrode contacts
from subdural strips covering the dorsolateral frontal region; interhemisph, electrode contacts from subdural strips
reaching the cingulate gyrus.
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contusion, electrodes were removed, and the surgerypostponed.
Case 6 had, since age 21 years, seizures characterized byan initial swelling sensation over the thorax, throat, andlower jaw, immediately followed by fear, anxiety, andsometimes d�j� vu, ending with alteration of conscious-ness, verbal automatisms, spitting, and postictal confusion.Evaluation revealed no epileptogenic lesion, no clear inte-rictal spikes, right centrotemporal rhythmic h ictal activitywith rapid spread, significant right temporal and milderright frontal, insular, and parietal activation sites on threeseparate ictal SPECT, and moderate right temporalhypometabolism on PET. Depth electrodes were implantedin the right insula, amygdala, and hippocampus in additionto subdural strips for lateral temporal regions (Fig. 1).Spikes were found over the right insula, superior temporalgyrus, and mesiotemporal structures. Three seizures origi-nated from the superior temporal gyrus, and three seizurescame from a temporoinsular epileptogenic zone with a lowvoltage fast activity seen concomitantly over themesiotemporal and insular contacts. Cortical stimulationof insular contacts reproduced the initial swelling sensa-tion, while stimulation of the amygdala reproduced thefear, anxiety, and d�j� vu. She underwent a right temporallobectomy plus insulectomy with no subsequent seizures(follow-up 17 months). Pathology showed ectopic giantneurons.
Electrical stimulation of the insular cortexNine patients with insular intracerebral electrodes
underwent cortical stimulation. Stimulations were per-formed in 36 insular sites. These 36 insular sites were stim-ulated one to three times each, with a total of 96intracortical insular stimulations. Clinical responses wereevoked in seven of the patients (7 of 9 patients; 78%), in 32sites (32 of 36; 89%). Elicited responses were evoked inthe absence of an AD on 14 sites or a very brief localizedAD, which remained over the stimulated contacts in 21sites. Evoked response at one insular site was associatedwith a diffusing AD and excluded from topographical anal-ysis. Somatosensory symptoms were the most frequentlyencountered responses, representing 62% of all evokedresponses. Sensations were described as a numbing, tin-gling, warmth, electric, or airflow feeling. Areas involvedincluded the nasooropharyngealcervical but also limbareas. When somatosensory symptoms involved limbs,most responses were controlateral (six responses), but asignificant number were bilateral (four responses). Vis-ceral symptoms were next in line, representing 12% of theelicited responses. Half were described as nausea, abdomi-nal buzz, or rising warmth sensation in the digestive sys-tem, while the other half were special taste sensations.Motor symptoms were evoked in 12% of the responsesconsisting of ocular movements causing difficulty to focusor fixate an object and contralateral elevation of the right
arm. Auditory responses represented 9% of the evokedresponses and were portrayed as a distant sound, a feelingof hearing things in echo, or the sensation that his right earwas obstructed. Vertigo (3%) and arrest of speech (3%)were rare. Heart rates prior to and during stimulationrevealed no significant change.
Correlation between the site of stimulation and symptomsevoked
The topographic analysis of our responses was per-formed by pooling sites where responses were obtained ona single sagittal insular image. Viscerosensory-evoked sen-sations were all located in the anterior portion of the insula(Fig. 3B), while somatosensory-evoked responses werewidely distributed (Fig. 3A). Interestingly, somatosensorysymptoms involving the facial area (eyes, nose, mouth,neck) were all located in the anterior insula, while somato-sensory symptoms involving limbs were more posteriorlylocated. Motor responses (Fig. 3C) involving ocular move-ments were situated in the anterior insula, while limbmovements were in the posterior insula. The only vestibu-lar response noted was positioned in the anterosuperiorinsula (Fig. 3D). Auditory symptoms were in the posteriorinsula (Fig. 3D). Finally, the two sites that evoked lan-guage difficulties were in the anterosuperior insula in thedominant hemisphere (Fig. 3D).
Discussion
The work of Guillaume & Mazar (1949a, 1949b), fol-lowed by Penfield & Jasper (1954) paved the way to theconcept of insular cortex epilepsy. Based on the presenceof rich electrocorticographic interictal spiking found in TLepilepsy patients and the similarity of insular intraopera-tive stimulation-evoked symptoms to TL semiology, theysuggested that temporal lobectomy failures could be due tothe lack of recognition of insular seizures mimicking TLseizures (Guillaume et al., 1953; Penfield & Faulk, 1955).This concept eventually fell into disuse when Silfveniusand coworkers (1964) showed that insular resection, whenadded to temporal lobectomy, failed to increase epilepticcontrol, while significantly increasing surgical morbidity.Interest in insular cortex epilepsy was however reignitedby Isnard et al. (2000) who reported the first intracorticalrecording of insular seizures in two out of 21 atypical TLepileptics implanted due to the presence of ictal symptomsor scalp EEG data suggestive of an early spread of seizuresto the opercular cortices. These two patients continued tohave seizures following temporal lobectomy. Apart fromresembling TL epilepsy, insular epilepsy may also mimicPL epilepsy (Cascino & Karnes, 1990; Aghakhani et al.,2004; Isnard et al., 2004). Benefiting from three additionalcases and findings from insular cortical stimulation, thesame group from Lyon later concluded that insular seizureswere typically associated with a sensation of laryngeal
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Figure 3.
Distribution of stimulated sites according to categorical evoked responses displayed in axial and sagittal views.
Categorized responses are filled with selective colors. Right insular contacts are represented by circles and left
insular contacts by squares. Numbers in semibold italic indicate evoked discharges that were followed by a brief
localized afterdischarge. (A) Somatosensory responses are in green. (B) Visceral responses are in light blue. (C)
Motor association area responses are in navy blue. (D1) Vestibular responses are in purple. (D2) Auditory
responses are in red. (D3) Language or speech arrest responses are in orange.
Epilepsia ILAE
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constriction and paresthesias with or without dysarthria,auditory hallucinations, or motor signs (Isnard et al.,2004). The same year, Aghakhani et al. (2004) alsoreported six very interesting cases with electrographicalfindings suggestive of TL epilepsy but also with somato-sensory auras suggestive of PL epilepsy. Four patients hadpreresection intracranial EEG monitoring, which sug-gested an epileptogenic zone in the posterior temporal andinferior parietal area in two patients, in the TL in onepatient, and was inconclusive in the last patient. A secondintracranial study was performed in three of the patientsafter a first anterior temporal resection and suggested aposterior temporal neocortical localization in two patientsand a posterior temporal-inferior parietal localization inone patient. Overall, only limited improvement occurreddespite one to four operations for each of these six patients,leading the authors to conclude that anteromesial resectionwas ineffective for patients with posterior temporoparietalclinical ictal features. They acknowledged that the insulamight have participated in the complex epileptogenic net-works observed in their patients, although they could notconfirm it due to the lack of intracerebral electrodes placeddirectly within the insula. Finally, recent reports suggestthat insular cortex epilepsy may emulate FL epilepsy.Ryvlin and coworkers (2006) reported three patients withrefractory nonlesional drug-resistant nocturnal hypermotorseizures, whose intracerebral EEG ictal onset primarilyinvolved the insula. Kaido et al. (2006) also reported twosimilar cases of hyperkinetic seizures, but associated witha slight signal change in the right posterior ventral insularcortex, and only cured once the posterior ventral insularand lateral temporal cortices were resected. More recently,Dobesberger et al. (2008) reported a nonlesional patientwith an insular seizure onset and nocturnal hypermotor sei-zures who became seizure-free following a limited resec-tion of the anterior part of the right insula and frontaloperculum. Findings from insular cortical stimulation alsosupport the notion that the insula may generate misleadingsymptoms. From 1945 to 1953, Penfield stimulated 82 sep-arate insular points from 36 awake patients after temporallobectomy (Penfield & Jasper, 1954; Penfield & Faulk,1955). Forty percent of the stimulations produced visceralresponses, while another 40% resulted in various sensoryresponses. The Lyon group has also reported, morerecently, the clinical responses obtained by stimulating upto 144 insular sites in 50 patients with atypical TL epilepsystudied by stereoelectroencephalography (Ostrowskyet al., 2000, 2002; Isnard et al., 2004). They found (indecreasing order of frequency) somatosensory, viscerosen-sitive, and auditory responses, as well as dysarthria andother miscellaneous responses.
In our series of four patients with insular seizures, two hadTL-like epilepsy, one had FL-like epilepsy, and one had PL-like epilepsy. Insular cortical stimulations evoked responsesthat were coherent with data found in the literature, as all
previously reported responses were reproduced: Somatosen-sory including pain, viscerosensitive including gustatory,motor association area-evoked responses, vestibular, audi-tory, and language disturbances. Similar to Isnard et al.(2004), visceral responses were mainly evoked from theanterior insula. However, sites evoking somatosensorysymptoms were widely distributed and not clearly limited tothe posterior three-quarters of the insula as previouslyreported (Isnard et al., 2004). Such diversity in spontaneousseizure semiology and the fact that the insula may generatesuch a variety of responses following cortical stimulationsupport the notion that insular cortex epilepsy is a greatmimicker and that some prior cases of refractory TL-, PL-,or FL-like epilepsy could have had a poor surgical outcomefrom lack of insular lobe intracranial sampling.
Recognizing insular cortex epilepsyAlthough the insula may seem like a great mimicker,
careful analysis of our data and the literature indicate that itis possible to recognize insular cortex epilepsy in mostcases. Due to the confluence of functions in a restrictedregion, as demonstrated by cortical stimulation, we believethat insular seizures should be suspected whenever visceralor motor and especially somatosensory symptoms are com-bined early into a seizure. Hence, independent insular sei-zures should be suspected (1) in TL-like epilepsy patientsif there is early occurrence of somatosensory (e.g., laryn-geal discomfort, throat constriction, limb paresthesias) ormotor ictal symptoms (e.g., arm elevation, trashing, or ped-aling) preceding or concomitant to typical mesiotemporallobe symptoms (e.g., d�j� vu); (2) in PL-like epilepsypatients especially if paresthesias are restricted to perioralor intraoral areas, distributed to a large cutaneous territory,or bilateral; (3) in FL-like epilepsy patients in the presenceof occasional somatosensory symptoms prior to hyper-motor manifestations. Because most patients are usuallyunable to remember any of the subective symptoms experi-enced during nocturnal seizures, the clinician needs to bevigilant about the aura reported during the rare diurnalspells patients might experience. Similar to case 5 in ourseries, patient 1 in Ryvlin’s series (2006) reported an initialtingling sensation, while the two patients reported byRoper et al. (1993) respectively felt throat butterflies andleft arm/leg tingling prior to complex motor behavior.
Investigation of insular cortex seizuresAs seen in our series and the Lyon series (Isnard et al.,
2004), scalp EEG is unable to differentiate insular seizuresfrom TL, PL, or FL seizures. MRI should be carefullyreviewed for any suspicious signal changes, as found inpatient 5 and the two patients reported by Kaido et al.(2006), as they may be easily overlooked or regarded asnonspecific/unrelated to the epileptic disorder. Rather thanproducing unequivocal insular activation, ictal SPECT willmost likely reveal multisite activations including the
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insula. The latter should however raise the level of suspi-cion in the right clinical context. Once insular seizures aresuspected, and in absence of a congruent epileptogeniclesion, confirmation by intracerebral ictal recordings is nec-essary, since electrocorticography is unreliable (Silfveniuset al., 1964; Isnard et al., 2000). Considering the cost andrisk of intracranial studies, it may be preferable to identifythe subset of patients for whom insular intracerebral elec-trodes would yield best results rather than generallyimplant more patients. Better characterization of insularcortex epilepsy will eventually permit to do so. For themoment, we submit that sampling of the insula should beconsidered in patients with nonlesional PL- or TL-like epi-lepsy exhibiting a combination of visceral or motor, andparticularly somatosensory, symptoms at seizure onset.For patients with nonlesional FL-like epilepsy, identifyingthose with insular origin is more difficult. Surely, patientswith nonlesional FL-like epilepsy reporting occasionalsomatosensory symptoms during diurnal seizures, withinnocuously-looking millimetric MRI signal changes, orwith any type of presurgical functional imaging data sug-gesting insular involvement could benefit from insularintracranial sampling.
For patients with atypical TL-like epilepsy associatedwith hippocampal sclerosis, the decision to proceed to anintracranial study with sampling of the insula is less clearand should at the present time be individualized based onthe strength of the hypothesis produced by the noninvasiveevaluation. One could argue that these patients should firstundergo a temporal lobectomy considering the relativelylower incidence of insular cortex epilepsy and the risk ofan intracranial study. An intracranial study would then onlybe performed in posttemporal lobectomy failures. In theseries by Isnard et al. (2000), all 13 patients with lesional[i.e., hippocampal sclerosis, dysembryoplastic neuroepi-thelial tumor (DNET), or hyperintense T2 signal] atypicalTL epilepsy had a good postsurgical outcome followingtailored temporal lobectomy, anterointernal lobectomy,c-knife internal lobectomy, or temporal lobectomy (with-out insular resection). On the other hand, others wouldfavor an invasive investigation prior to surgery to identifycases of ‘‘temporal plus epilepsy,’’ a term coined by Ryvlin& Kahane (2005) to better delineate specific forms of mul-tilobe epilepsy characterized by a prominent ictal involve-ment of the temporal lobe, electroclinical featuresprimarily suggestive of TL epilepsy, and MRI findings thatare either unremarkable or show signs of hippocampalsclerosis. In our series, two of the patients with insular sei-zures also had a temporomesial epileptogenic zone. In theseries by Isnard et al. (2000), both their patients with insu-lar seizures also had temporal lobe seizures.
Insular cortex epilepsy: Not so rare?By being increasingly aware of the various faces of insu-
lar cortex epilepsy and broadening our indications for insu-
lar intracerebral electrodes, our group found four patientswith insular seizures from a series of 18 consecutive intra-cranial studies. In comparison, Isnard et al. (2004) foundfive cases of stereotactically proven insular epilepsy froma series of 50 patients. The discrepancy in prevalence couldbe related to differences in patient selection for intracranialstudies. The latter series included only atypical TL epi-lepsy patients as in ours, all intracranial studies (temporaland extratemporal) were reviewed. Out of our 18 patients,four (patients 3, 4, 5, and 8) were suspected of having a me-siofrontal epileptic focus, and implantation was requireddue to the lack of congruent noninvasive investigations.Insular intracerebral electrodes were justified due toreports of insular nocturnal hypermotor seizures (Kaidoet al., 2006; Ryvling et al., 2006; Dobesberger et al., 2008)and because patient 3 and 5 reported occasional thoracicoppression and rare diurnal hand paresthesias, respec-tively, prior to hypermotor features. Four patients (patients1, 6, 7, and 10) were suspected to have a TL epileptic focus,but implantation of intracerebral electrodes with samplingof the insula was justified by early throat paresthesia inpatient 1, absence of an epileptogenic lesion in patients 6and 7, and left hippocampal atrophy noncongruent with ic-tal recordings in patient 10. Two patients (patients 2 and 9)were suspected to have PL epilepsy based on ictal semiol-ogy. Implantation of intracerebral electrodes was neces-sary for patient 2, due to inadequate localization fromnoninvasive tests. As for patient 9, ictal semiology sug-gested a parietal focus rather than a frontal focus, wherethe suspected dysplastic lesion was found.
Despite confirmation by intracerebral recordings in fourof our patients, we acknowledge that final proof of aninsular focus by seizure freedom postinsular resection wasnot demonstrated; one patient declined insular resection,another became seizure-free only after adjunctiveradiosurgery with a limited 4-month seizure-free status atthis time, and two patients also had anterior temporallobectomies in addition to insular resections. It is uncertainwhat would have happened to these patients without theinsular resection, but because both patients with indepen-dent insular and TL seizures reported by Isnard et al.(2000) continued to have insular seizures following tempo-ral lobectomies, we elected to proceed with the additionalinsular resection.
Conclusion
A nonnegligeable proportion of surgical candidates withdrug-resistant epilepsy have an epileptogenic zone thatinvolves the insula. Our observations made from the evalu-ation of four patients with insular cortex epilepsy andextraoperative cortical stimulation in nine subjectsimplanted with insular intracerebral electrodes add to thegrowing body of literature of this neglected localization-related syndrome. Increased awareness of clinical
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characteristics of insular cortex epilepsy should hopefullyreduce the number of epilepsy surgery failures.
Acknowledgments
The authors would like to thank all the EEG technicians (N. L�vesque,J. Forand, H. Cossette, S. Lebrun, and G. Imbeault). This work wassupported by a Clinical Scientist Research Bursary from the Centre deRecherche du CHUM awarded to D.K.N.
Conflict of interest: We confirm that we have read the Journal’s positionon issues involved in ethical publication and affirm that this report is con-sistent with these guidelines. The authors have no conflicts of interest todisclose.
References
Aghakhani Y, Rosati A, Dubeau F, Oliver A, Andermann F. (2004) Patientswith temporoparietal ictal symptoms and inferomesial EEG do notbenefit from anterior temporal resection. Epilepsia 45:230–236.
Cascino GD, Karnes WE. (1990) Gustatory and second sensory seizuresassociated with lesions in the insular cortex seen on magnetic reso-nance imaging. J Epilepsy 3:185–187.
Collins DL, Zijdenbos AP, Kollokian V, Sled JG, Kabani NJ, Holmes CJ,Evans AC. (1998) Design and construction of a realistic digital brainphantom. IEEE Trans Med Imaging 17:463–468.
Dobesberger J, Ortler M, Unterberger I, Walser G, Falkenstetter T,Bodner T, Benke T, Bale R, Fiegele T, Donnemiller E, Gotwald T,Trinka E. (2008) Successful surgical treatment of insular epilepsywith nocturnal hypermotor seizures. Epilepsia 49:159–162.
Guillaume MMJ, Mazars G. (1949a) Cinq cas de foyers �pileptog�nesinsulaires op�r�s. Soc FranÅaise de Neurol 766–769.
Guillaume MMJ, Mazars G. (1949b) Technique de r�section de l’insuladans les �pilepsies insulaires. Rev Neurol 81:900–903.
Guillaume MMJ, Mazars G, Mazars Y. (1953) Indications chirurgicalesdans les �pilepsies dites ‘temporalis.’ Rev Neurol 88:461–501.
Isnard J, Guenot M., Ostrowsky K, Sindou M, Maugui�re F. (2000) Therole of the insular cortex in temporal lobe epilepsy. Ann Neurol48:614–623.
Isnard J, Guenot M, Sindou M, Maugui�re F. (2004) Clinical manifesta-tions of insular lobe seizures: a stereo-electroencephalographic study.Epilepsia 45:1079–1090.
Kaido T, Otsuki T, Nakama H, Kaneko Y, Kubota Y. (2006) Complexbehavioral automatism arising from insular cortex. Epilepsy Behav8:315–319.
Ostrowsky K, Isnard J, Ryvlin P, Gu�not M, Fischer C, Maugui�re F.(2000) Functional mapping of the insular cortex: clinical implicationin temporal lobe epilepsy. Epilepsia 41:681–686.
Ostrowsky K, Magnin M, Ryvlin P, Isnard J, Gu�not M, Maugui�re F.(2002) Representation of pain and somatic sensation in the humaninsula: a study of responses to direct electrical cortical stimulation.Cerebral Cortex 12:376–385.
Penfield W, Jasper WW. (1954) Epilepsy and the functional anatomy ofthe human brain. Little Brown, Boston.
Penfield W, Faulk ME. (1955) The insula: further observations on itsfunction. Brain 78:445–470.
Roper SN, L�vesque MF, Sutherling WW, Engel J Jr. (1993) Surgicaltreatment of partial epilepsy arising from the insular cortex. J Neuro-surg 79:266–269.
Ryvlin P, Kahane P. (2005) The hidden causes of surgery-resistant tem-poral lobe epilepsy: extratemporal or temporal plus? [editorialreview]. Curr Opin Neurol 18:125–127.
Ryvlin P. (2006) Avoid falling into the depths of the insular trap. Epilep-tic Disord 8(Suppl 2):37–56.
Ryvlin P, Mnotu L, Demarquay G, Hirsch E, Arzimanoglou A, HoffmanD, Gu�not M, Picard F, Rheims S, Kahane P. (2006) Nocturnal hyper-motor seizures, suggesting frontal lobe epilepsy, can originate in theinsula. Epilepsia 47:755–765.
Silfvenius H, Gloor P, Rasmussen T. (1964) Evaluation of insular abla-tion in surgical treatment of temporal lobe epilepsy. Epilepsia 5:307–320.
520
D. K. Nguyen et al.
Epilepsia, 50(3):510–520, 2009doi: 10.1111/j.1528-1167.2008.01758.x
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