EPILEPSY CURRENTS

Current Review
In Clinical Science

Epilepsy Currents
1-11
The Insula and Its Epilepsies ª The Author(s) 2019
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DOI: 10.1177/1535759718822847
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Barbara C. Jobst, MD, PhD1*, Jorge Gonzalez-Martinez, MD, PhD2,

Jean Isnard, MD, PhD3, Philippe Kahane, MD, PhD4, Nuria Lacuey, MD5,
Samden D. Lahtoo, MD, FRCP5, Dang K. Nguyen, MD, PhD6,
Chengyuan Wu, MD7, and Fred Lado, MD, PhD8
1
Geisel School of Medicine at Dartmouth, Hanover, NH, USA
2
Cleveland Clinic, Cleveland, OH, USA
3
Hospices Civils de Lyon, Hospital for Neurology and Neurosurgery, Lyon, France
4
Grenoble-Alpes University, Grenoble, France
5
University Hospitals Cleveland Medical Center, Cleveland, OH, USA
6
CHUM, University of Montreal, Montreal, Canada
7
Thomas Jefferson University, Philadelphia, PA, USA
8
Northwell Health, Great Neck, NY, USA
*Correspondence: Barbara Jobst, MD, PhD, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Epilepsy Center,
One Medical Center Drive, Lebanon, NH 03755, USA; e-mail: [email protected]

Abstract
Insular seizures are great mimickers of seizures originating elsewhere in the brain. The insula is a highly connected brain structure.
Seizures may only become clinically evident after ictal activity propagates out of the insula with semiology that reflects the
propagation pattern. Insular seizures with perisylvian spread, for example, manifest first as throat constriction, followed next by
perioral and hemisensory symptoms, and then by unilateral motor symptoms. On the other hand, insular seizures may spread
instead to the temporal and frontal lobes and present like seizures originating from these regions. Due to the location of the insula
deep in the brain, interictal and ictal scalp electroencephalogram (EEG) changes can be variable and misleading. Magnetic reso-
nance imaging, magnetic resonance spectroscopy, magnetoencephalography, positron emission tomography, and single-photon
computed tomography imaging may assist in establishing a diagnosis of insular epilepsy. Intracranial EEG recordings from within
the insula, using stereo-EEG or depth electrode techniques, can prove insular seizure origin. Seizure onset, most commonly seen
as low-voltage, fast gamma activity, however, can be highly localized and easily missed if the insula is only sparsely sampled.
Moreover, seizure spread to the contralateral insula and other brain regions may occur rapidly. Extensive sampling of the insula
with multiple electrode trajectories is necessary to avoid these pitfalls. Understanding the functional organization of the insula is
helpful when interpreting the semiology produced by insular seizures. Electrical stimulation mapping around the central sulcus of
the insula results in paresthesias, while stimulation of the posterior insula typically produces painful sensations. Visceral sensations
are the next most common result of insular stimulation. Treatment of insular epilepsy is evolving, but poses challenges. Surgical
resections of the insula are effective but risk significant morbidity if not carefully planned. Neurostimulation is an emerging option
for treatment, especially for seizures with onset in the posterior insula. The close association of the insula with marked autonomic
changes has led to interest in the role of the insula in sudden unexpected death in epilepsy and warrants additional study with
larger patient cohorts.

Introduction in Washington DC. The faculty, through their amazing enthu-

siasm, delivered outstanding content so that nearly everyone in
Barbara C. Jobst, MD, PhD, and Fred Lado, MD, PhD
the room learned something new. The symposium was aimed at
This review is a report from the Epilepsy Specialist Sympo- understanding the semiology of insular seizures, the invasive
sium presented at the 2017 American Epilepsy Society Meeting and noninvasive investigation of the insula, and surgical

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distribution of the work as published without adaptation or alteration, without further permission provided the original work is attributed as specified on the
SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
2 Epilepsy Currents

Figure 1. A, The insula is anatomically subdivided in an anterior part that comprises 3 short gyri (a, anterior; m, middle; p, posterior) and a
posterior part that comprises 2 long gyri (A, anterior; P, posterior). B, The insula is covered by the suprasylvian and infrasylvian opercular
regions that are essential for motor, sensory, auditory, and language processing. Numbers refer to Brodmann’s area. CS indicates central sulcus
of the insula.

approaches. As the organizers, we would like to thank the

faculty for their excellent contributions and for setting a high
standard for future symposia.

Anatomy of the Insula

The insular lobe is a thin cortical structure located deep in the
Sylvian fissure, covered by a rich vascular network and hidden
by the fronto-parieto-temporal operculum. These anatomic
constraints make its evaluation and surgical access difficult
(Figure 1). The insula is a complex structure, with 7 cytoarch-
itectonic subdivisions that encompass 5 gyri1 and 4 different
Figure 2. Various spread patterns of insula seizures to symptoma-
functional areas (cognitive, social-emotional, chemical- togenic zones. Peri-S indicates perisylvian.
sensory, and sensory-motor) that overlap.2 Despite its name,
the insula is not isolated.3 It is rather a highly connected brain
region, and therefore seizures originating in the insula are great (EEG) studies demonstrated that besides this “perisylvian”
mimickers of seizures originating elsewhere. Insular epilepsy, clinical pattern, insular seizures could also manifest with
although reported for a long time, is a form of epilepsy that “temporal-like” symptoms (altered awareness with oroalimen-
remains difficult to recognize, evaluate, and treat surgically. tary and manual automatisms),7-9 “frontal-like” symptoms
(hyperkinetic behaviors or tonic motor signs),10 and even with
epileptic spasms,11 therefore supporting the idea that insular
Clinical Semiology of Insular Seizures epilepsy is a great mimicker, depending on the pattern of sei-
Barbara Jobst, MD, PhD, and Phillipe Kahane, MD, PhD zure spread (Figure 2).
The insula is a multiconnected brain region that receives and Patients with insular epilepsy often undergo a long
sends information to frontal, temporal, and posterior cortical “odyssey” searching for help for their drug-resistant seizures
structures, which explains its strong involvement in cognitive, until finally a diagnosis of insular epilepsy is made. Seizures
behavioral, and sensory processing.4 As such, seizure semiol- can be misidentified as psychogenic nonepilepsy seizures for a
ogy of insular lobe seizures is far from being homogeneous, lack of clear EEG correlates or misidentified as seizures origi-
and a number of subjective and objective ictal clinical signs nating in the frontal or temporal lobes. Patients may even have
have been reported, including viscerosensory, somatosensory, undergone previous unsuccessful epilepsy surgery until insular
olfactory, gustatory, and auditory auras; autonomic symptoms epilepsy is identified. Therefore, a careful analysis of seizure
(vomiting, piloerection, heart rate changes); automotor and history, especially addressing patient-reported auras, is
hypermotor behaviors; tonic and/or clonic motor manifesta- essential.
tions; and language disturbances.5 As insular seizures frequently begin with preserved aware-
In 2004, Isnard et al6 elegantly brought attention to a clinical ness, a clear description of the aura may yield important infor-
pattern highly suggestive of insular lobe seizures, which mation that points to an insular onset. A feeling of suffocation
included laryngeal constriction, perioral unpleasant paresthe- and breathlessness, painful sensations,12 or gustatory auras7 are
sias, lateralized somatosensory sensations, dysarthria, and focal highly suggestive of an insular or insulo-opercular ictal origin.
somatomotor signs. Further intracranial electroencephalogram Interestingly, and possibly because the insula is a multimodal
Jobst et al 3

area involved in the processing of various sensory stimuli, Magnetoencephalography

insulo-opercular seizures may also manifest as eating-,
Magnetoencephalography (MEG) is one of the most useful
audiogenic-, and somatosensory-evoked reflex seizures.7,13
tests to identify potential operculo-insular patients.20 Mohamed
Additionally, ecstatic seizures, which have been proposed to
and colleagues21 reviewed MEG data of 14 patients with
involve the anterior insular cortex, can be triggered by thinking
refractory insular seizures and identified the following 3 main
about specific memories or a pleasant emotional context.14
patterns of spike sources: 7 (50%) had an anterior operculo-
insular cluster, 2 (14%) had a posterior operculo-insular clus-
ter, and 4 (29%) showed a diffuse perisylvian distribution. No
Noninvasive Investigation of spikes were detected in the remaining patients. Spike sources
Operculo-Insular Epilepsy showed uniform orientation perpendicular to the Sylvian fis-
sure. Nine patients underwent insular epilepsy surgery with
Dang Khoa Nguyen, MD, PhD
favorable surgical outcome.
The heterogeneous clinical manifestations of insular seizures
highlight the need for confirmation with noninvasive diagnos-
tic tests. Single-Photon Computed Tomography and Positron
Emission Tomography
Video EEG Single-photon computed tomography (SPECT) can identify an
operculo-insular epileptic focus. In a retrospective study of 17
Most auras in insular seizures cannot be appreciated on video,
patients with confirmed operculo-insular epilepsy, ictal SPECT
but certain clinical signs (eg, expression of pain, hand move-
correctly identified the focus in 65% and provided misleading
ment to the throat, long latency between electrical onset, and
information in 18%.22 Secondary activations in areas con-
hypermotor manifestations) suggest an insular focus. On scalp
nected to the insula were common, but generally less intense.
EEG, because the insula is a deep structure, insular spikes are
By contrast, interictal positron emission tomography (PET)
seen only if they project to the surface. Interictal epileptiform
yielded more equivocal findings, as it correctly identified the
discharges are regularly found over frontopolar and frontotem-
operculo-insular focus in 47% cases and was misleading in
poral regions with anterior operculo-insular foci, and over the
24%.23
midtemporal region extending to frontotemporal regions and/or
central leads with posterior foci.15,16 During seizures, various
nonspecific patterns can be seen when the discharge reaches Genetic Testing
surface electrodes. Interictal and ictal discharges generally
allow lateralization of the epileptic focus. Genetic defects have been reported in operculo-insular epi-
lepsy cases, including mutations in the CHRNB2 and CHRNA4
genes in 2 patients with sleep-related hypermotor seizures
Magnetic Resonance Imaging (functional testing under way).24 A subtle insular focal cortical
Clinical diagnosis of insular epilepsy is greatly facilitated by dysplasia was reported in a patient with familial focal epilepsy
the identification of an insular epileptogenic lesion, although associated with DEPDC5 mutation.25 Finally, Nguyen and col-
nonlesional cases are frequent. Among 25 patients who under- leagues26 described an epileptogenic network involving the
went nontumoral epilepsy surgery involving operculo-insular temporo-insular region in a family with reflex bathing epilepsy
resection, presurgical magnetic resonance imaging (MRI) of associated with a Q555X mutation of synapsin 1 on chromo-
the operculo-insular area was normal or revealed questionable some Xp11-q21.
nonspecific findings in 18 (72%).17 Malformations of cortical
development were commonly associated with medication resis-
tant seizures.18 Invasive Recordings of Insular Lobe Seizures
Philippe Kahane, MD, PhD
Magnetic Resonance Spectroscopy The stereotactic intracerebral EEG (SEEG) method is espe-
Magnetic resonance spectroscopy (MRS) of the insula may be cially well suited to evaluate insular epilepsy because it gives
difficult compared with other regions due to its curved/pyrami- access directly to deep brain structures that cannot be
dal shape and the presence of cerebrospinal fluid in the Sylvian recorded using subdural grids or strips. As for every SEEG
fissure. The value of proton MRS in identifying patients with study, a strong semiologically based hypothesis for seizure
insular epilepsy was assessed in 12 nonlesional cases with con- onset as well as for seizure propagation is a prerequisite for
firmed operculo-insular focus.19 Voxels were positioned to successful investigation of insular lobe epilepsy. Extensive
include bilateral anterior and posterior insular regions. Metabo- knowledge of the structural, cytoarchitectonic, and functional
lite concentrations and ratios did not differ from those of non- anatomy of the insular lobe and its connections to the frontal,
insular epileptic patients and healthy controls, and asymmetry temporal, and posterior cortical structures are additional
indices fared poorly in lateralizing the focus. prerequisites.
4 Epilepsy Currents

Figure 3. SEEG recording of a patient with very localized insular onset and subsequent insular resection. A, The SEEG study was focused on the
right insulo-opercular region with additional electrodes sampling the right temporal and frontal lobes and the left insular and temporal regions. B,
SEEG activity at seizure onset (upper panel) exhibits spikes and polyspike discharges quickly followed by a low-voltage fast activity in the superior
part of the anterior long gyrus of the right insula (R Ins) that spreads to the right opercular cortex (R Op). Note the almost immediate
involvement of the contralateral insula (L Ins). The patient describes a painful tingling sensation in the left hand and then (lower panel) loses
contact and presents temporal-like symptoms when the seizure spread to the right mesiotemporal lobe (R mT), anteroinferior part of the insula
(R Ins), and lateral temporal cortex (lT). The orbitofrontal cortex (Of) is spared. C, Schematic representation of the insular contacts involved in
seizure onset before spreading to extrainsular regions. D, Epileptogenicity map indicating the highest value of activation in the 60- to 100-Hz
frequency band at seizure onset. E, Tailored resection of the right anterior long insular gyrus. Postoperatively, there was transient dysgeusia that
resolved completely. The patient has been seizure free without medication for 6 years. Pathological examination revealed a focal cortical
dysplasia type IB. SEEG indicates stereo electroencephalogram.

Seizure onset within the insula widely varies across gamma activity7 are not uncommon (Figure 3B and C); (2)
patients. Seizure onset can be very restricted in space, and seizures often start very focally with a limited intrainsular
to differentiate insular from opercular seizure onset, exten- spread before extrainsular propagation (Figure 3B-D), which
sive insulo-opercular coverage is necessary. The best therefore allows tailored limited resections (Figure 3E)35; (3)
approach is to combine a lateral orthogonal trajectory extrainsular spread explains clinical variability of insular
through the frontoparietal and temporal operculum27 with lobe seizures; in particular, complex motor manifestations
an oblique approach through the frontal or parietal cortices were shown to occur when the discharge spread over fronto-
to allow a larger insular sampling28 (Figure 3A). Combined mesial and/or mesial and lateral temporal regions.16 This is in
depth and subdural electrodes29,30 or hybrid operculo-insular accordance with directed functional coupling analysis that
electrodes 31 can be also used to investigate the insulo- reported a specific association between the insula and mesial
opercular complex. To better evaluate the extent of the future frontal lobe during the propagation of insular seizures34; (4)
resection and to exclude any extrainsular onset, seizure corticocortical evoked potentials have showed that the 2 insu-
spread must be examined, especially in MRI-negative cases. las are closely connected,36 with 8- to 24-milliseconds time
This includes appropriate sampling of extrainsular regions to to propagate from one to the other homotopic insular par-
which the insula is closely connected, taking into account the cel37; therefore, insular seizures may propagate very quickly
different patterns of connectivity that vary as a function of to the contralateral insula (Figure 3B) so that false lateraliza-
each insular gyrus32 with a rostrocaudal organization.33 The tion may occur in insular or even temporo(-insular) epi-
SEEG investigations of insular lobe seizures have shown the lepsy38; (5) typical insular signs can occur in seizures of
following: (1) Seizure onset patterns can be variable in the extrainsular origin; in particular, insular spread is very com-
insula, but low-voltage fast discharge34 or high-frequency mon in seizures of temporal lobe origin22,39 and therefore
Jobst et al 5

may result in misleading seizure auras; and (6) the morbid- 27 sites (Figure 4.2B). Viscero-psychic symptoms, such as
ity rate directly related to insular electrodes is low. In par- thoracic or abdominal heaviness associated with a feeling of
ticular, none of the patients (including children) reported in fear, were elicited at 14 insular sites (Figure 4.2C).
3 recent large studies experienced any hemorrhagic
complications.40,41 Other Insular Responses
Less common responses were vestibular sensations, which
Functional Mapping of the Insula: were described as a feeling of body motion (Figure 4.3) and
Contributions to Semiology of Insular auditory sensations, which were evoked by stimulating the very
Seizures posteroinferior part of the insula (Figure 4.4). Speech impair-
ments, which consisted of speech arrest, slurred speech, or
Jean Isnard, MD, PhD
lowering of voice intensity (Figure 4.5), were evoked both in
Electrical stimulation of cerebral cortex evokes clinical the nondominant and dominant hemispheres for language. Gus-
responses that mimic symptoms occurring at the onset or dur- tatory and olfactory sensations were very rare and represented,
ing the spread of the epileptic discharge. Thus, stimulation respectively, 2.7% and 1% of all responses (Figure 4.5).
studies directly contribute to the localization of ictal symptoms, Overall, none of the clinical signs evoked by stimulation is
as shown for the insular cortex in the pioneering work of Pen- absolutely specific of insular onset. An exception are nocicep-
field and Faulk.42 Since then, a number of insular stimulation tive symptoms, which are highly suggestive of an insular lobe
studies have been performed during SEEG investigations,6 origin.12
which all point to the great variety of clinical responses that
can be observed. This is illustrated below by the results of the
largest published series of insular stimulation in which 679 Pros and Cons of Insular Resection
electrical stimulations were delivered in the insular cortex of
222 patients during SEEG procedures43 with 550 positive Pro: Insular Resection Should Be the First-Line
responses (Figure 4). Intervention for Drug-Resistant Insular Epilepsy
Chengyuan Wu, MD
Somatosensory Sensations Surgical resection of the epileptogenic zone remains the first-
Somatosensory sensations represented the majority (n ¼ 335, line option for patients with drug-resistant epilepsy. Long-term
61%) of all evoked symptoms.44 Paresthesias were most fre- seizure freedom rates are 66% in temporal lobe epilepsy, 46%
quent (Figure 4.1A), followed by thermal sensations. Thermal in occipital and parietal lobe epilepsy, and 27% in frontal lobe
responses were evoked by stimulation around the central sulcus epilepsy.47 With the increased adoption of invasive EEG, the
of the insula (Figure 4.1B). Painful sensations were elicited diagnosis of epilepsy of insular onset has increased. The liter-
mostly from the posterior third of the insula and described as ature supports surgical resection for insular epilepsy. Across 5
burning, electric shock, painful pins, or cramps (Figure 4.1C). separate case series involving 74 patients with an average
Painful responses to insular stimulation were first observed by follow-up of 3.5 years, 73% of patients were seizure free.48
Ostrowsky et al45 and then further confirmed by Mazzola As with all surgical interventions, we must weigh benefits
et al.46 This later study showed that painful responses were with surgical risk. Unfortunately, early experience with open
rare (60 of >4000 stimulations) and were only elicited by insular resections resulted in high morbidity and mortality.49
insular and secondary somatosensory cortex (SII) stimulations. Resection of insular tumors continues to associate with morbid-
They were never observed when stimulating primary somato- ity rates from 20% to 45.5%.50 The insula certainly challenges
sensory cortex (SI) or any other cortical area. These results are surgeons with its deep-seated location, hidden by the frontal and
in line with the SEEG study of Montavont et al,12 in which the temporal opercula, and its intimate relationship with the
insula or SII was systematically involved at seizure onset in all “candelabra” of the middle cerebral artery (MCA). Surgical risk,
5 patients suffering from painful seizures and in which ictal therefore, stems primarily from retraction injury and from dam-
pain was reproduced by the stimulation of these 2 regions. age of lenticulostriate arteries or MCA branches.51 An improved
understanding of these concerns along with advances in surgical
techniques has significantly reduced the risk of insular lobe
Visceral Symptoms surgery. In a more recent series, insular lesionectomy was asso-
They accounted for 82 (15%) of insular lobe responses and thus ciated with a permanent morbidity of 8% and no mortalities.50
represented the second largest group of electrically induced With invasive EEG serving as the means by which insular
symptoms. Constrictive sensations located in the pharyngo- epilepsy can be properly diagnosed, we believe that the tech-
laryngeal, retrosternal, or abdominal region were observed at nique of electrode implantation should be informed by the
41 electrical stimulation sites; they ranged from a simple dis- method of surgical resection. Although the Talairach’s method
comfort to a frightening sensation of strangulation. Viscero- of insular investigation involves orthogonal transopercular
vegetative signs, including nausea, salivation, facial blush, electrode trajectories,41 we favor an oblique approach as
dyspnea, urge to urinate, and sweaty hands, were elicited from described by Afif et al.52 We have taken this approach one step
6 Epilepsy Currents

Figure 4. Location and type of symptoms evoked by electrical stimulations of the insular cortex. (1) Somatosensory responses, including
nonpainful, nonthermal sensations (light blue, 1A), thermal sensations (medium blue, 1B), and painful sensations (deep blue, 1C). (2) Visceral
sensations, including constrictive sensations (light pink, 2A), viscero-vegetative sensations (deep pink, 2B), and viscero-psychic symptoms ( pink,
2C). (3) Vestibular sensations (orange). (4) Auditory sensations (green). (5) Speech disturbances (violet). (6) Olfactogustatory sensations (red
for taste, yellow for smell).

further by implanting 3 or 4 electrodes in a manner that recre- electrodes can then be used as internal landmarks to facilitate
ates the borders of the tetrahedron-shaped insula (Figure 5). adequate, appropriate, and safe insular resection (Figure 6).
In addition to improving our ability to localize the seizure onset In scenarios where the epileptogenic zone cannot be safely
zone to a particular region of the insula, this method of SEEG resected, neuromodulation is a viable option. When consider-
implantation allows us to take a “fence-post” approach to surgical ing responsive neurostimulation (RNS), deep brain stimulation
resection of the insula.53 Because their entry points are distant (DBS), or vagal nerve stimulation (VNS), however, we must
from the craniotomy needed to access the insula, the electrodes understand that these modalities provide significant seizure
remain in place during surgical resection. Consequently, the reduction, but rarely seizure freedom. Specifically, although
Jobst et al 7

Figure 5. The insula is shaped like a tetrahedron or triangular pyramid (left). By taking oblique approaches to the insula and implanting 4
electrodes, we are able to mimic this anatomy and define the borders of the insula (right).

intrinsically related to the heterogeneous semiological features

of seizures arising from the insula and adjacent structures, the
difficult access to the insular cortex, and the relative high mor-
bidity associated with insula and perisylvian resections.
Regarding the technique of insular implantation, several
series have addressed the technique and safety of insular explo-
ration by the SEEG methodology.40,41 The SEEG is arguably
the most common and appropriate surgical method to explore
the insula cortex among other invasive techniques. Since its
inception by Talairach and Bancaud,57 the SEEG methodology,
and in particular its technique, evolved over the years. Never-
theless, the common denominator among different techniques
is accurate vascular imaging, particularly important for insula
explorations. Even in the highly vascular insular cortex, SEEG
Figure 6. Intraoperative view of SEEG electrodes serving as internal can still be performed safely if planning and technique are
landmarks during insular resection. A complete anterior insulectomy performed carefully.
has been performed, as superior, inferior, and anterior insular elec- The most common SEEG depth electrode implantation tech-
trodes can be seen at the borders of the resection. SEEG indicates nique is the transopercular approach,27 in which orientation of
stereo electroencephalogram. electrodes is perpendicular to the sagittal plane, as defined by
the anterior commissure–posterior commissure line. The
RNS, DBS, and VNS, in general, have reported seizure reduc- advantages of this approach include its common and wide-
tion rates of 70%, 40%, and 44%, respectively, they are asso- spread clinical application, its safety and efficacy for accessing
ciated with seizure freedom rates of 15% (for 1 year), 6%, and the insula cortex and adjacent areas, and its ability to sample
less than 10%.54-56 In comparison to the potential for seizure medial and lateral portions of the insula, as well as the adjacent
freedom with surgical resection, neuromodulation is defini- frontal and temporal opercula.
tively inferior and as such should only be considered when Once localization methods confirm that seizures are in fact
resection cannot be performed. arising from the insula cortex, and the extent of the epilepto-
Overall, open resection of the insula is a safe and the most genic zone is defined, the surgical treatment strategies become
effective approach to drug-resistant insular epilepsy and should the main challenge. Several published manuscripts reported the
be considered as the first-line surgical option. outcome and morbidity related to insula epilepsy sur-
geries.11,35,48,58 Alomar et al40 reported the results of 17
Con: Diagnosis and Treatment of Medically Refractory patients with nonlesional imaging who were surgically treated
Insula Epilepsy: Challenges and Pitfalls for medically intractable epilepsy (15 resection and 2 laser
ablations). Overall, 11 of 15 patients with insular resection had
Jorge Gonzalez-Martinez, MD, PhD favorable outcome (Engel I and Engel II), of whom 5 (33.3%)
Insular epilepsy is a particularly challenging topic in medically had an Engel I outcome and 6 (40%) an Engel II outcome. The
refractory epilepsies. The clinical and surgical challenges are remaining patients had either an Engel III (n ¼ 3, 20%) or an
8 Epilepsy Currents

epilepsy accounts for the scant knowledge of SUDEP risk in this

condition. Similarly, although the insula is part of the epilepto-
genic zone in some temporal, frontal, and opercular epilepsies,
these too are relatively undercharacterized syndromes.
Among the few reported cases of insular epilepsy related to
SUDEP is an SEEG proven case of left insular epilepsy with
sleep-related seizures with hyperkinetic automatisms and ante-
rosuperior insular seizure onset. The patient refused resective
surgery and died of SUDEP 2 years after assessment.59 MOR-
Tality in Epilepsy Monitoring Unit Study (MORTEMUS), a
study of SUDEP or near SUDEP in the epilepsy monitoring
unit, reported 2 insular cases associated with near-SUDEP.60
Both patients experienced cardiac/cardiorespiratory compro-
mise in the peri-ictal period of seizures with loss of awareness.
One 10-year-old female patient had cardiorespiratory arrest in
the postictal period and cardiopulmonary resuscitation (CPR)
was instituted successfully within a minute of seizure end. The
Figure 7. Postoperative T2 MRI image (coronal orientation) after other was a 54-year-old female patient who suffered ictal asys-
right caudal rostral insula resection in a 22-year-old female, resulting in
tole and underwent CPR. Given current knowledge of the rel-
symptomatic infarct in the ipsilateral corona radiata (red arrow). The
procedure resulted in seizure freedom, but with a only partially recov- atively benign, self-limited nature of ictal asystole, the
ered left side hemiparesis. MRI indicates magnetic resonance imaging. resuscitation instituted within a minute may have been super-
fluous, and the near-SUDEP label debatable.
The contribution of the insula to seizure-related cardiore-
Engel IV outcome (n ¼ 1, 6.7%). In this cohort, 3 patients
spiratory dysfunction and subsequent SUDEP is worthy of dis-
developed permanent neurological deficits related to hemipar-
cussion. The insula is known to play a central role in the
esis (17.6%), with an additional 4 patients developing transient
regulation of cardiac functions,61 and a few case reports have
deficits and mild complications. Therefore, the total complica-
suggested that seizures of insular lobe origin, or seizures that
tion rate in this series was approximately 41%. Interestingly, all
spread to the insula, might provoke bradycardia,62,63 an atrio-
permanent motor deficits were related to the resection of the
ventricular block,64 or asystole.65 Both left and right insular
caudal dorsal insula and adjacent parietal operculum, possibly
damage are known to affect prognosis and mortality in
due to damage of the small caliber performant arteries originat-
stroke.66,67 Insular damage, in epilepsies emanating outside
ing from the MCA, which exclusively provide vascular supply
this structure, may lead to potentially fatal scenarios. Dysfunc-
to the more caudal aspect of the corona radiata, harboring
tional brain networking, with high insular connectivity, is
motor, and sensory fibers (Figure 7).
known to exist in high SUDEP-risk patients.68 Direct structural
In conclusion, the authors highlighted the dangers related to
damage to the insula, whether seizure induced or iatrogenic,
the dorsal caudal insula resections. Because of the relatively
has been associated with SUDEP in 2 intractable epilepsy
high morbidity associated with open resections in the most
cases.69 In a 33-year-old patient with left hemibody sensory
caudal–rostral aspect of the insular cortex, preoperative discus-
and generalized convulsive seizures, PET hypometabolism in
sion should include alternative treatment approaches including
the left posterior parieto-opercular region, and depth electrodes
RNS and focal laser ablation. In order to overcome the poten-
demonstrating unequivocal fast frequency (gamma) discharges
tial high morbidity related to this area, 2 patients at our center
in the left posterior insula (Figure 8), posterior insular resection
underwent MRI-guided stereotactic laser ablation targeting the
failed to produce seizure freedom. Serial assessments of inter-
dorsal–caudal insula cortex, resulting in no complications and
ictal heart rate variability (HRV) demonstrated significant
good control of focal seizures.
HRV decrease in the postsurgical period compared with the
presurgical period; notably, he had marked sinus tachycardia
Is SUDEP Risk Increased in Insular Epilepsy? in the postictal period that continued for more than 25 minutes.
The insular resection may have contributed via changes in
Nuria Lacuey, MD, and Samden Lhatoo, MD, FRCP HRV to a tendency for ventricular arrhythmia and subsequent
The intimate role played by the insula in autonomic control and SUDEP, 2 years after surgery. In a second case, similarly
modulation renders it suspect in sudden unexpected death in intractable in the postsurgical period, milder left inferior insu-
epilepsy (SUDEP) pathophenomenology. There are 2 possible lar damage was noted secondary to a temporal lobectomy.
types of insular involvement in SUDEP: first, as the epilepto- However, increasing HRV was noted over a 3-year period,
genic zone from where the fatal seizure arises, or second, as the indicating increased vagal tone and a confirmed tendency to
structure, whether damaged or intact, critical to the genesis of postictal bradycardia. The SUDEP was confirmed 21 months
autonomic, and/or respiratory seizure features, to which the sei- after his last assessment with possible contribution of auto-
zure discharge secondarily spreads. The relative rarity of insular nomic dysfunction as described.
Jobst et al 9

Figure 8. A, Postoperative MRI FLAIR sequence shows evidence of a left posterior temporo-insular resection cavity with surrounding gliosis in
a patient with later SUDEP. B, Heart rate plots show ictal sinus tachycardia, followed by sustained postictal sinus tachycardia lasting at least 25
minutes after a nonfatal generalized convulsive seizure. C, Heart rate time and frequency domain parameters calculated during the presurgery
(2006) and postsurgery (2011) epilepsy monitoring unit (EMU) evaluations and the results from generalized estimating equation (GEE) analysis.
D Extent of insular resection and damage, after 3-dimensional reconstruction of pre- and postoperative MRI is delineated in red. MRI indicates
magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; SUDEP, sudden unexpected death in epilepsy; MNN, mean of normal
to normal heart beats; SDNN, standard deviation of normal to normal heart beats.

Whereas it is easy to speculate on insular contributions to investigations. Surgical approaches have to be weighted
SUDEP, it is less easy to extrapolate anecdotal evidence to carefully but can be very successful in treating insular
larger populations. Thus, cohort studies, with appropriate mul- epilepsy.
timodal seizure assessments, are required to resolve these
issues.
In conclusion, insular epilepsy can be difficult to recognize. Declaration of Conflicting Interests
Surgical treatment of insular epilepsy has it challenges but can The author(s) declared no potential conflicts of interest with respect to
be addressed with diligent clinical and electrophysiological the research, authorship, and/or publication of this article.
10 Epilepsy Currents

Funding 18. Chevrier MC, Bard C, Guilbert F, Nguyen DK. Structural

The author(s) received no financial support for the research, author- abnormalities in patients with insular/peri-insular epilepsy: spec-
ship, and/or publication of this article. trum, frequency, and pharmacoresistance. AJNR Am J Neurora-
diol. 2013;34(11):2152-2156.
19. Aitouche Y, Gibbs SA, Gilbert G, Boucher O, Bouthillier A,
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