The role of periventricular nodular heterotopia in ...

doi:10.1093/brain/awh388 Brain (2005), 128, 641–651

The role of periventricular nodular heterotopiain epileptogenesis

Yahya Aghakhani,1,2 Demet Kinay,1 Jean Gotman,1 Lahbib Soualmi,1 Frederick Andermann,1

Andre Olivier1 and Francois Dubeau1

Correspondence to: Francois Dubeau, 3801 University St.,

Montreal, Quebec, Canada, H3A 2B4

E-mail: [email protected]

1Department of Neurology and Neurosurgery, Montreal

Neurological Hospital and Institute, McGill University,

Quebec, Canada2Present address: Department of Internal Medicine, Section

of Neurology, University of Manitoba, Winnipeg, Manitoba,

Canada, R3A 1R9.

SummaryA temporal resection in patients with periventricularnodular heterotopia (PNH) and intractable focal seizures

yields poor results. To define the role of heterotopic

grey matter tissue in epileptogenesis and to improve out-

come, we performed stereoencephalography (SEEG)

recordings in eight patients with uni- or bilateral PNH

and intractable focal epilepsy. The SEEG studies aimed

to evaluate the most epileptogenic areas and included the

allo- and neocortex and at least one nodule of grey mat-ter. Interictal spiking activity was found in ectopic grey

matter in three patients, in the cortex overlying the

nodules in five and in the mesial temporal structures

in all. At least one heterotopion was involved at seizure

onset in six patients, synchronous with the overlying

neocortex or ipsilateral hippocampus. Two patients had

their seizures originating in themesial temporal structures

only. Six patients had surgery and the resected areasincluded the seizure onset, with follow-up from 1 to

8 years. An amygdalo-hippocampectomy was performed

in two (Engel class Id and III), an amygdalo-

hippocampectomy plus removal of an adjacent heteroto-

pion in two (class Ia), and a resection of two contiguous

nodules plus a small rim of overlying occipital cortex in

one patient (class Id). One patient with bilateral PNH

had three adjacent nodules resected and an ipsilateralamygdalo-hippocampectomy resulting in a reduction of

the number of seizures by 25–50%. The best predictor of

surgical outcome is the presence of a focal epileptic

generator; this generator may or may not include the

PNH. Invasive recording is required in patients with

PNH; it improves localization and is the key to better

outcome.

Keywords: periventricular heterotopia; epileptogenesis; electroencephalography; MRI; seizure

Abbreviations: IEA = interictal epileptiform activity; PNH = periventricular nodular heterotopia;

SEEG = stereoencephalography

Received August 7, 2004. Revised December 3, 2004. Accepted December 6, 2004. Advance Access publication

January 19, 2005

IntroductionPeriventricular nodular heterotopia (PNH) are a well-defined

pathological entity among migrational neuronal disorders

characterized by aggregates or masses of grey matter

adjacent to the lateral ventricular walls just beneath

and abutting the ependyma (Friede, 1989; Barkovich

and Kjos, 1992; Raymond et al., 1994). They probably

result from an arrest in the migrational progress

of neuroblasts from the periventricular layer to the

cortex, which usually occurs maximally between the 7th

and 16th gestational weeks, along radial glial fibres

(Rakic, 1978, 1985, 1995; Sarnat, 1991), or are due to a

failure of programmed cell death of groups of neuroblasts

within the periventricular germinal matrix (Kuida et al.,

1996).

The pathogenic mechanisms of grey matter heterotopia are

not fully understood, but they lead to distinct clinico-

radiological syndromes and genetic characteristics that have

been described recently (Barkovich and Kuzniecky, 2000).

Subependymal or periventricular heterotopia are the most

commonly identified type of heterotopia in clinical practice

# The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]

Dow

nloaded from https://academ

ic.oup.com/brain/article/128/3/641/693012 by guest on 26 July 2022

(Barkovich and Kjos, 1992; Raymond et al., 1994; Dubeau

et al., 1995; Li et al., 1997).

The prevalence of PNH in patients with epilepsy is

unknown. While most patients reported in the literature

have had refractory seizures, this may represent a referral

bias, and some individuals (�20%) have no seizures (Dubeau

et al., 1995). The associated epilepsy syndrome is variable and

seizures may be generalized or focal, often suggesting mesial

or neocortical temporal and parieto-occipital onset (Raymond

et al., 1994; Dubeau et al., 1995; Battaglia et al., 1997).

The clinical and electrographic features of epilepsy in

patients with PNH pointing to mesial temporal lobe origin

are misleading, however. We demonstrated that resecting the

temporal structures only in patients with PNH and intractable

focal epilepsy usually led to unsatisfactory surgical results

(Li et al., 1997). We previously proposed that PNH may either

be the epileptogenic source or part of a more widespread

epileptogenic network involving the hippocampus, and the

overlying or distant neocortex. Very few electrophysiological

studies recording directly from heterotopia were performed in

humans (Morrell et al., 1992; Francione et al., 1994; Li et al.,

1997; Preul et al., 1997; Kothare et al., 1998; Mai et al.,

2003), and onset of seizures in the PNH was reported in an

even smaller number of patients (Li et al., 1997; Preul et al.,

1997).

In an attempt to clarify the role of PNH in epileptogenesis,

we studied eight patients with PNH and medically intract-

able focal epilepsies who underwent intracranial stereoence-

phalography (SEEG) evaluations exploring at least one PNH

in addition to the adjacent and distant cortex and including the

mesial temporal structures.

Subjects and methodsSince 1990 we evaluated >30 patients with PNH. The majority (80%)

had seizures. Clinical and laboratory findings as well as surgical

results in some were discussed in two previous publications (Dubeau

et al., 1995; Li et al., 1997). Eight patients with PNH and pharma-

cologically resistant focal epilepsy underwent SEEG evaluation

between February 1994 and May 2003 on the basis of intractable

focal epilepsy. These patients were selected because they had parti-

cularly severe and disabling focal epileptic syndromes. Clinical,

imaging and electrophysiological data are summarized in Table 1.

Post-processing MRI analyses (Philips, 1.5 T) were performed in all

subjects by one of us (D.K.), allowing evaluation of the shape and

orientation of the hippocampi (Lehericy et al., 1995; Baulac et al.,

1998), quantification of mesial temporal structures according to a

protocol developed in our institution (Bernasconi et al., 2003) and

better visual evaluation of the cortex (Bastos et al., 1995).

Three additional implanted patients followed at our institution

were not included in this study, one because complications of the

implantation confounded some of the electrophysiological results,

and the other two because of the lack of adequate EEG information

(these patients were implanted in the 1980s before we discovered

the presence of bilateral occipital and trigonal PNH).

Depth and epidural electrodes were implanted stereotactically

using an image guidance system (SSN Neuronavigation

System Inc., Mississauga, Ontario, Canada). This is the only

method that allows recording directly from the nodules. Intracerebral

electrodes with nine contacts (each with a diameter of 0.5 mm),

5 mm apart, were placed in the lobe(s) suspected of containing

the epileptic focus, in the adjacent or distant regions and in at

least one heterotopion. Four patients had bilateral and four unilateral

electrode implantations (Table 1). All had at least one temporal lobe

evaluated with samples obtained from both mesial and neocortical

structures. Four had in addition central or centroparietal electrodes,

two had frontal leads and two had mesial and lateral occipital

exploration. The number of nodules studied varied from one to

six per patient. In seven patients, all MRI-determined nodules

were explored (Fig. 1). In the remaining patient (patient 1) who

had bilateral diffuse and contiguous PNH, only one electrode

aimed to the frontal PNH. This case obviously showed definite

sampling limitation. Epidural contacts were used in the majority

of patients (n = 6) to improve surface neocortical sampling. In six

patients, the exact positions of electrodes and recording contacts

relative to the PNH and overlying cortex were verified by a post-

implantation MRI (Fig. 2). One patient had a post-implantation

temporal abscess without sequelae. Long-term video-SEEG

recordings were performed (Harmonie Monitoring System, Stellate,

Montreal, Canada) using 32 or 64 channels. Non-epileptiform activity

and interictal and ictal (electro-clinical and pure electrographic

seizures) epileptiform anomalies were analysed visually in all

patients and in every structure explored. The epileptic focus

was defined according to the results of the intracranial ictal

recordings. Patients gave informed consent for their participation

in this study according to the rules of the Montreal Neurological

Institute and Hospital ethics committee.

ResultsThe eight patients (five men) had a mean age at evaluation of

34 years and at seizure onset of 12 years. All had a compre-

hensive investigation including clinical evaluation, classifica-

tion of seizure semiology, routine and long-term scalp EEG

recordings, high-resolution MRI studies and complete

neuropsychological evaluation. Neurological examinations

were unremarkable. On neuropsychological assessment,

mean full-scale IQ was in the low borderline range at 84

(range 69–107) with uni- or bilateral diffuse cerebral

dysfunction in five, temporal dysfunction in two, and

temporo-parietal cognitive deficit in one.

MRI findings and PNH distributionPatients showed variable distribution of the periventricular

malformations along the lateral ventricles (Table 1 and

Fig. 1). None had nodules along the third or fourth ventricles.

Nodules were bilateral, diffuse and contiguous along both

lateral ventricles in one (patient 1), bilateral focal in two

(patients 6 and 8) and unilateral focal in the remaining five

(patients 2, 3, 4, 5 and 7). One patient had in addition a parietal

abnormal gyral pattern with subcortical heterotopia (patient 3),

and another, closed-lip schizencephaly (patient 7). Six of eight

patients had uni- or bilateral hippocampal atrophy,

contralateral to the PNH in one (patient 2), and five had

uni- or bilateral abnormal shape and positioning of the

hippocampus (Table 1).

642 Y. Aghakhani et al.

Dow



Seizure semiology and scalp EEGIctal semiology suggested temporal lobe seizure in

five patients, posterior temporo-occipital in two and

occipital in one. Scalp EEGs showed interictal epileptiform

activity (IEA), synchronous or independent, predominating

in the temporo-occipital regions in patients with bilateral

diffuse and bilateral focal PNH (Table 1). It was ipsilateral

(n = 1) to the PNH or bilateral (n = 4) in patients with

unilateral focal PNH and maximal over temporal areas.

Seizures were bilateral at onset in patients with bilateral

diffuse or bilateral focal PNH, and unilateral at onset in

those with unilateral focal PNH (in patient 2, onset was

contralateral to the PNH), with maximal activity again over

temporal areas.

Table 1 Demographic, MRI and EEG findings

Pt Sex, age,onset(years)

MRI Seizure type Scalp EEGfindings

SEEG interictal SEEG ictal

1 F, 37, 13 Bil diffuse PNH,multiple, contiguousnodules; R Hc atrophy

No aura; oral andmotor automatisms

ii: R CT, L T;i: bil CT

Bil Amand Hc, R>L

85%: R Hc,15%: Bil Hc

2 M, 43, 14 Uni PNH, one nodule,R trigone; L Hcand entorhinal atrophy

Visual aura; oral andmotor automatisms,vocalizations

ii: bil T; i: bil T Bil Am and Hc,L>R

100%: L Amand Hc

3 M, 39, 19 Uni PNH, one nodule,R trigone; R P subcorticalNH; R round Hc andthick subiculum

Auditory andepigastric aura;staring spells

ii: R T; i: R FT R Am and Hc;R T neocortex;R supramarginalgyrus

100%: R Am, Hcand adjacent PNH

4 M, 31, 1 Uni PNH, 3 nodules,R trigone and T horn;bil Hc, ParaHc, Am,and entorhinal atrophy;bil round Hc, misplacedfimbria and thicksubiculum

No aura; head to L,L arm posturing

ii: R T, bil FT;i: R T

R Am; R Hcand PNH

37%: R Am andcingulate gyrus63%: R Hc andPNH (mostlyEEG seizures)

5 M, 43, 13 Uni PNH, 2 nodules,L O horn; bil Hc, Am, andentorhinal atrophy; L roundHc, deep collateral sulcus,and thick subiculum.

Visual and epigastricaura, fear; staringspells

ii: bil T;i: L TPO

L Lat O neocortexand PNH; L Amand Hc

100%: L lat Oneocortex, PNHand post paraHc

6 F, 16, 5 Bil multiple nodules inboth trigones and T Ohorns; R Hc atrophy; bilround and vertical Hc,paraHc and entorhinal atrophy,misplaced fimbria and thicksubiculum

Visual aura, fear;head and eyes toL and staring spells

ii: bil TPO;i: bil TPO

Multifocal spikingin PNH, O Tneocortex, andmesial T, R>L

50%: Bil Hc, PNHand TO neocortex;30%: R Hc, PNHand TO neocortex;20%: L PNH andTO neocortex;several EEG seizuresin L and R PNH,independent orsynchronous withoverlying neocortex

7 F, 26, 16 Uni multiple PNH inR trigone and T horn;R post TP closed-lipschizencephaly

Feeling of head moving;staring spells, R armand leg automatisms,oral automatisms,head to R

ii: bil T;i: R hem

R ant and post Tneocortex;R Am and Hc

95%: R post Tneocortex andadjacent PNH (26%clinical, 69% EEGseizure only) 5%:R Am (EEGseizures only)

8 F, 38, 16 Bil PNH, 2 nodules in eachtrigone and O horn; L Hcand entorhinal atrophy;L round Hc and thicksubiculum

Strange feeling;staring spells

ii: bil T;i: bil T

Bil TO neocortex;L Am and R Hc

30%: R TO neocortex;30%: L TO neocortex;40%: PNH only(EEG seizures)

Bil = bilateral, uni = unilateral, T= temporal, P = parietal, O = occipital, C = central, F = frontal, P = parietal, hem = hemispheric, R = right,L = left, Hc = hippocampus, Am = amygdala, PNH = periventricular nodular heterotopia, SH = subcortical heterotopia, ant = anterior,post = posterior, lat = lateral, ii = interictal, i = ictal.

Epileptogenesis of PNH 643

Dow



Stereo-EEG findings, rationale for surgicalapproach and outcomesDepth interictal and ictal EEG findings are summarized in

Table 1, and extension of epileptogenesis, surgical approaches

and outcomes in Table 2. Non-epileptiform EEG activity

was analysed in the eight patients. We recorded different

frequencies in the d, a and b bands. The background

activity recorded from the nodules was the same and

synchronous with that recorded from the cortex, indicating

probable connections between these malformations and the

cortex. Interictal spike discharges were found in the PNH,

independent of cortex or mesial temporal structures, in

only three patients (4, 5 and 6, Fig. 3). The lack of IEA in

nodules of six other patients may be explained by the

haphazard organization of the cells within the malfor-

mation, and the possibility that neurons generate electrical

potentials too small to be recorded with our method

(see Discussion). Three distinct SEEG ictal patterns were

observed during monitoring.

SEEG ictal pattern no. 1 (patients 1 and 2)Onset was in mesial temporal structures exclusively.

These patients had seizure semiology suggestive of temporal

lobe epilepsy, and SEEG evaluation showed epileptiform

abnormalities confined to the amygdala and hippocampus

Pt 6Pt 6

Pt 5Pt 5

L

*

Pt 8Pt 8

*

**

*

Pt 2Pt 2*

Pt 3Pt 3 *

R **

Pt 4Pt 4

Pt 7Pt 7

*

*

*

*

* *

* *

**

R L

Pt 1Pt 1

**

R

Fig. 1 Topographic distribution of PNH in eight patients with PNH and intractable focal epilepsy. Asterisks indicate heterotopia thatwere explored with SEEG.

L

R

Fig. 2 Patient 6. Post-implantation MRI (T1 axial and sagittalsections), depth electrode tracts aimed at PNH (arrows).

Table 2 Summary of epileptic activity found in PNH,neocortex and mesial temporal structures

Pt PNH Neocortex AmandHc

Type ofsurgery/PNHresection

Outcome

1 No No Yes R SAH/nodulenot removed

III,8 years

2 No No Yes* R SAH/nodulenot removed

Id,5 years

3 Yes** Yes Yes R SAH/one oftwo nodules

Ia,1 year

4 Yes** No No R SAH/three ofthree nodules

Ia,1 year

5 Yes*** Yes Yes Transcorticaloccipitalapproach/two oftwo nodules

Id,5 years

6 Yes**/***/**** Yes Yes R SAH/three ofsix nodules;waiting forsecondsurgery withtranscorticalremoval ofthree nodules inL trigonal area.

IV,1 year

7 Yes*** Yes Yes Waiting forsurgery

–

8 Yes Yes Yes Not operated(refused surgery)

–

*, main epileptogenic focus was contralateral to PNH;**, epileptic activity in PNH, synchronous with ipsilateralHc and Am; ***, synchronous with neocortical epilepticactivity; ****, independent epileptic activity; SAH = selectiveamygdalo-hippocampectomy.


Dow



without involvement of the explored heterotopia or

evidence of more widespread epileptogenicity. The first

patient with bilateral contiguous and diffuse PNH had

unilateral hippocampal atrophy, but only one nodule was

studied. In this case, this clearly represents a sampling

limitation. The second patient also had typical hippocampal

atrophy contralateral to a unique nodule of grey matter in

the trigone, which was explored. Both had satisfactory

surgical outcome after resection of the epileptogenic hippo-

campus and amygdala (Engel class 3 for patient 1, and class

1d for patient 2) after 8 and 5 years of follow-up. The first

patient remained on polytherapy after surgery, while the

second is now taking only one antiepileptic drug. The

satisfactory result assured us that PNHs did not have a

major role in the epileptogenicity of these patients. No

heterotopic neurons were found in their pathological

specimens, and the hippocampus in both cases showed

neuronal loss and gliosis.

SEEG ictal pattern no. 2 (patients 3 and 4)There was focal onset in mesial temporal structures and ipsi-

lateral adjacent heterotopia. One patient (3) presented with

clinical features suggestive of mesial and neocortical tem-

poral origin, and the other had a non-specific focal clinical

pattern. Both had epileptiform discharges primarily in mesial

temporal structures, but with simultaneous involvement of an

adjacent heterotopion. The first had a right anterior temporal

resection that included the heterotopion abutting the posterior

temporal horn but excluded a large parietal subcortical

heterotopia, which did not generate independent epileptic

activity and was not involved in seizure onset. This patient

is seizure free after 1 year follow-up. The second patient had

a selective amygdalo-hippocampectomy a year ago with

resection of three heterotopic nodules in the wall of the

ipsilateral temporal horn and trigone), and so far has been

seizure free. Both patients were maintained after surgery on

the same drug regimen.

LA1-LA2

LA3-LA5

LH1-LH2

LH3-LH5

LS1-LS2

LS3-LS4

LS5-LS6

LO1-LO2

LO3-LO5

LP1-LP2

LP3-LP4

LP5-LP6

RA1-RA2

RA3-RA5

RH1-RH2

RH3-RH5

RS1-RS2

RS3-RS4

RS5-RS6

RC1-RC2

RC3-RC4

RC6-RC7

500 uV

1 S

Fig. 3 Patient 6. Interictal SEEG recording. Four SEEG epochs showing interictal epileptiform activity in PNH (black arrows) andoverlying cortex (open arrows). Spiking was seen in all heterotopia recorded (LS2, LO1, LP1-2 and RC1-2). The figure alsodemonstrates epileptic discharges in the right amygdala (RA1-2) and both hippocampi (LH1-2 and RH1-2).


Dow



SEEG ictal pattern no. 3 (patients 5, 6, 7 and 8)A regional or widespread neocortical pattern was found with

heterotopia involvement. Patients presented with focal

seizures suggestive of temporal or temporo-occipital origin,

and surface EEG findings were bilateral or widespread. Two

of them had bilateral ectopic grey matter (patients 6 and 8),

and another (patient 7), with unilateral temporo-trigonal

nodules, had an associated ipsilateral temporo-parietal

cortical malformation. The epileptic activity was mostly

neocortical, but synchronous or independent epileptic

discharges were also recorded from the heterotopia in all

cases, as well as from the mesial temporal structures.

In the first patient (5), the epileptogenic area was mainly

neocortical, confined to one occipital neocortex, but syn-

chronous with the activity found in the underlying recorded

heterotopion (Fig. 4). This patient was the only one of this

group to have a very localized lesion and a good surgical

outcome (Engel class 1d) after removal of two adjacent occi-

pital heterotopia plus a rim of overlying occipital cortex

(5 years follow-up). This patient is now on monotherapy.

Histopathological findings showed clusters of large

multipolar neurons mixed with smaller neurons and some

pyramidal cells in a haphazard fashion. No balloon cell,

gliosis or cortical abnormalities were seen in the surgical

specimen available for histology.

The second patient (6), the most intractable of the series,

had abundant, bilateral and multifocal interictal spikes in the

neocortex, amygdala, hippocampus and in the six nodules

explored (Fig. 3). Numerous seizures were recorded in this

patient, some with focal onset in a nodule (Fig. 5). The major-

ity, however, showed synchronous involvement of the

occipito-temporal neocortex, mesial temporal lobe structures

and the nodules. A two-step palliative surgical approach was

considered, consisting first of a lesionectomy (removal of the

nodules through a transcortical and intraventricular

approach) and ipsilateral amygdalo-hippocampectomy in the

non-dominant hemisphere. She improved somewhat (seizures

were reduced by 25–50%) with a follow-up of 1 year. The

second surgery will aim at removing only the three nodules

lying in the left trigonal area.

In the third patient, almost all seizures originated simulta-

neously in one heterotopion and overlying temporal neocortex

of the non-dominant hemisphere. Rare electrographic seizures

were recorded independently from the ipsilateral amygdala.

This patient is awaiting surgery and an extensive temporal

resection is planned including the amygdala, the temporal

horn grey matter nodule and the temporal neocortex, but

excluding the hippocampus and the parietal neocortical

malformation. Finally, in the fourth patient, epileptic

activity was scarce, but independent, in the two PNH

explored (one on each side). The main ictal epileptiform

activity was in the temporo-occipital cortex just

overlying the trigonal heterotopia on both sides. Surgery

was not considered in this patient.

In summary, we confirmed that nodules of heterotopic grey

matter can generate both normal and abnormal electrical

activity. The interictal discharges are independent or syn-

chronous with those from allo- and neocortex. The ictal

epileptiform activity recorded from the nodules is usually

synchronous with cortical discharges. Three different ictal

patterns were found: in the first, the mesial temporal structures

are exclusively involved; in the second, we see synchronous

la1-la2

la3-la4

la5-la6

lh1-lh2

lh5-lh6

lh7-lh8

li1- li2

li2- li3

li6- li7

li7- li8

ln4-ln5

lh2-lh3

la6-la7

li4- li5

ln1-ln2

ln2-ln3

ln4-ln5

ln5-ln6

ln6-ln7

ln7-ln850 uV

1 S

Fig. 4 Patient 5. Ictal SEEG recording. Regional seizure onset in left occipital lateral neocortex (ln 3–8) and left posteriorparahippocampus (li 1–3) with immediate seizure propagation to the anterior hippocampus (lh 1–3).


Dow



involvement of mesial temporal structures and adjacent

heterotopia; and, in the third, there is a regional or widespread

cortical onset with implication of the heterotopia.

DiscussionAll eight patients had extensive exploration of the epilepto-

genic area with intracranial depth electrodes, and at least one

periventricular heterotopion was studied in each case. This is

the first study that attempts to analyse the respective roles

of heterotopia, temporal and extra-temporal neocortex and

mesial temporal lobe structures in the generation of

epileptic activity in a relatively large series of patients with

PNH and focal epilepsy. Another aim of the study was to

define guidelines and approaches for the evaluation and

surgical treatment of patients with intractable focal seizures

and PNH.

Invasive electrophysiological evaluations have been

reported in very few patients with grey matter heterotopia,

and hence analyses that looked at the epileptic activity from

both the lesion and surrounding or distant cortex are scarce.

The first study came from Morrell et al. (1992) who presented

an 11-year-old child with intractable parietal seizures and a

band heterotopia (double cortex syndrome) on MRI. Acute

peroperative cortical and intra-lesional EEG recording

showed that the heterotopic cell population exhibited

apparently normal electrical patterns similar to those

observed in normally organized cortex, but also high

voltage spike-and-wave activity independent of the spikes

arising in the adjacent overlying neocortex. No seizures

were recorded, but the authors thought that the

epileptiform patterns found in the heterotopic tissue

exhibited spatial distribution and temporal properties

suggesting recurrent inhibition in the heterotopic cortex.

Similar findings were found in another patient with band

heterotopia who underwent chronic recording with

intracranial electrodes (Mai et al., 2003). The authors

described, however, synchronous epileptic activity in the

band heterotopia and overlying neocortex suggesting

anatomical and functional interconnections. In 1994, the

Grenoble group (Francione et al., 1994) presented a

29-year-old woman with longstanding focal seizures who

had a focal band of heterotopic grey matter in the right

temporal white matter (as in our patient 3). Chronic SEEG

recording showed low voltage 14–16 Hz fusiform interictal

activity independent of or synchronous with temporal

interictal activity, independent spikes in the lesion and in

the temporo-parietal neocortex, and ictal discharges

generated simultaneously, but not independently, in the

heterotopia and adjacent temporo-parietal structures.

Resection of the lesion and ipsilateral amygdala,

hippocampus, temporal lobe and centro-parietal operculum

led to seizure freedom at 15 months follow-up. In 1997,

we reported a patient with intractable focal epilepsy and a

giant subcortical heterotopia (Preul et al., 1997). Abundant

epileptiform discharges were recorded from the cortex during

acute per-operative electrocorticography, but no spiking from

the lesion itself. Normal appearing EEG patterns were

recorded from the malformation. In 1998, Kothare and

colleagues evaluated three patients with intractable focal

seizures and PNH with multiple depth electrodes, including

LA1-LA2

LA3-LA5

LH1-LH2

LH3-LH5

LS1-LS2

LS2-LS3

LS4-LS5

LS6-LS7

LO1-LO2

LO3-LO5

LO5-LO7

LP1-LP2

LP3-LP4

LP6-LP7

RA1-RA2

RA3-RA5

RH1-RH2

RH3-RH5

RS1-RS2

RS2-RS3

RS3-RS4

RC3-RC4

RC6-RC7

500 uV

1 S

RS5-RS6

RC1-RC2

Fig. 5 Patient 6. Ictal SEEG recording. Focal electrographic seizure onset in right-sided PNH (RS3) with subsequent diffusesynchronization.


Dow



placement in the PNH, to determine whether seizures

originated from the PNH. The heterotopia were focal, left

occipital in two patients and bilateral occipital and

temporal in the third. They proposed that PNH might serve

as an epileptogenic source: in two patients, all seizures arose

from the PNH as a low voltage fast b activity with subsequent

spread to mesial temporal structures. In the third, 80% arose

from the hippocampi with or without simultaneous onset from

PNH and 20% from the heterotopia. There was, however,

no simultaneous recording from the overlying cortex, and

therefore they could not confirm if the seizures started in

the PNH or in the overlying neocortex and then spread

to the PNH or to mesial temporal structures. None of their

patients were operated (Kothare et al., 1998).

From our own data and from the literature, it becomes clear

that heterotopia can generate not only normal EEG activity

but also interictal and ictal epileptic discharges, usually syn-

chronous with, but sometimes independent from the surround-

ing allo- or neocortex. Epileptic interictal discharges were

found in a nodule in only three of our patients, but all patients

had uni- or bilateral mesial temporal spikes (confined to these

structures in two), also involving the cortex in the majority,

usually overlying the malformations. Heterotopic nodules

consist of a large number of cells, some collections in

small clusters of 4–5 cells with randomly organized

neurons, while others exhibit a pattern suggestive of

cortical lamination (Battaglia et al., 1996; Eksioglu et al.,

1996; Harding, 1997; Hannan et al., 1999). In the animal

models of PNH, the main axis of the majority of the

neurons has a radial orientation, with apical dendrites

directed towards the border of the heterotopia (Lee et al.,

1997; Sancini et al., 1998). They assume a relatively

preserved orientation pattern from the progenitor cell layer

in the proliferative ventricular zone toward their final

destination in subpial cortical structures (Rakic, 1995).

Perhaps only a small proportion of the neurons in the PNH

are firing synchronously, and are able to generate small

interictal potentials that may not be recorded even by a

closely located depth electrode.

Two patients had seizures originating exclusively from the

amygdala and hippocampus. In two others, seizures originated

in mesial temporal structures but usually with simultaneous

involvement of the heterotopia. The four remaining patients

showed regional onsets with synchronous involvement of

mesial temporal lobe structures, the heterotopia and portions

of the temporal and extratemporal neocortex. In these cases,

the neocortical extension of the epileptic activity paralleled

the distribution of grey matter ectopia. From analysis of

the different regions recorded, it seems that a network exists,

where the heterotopia by whatever means are connected with

distant cortical structures, and perhaps to each other, and

hence can participate in the generation of the epileptic dis-

charges.

Recent human and experimental studies have shown neur-

onal connections between heterotopia and between heterotopia

and cortex. These studies have suggested that intranodular

neurons have altered excitatory or inhibitory transmission.

Eksioglu et al. (1996) were the first to demonstrate in an

autopsy of a patient with bilateral and diffuse PNH that het-

erotopic neurons were rich in synaptophysin, a membrane

glycoprotein of synaptic vesicles used to investigate synapto-

genesis. They could not determine, however, if the synaptic

input was from within the nodules or from extranodular struc-

tures such as the cortex. Hannan et al. (1999) showed, in

surgical specimens obtained from epileptic children with

nodular heterotopia, that the heterotopia, either subcortical

or subependymal, had sparse connections with each other

and with other parts of the hemisphere, including the cortex.

They demonstrated that nodules contained immature

GABAergic neurons and suggested that the abnormal matur-

ity of the GABA network within nodules may be excitatory

rather than inhibitory. They proposed that intrinsic nodular

epileptogenicity might be communicated to the cortex, which

in turn may act as an amplifier to synchronized excessive

activity. Furthermore, they proposed that the local disinhibi-

tion secondary to immature GABAergic neurons could also

lead to synchronized multisynaptic excitatory interactions and

generate prolonged bursts and after-discharges.

There are three experimental rat models that present

anatomical and histological similarities with human PNH.

The first is the methylazoxymethanol-treated rat model

(MAM-rat) where prenatal exposure results in diffuse

cortical malformations, including heterotopia especially in

the hippocampus (Nagata and Matsumoto, 1969). The

second is the telencephalic internal structural heterotopia

(tish) rat, a neurological mutant, that exhibits bilateral

cortical heterotopia similar to those found in human double

cortex (Lee et al., 1997). The third results from exposure of

fetal rats to external radiation causing diffuse cortical

dysplasia, and subcortical and periventricular heterotopia

(Cowan and Geller, 1960).

Different studies using the MAM-rat model described

definite connectivity between heterotopia and cortex

(Colacitti et al., 1998; Sancini et al., 1998; Smith et al.,

1999). The neurons in dysplastic areas in this model are

frequently hyperexcitable. Heterotopic neurons in MAM-

rats exhibit K + channel abnormalities resulting in

increased neuronal firing (Castro et al., 2001). Alteration of

GABAergic circuitry was also demonstrated (Calcagnotto

et al., 2002). The authors provided evidence for a

significant alteration in inhibitory synaptic function at

heterotopic synapses but suggested increased GABA-

mediated inhibition that may serve to dampen the intrinsic

hyperexcitability in the nodular heterotopia. Other factors

were found that can contribute to heterotopic neuron

excitability such as limited neuropeptide Y susceptibility

(a potent, endogenous modulator of hippocampal

excitability) (Pentney et al., 2002), changes in molecular

organization of NMDA (N-methyl-D-aspartate) receptor

subunits and aberrant connectivity within heterotopia

(Castro et al., 2001; Calcagnotto et al., 2002; Pentney

et al., 2002; Gardoni et al., 2003). Overall, these changes


Dow



could produce an excess of excitatory over inhibitory

neuronal circuitry. Interestingly, Baraban and colleagues

demonstrated that when the heterotopia are isolated from

the hippocampus, they generate seizure-like activity by

themselves (Baraban et al., 2000).

Reciprocal connections between normal cortex and hetero-

topia have also been shown in the tish rat model (Schottler

et al., 1998; Chen et al., 2000). Cortical normotopic rather

than heterotopic neurons are responsible for initiating epilep-

tiform activity. Connections exist between the heterotopic

neurons and the overlying cortex, which contribute to seizure

propagation, but the presence of an abnormal adjacent cortex

appears in itself important and sufficient to generate seizures.

In the third model, a reduction of GABA-mediated inhibitory

activity was demonstrated in both the cortex and heterotopic

grey matter (Chen and Roper, 2003).

Given the common morphological features seen in human

PNH and in rat models, it may be assumed that the same

abnormal connectivity exists in humans, explaining the pres-

ence of synchronous epileptic discharges in the lesion, the

hippocampus and neocortex in our patients (Fig. 6). Their

connections with adjacent or distant structures may play a

role in amplification and synchronization of epileptiform

activity, and may explain the widespread epileptogenic

area often described in these patients. Such a network may

provide a number of loops, within the PNH and between PNH

and overlying cortex, to produce a seizure.

Mesial temporal structures are common epileptogenic sub-

strates (Dalby and Mody, 2001). We demonstrated that mesial

temporal structures are also highly epileptogenic in patients

with PNH; it appears that the hippocampus is not just an

innocent bystander and participates actively in epileptogen-

esis. The co-existence of hippocampal abnormalities occurs

in some patients with cortical developmental disorders, and

this could be due to common pathogenic mechanisms during

embryogenesis or early development (Raymond et al., 1994;

Cendes et al., 1999; Salanova et al., 2004). Six of eight

patients had uni- or bilateral hippocampal atrophy and five

had uni- or bilateral abnormal shape and positioning of the

hippocampus. Considering the two types of abnormalities

together, only one patient of our series had normal

appearing mesial temporal lobe structures. In our larger

surgical series of 20 patients with PNH who had a temporal

lobe resection, half had histological or radiological

hippocampal atrophy (unpublished data). Although in

exceptional cases (e.g. patient 2 of this study), resection of

temporal lobe structures in a patient with hippocampal

atrophy was sufficient to obtain a good surgical outcome,

in the majority this procedure does not result in long-term

cessation of seizures (Li et al., 1997).

Finally, abnormalities of cortical architecture, and of cor-

tical neuronal composition and connectivity, may allow the

cortex to act as a primary epileptogenic substrate (Preul et al.,

1997; Hannan et al., 1999; Sisodiya et al., 1999). Patients with

nodular heterotopia have a high incidence of cortical abnor-

malities such as atrophy and polymicrogyria in addition to

hippocampal atrophy (Sisodiya et al., 1995). In our series of

30 patients with subependymal nodular heterotopia, 54% had

visually detectable cortical abnormalities (unpublished data).

These cortical abnormalities may contribute significantly to

LA1-LA2LA2-LA3

LA5-LA7LH1-LH2LH2-LH3

LH5-LH7LS1-LS2

LS3-LS4

LS6-LS7LO1-LO2

LO7-LO8LP1-LP2

LP3-LP4

LP5-LP6LP6-LP7

RA1-RA2RA2-RA3RA5-RA7RH1-RH2RH2-RH3

RH5-RH7RS1-RS2RS3-RS4

RS5-RS6RS7-RS8RC1-RC2

RC3-RC4

RC6-RC7Ekg1-Ekg2

1 mV1 mV

1 S1 S

LO3-LO5

Fig. 6 Patient 6. Interictal SEEG recording. Synchronized epileptic discharges were recorded in the left hemisphere: spike-and-wave3.5 Hz activity is seen in the amygdala (LA1-2), hippocampus (LH1-2), neocortex (LO3–LO7 and LP5–LP7) and in the three heterotopicnodules (LS1-2, LO1-2 and LP1-2). On the right, less obvious rhythmic activity was recorded involving hippocampus (RH1-2),neocortex (RS7-8 and RC6-7) and at least one nodule (RS3).


Dow



the generation of seizures and are often remote from the EEG

discharges. This may represent an alternative explanation for

the failure of temporal resections.

In summary, patients with PNH and epilepsy represent a

heterogeneous group. Seizures result from complex interac-

tions between PNH and allo- or neocortex. Because of the

variety of demonstrated mechanisms and patterns of epilep-

togenesis, invasive recordings are essential in patients con-

sidered for surgical treatment. In some instances, it seems that

the PNH needs to be removed to stop the epileptogenic pro-

cess. At other times, the heterotopia appear to have an indolent

role and may not be involved in the epileptic network. The

results of our electrophysiological studies, however, provide

a definite role for the hippocampus and neocortex in the gen-

eration and propagation of seizures. When only few neigh-

bouring unilateral PNH are present, investigation by SEEG

may indicate a focal resection, with or without inclusion of the

PNH, and a good outcome may be expected. Bilateral multiple

or contiguous PNH are often associated with widespread epi-

leptogenesis, where classical surgical approaches are unlikely

to be effective. Stereotactic or endoluminal ablation of the

heterotopia with or without resection of the hippocampus and

neocortical structures may be considered. Experimental work

using animal models and human tissue from surgical resec-

tions, and analysis of the epileptogenic area with functional

methods such as diffusion studies, EEG–functional MRI and

magnetic resonance spectroscopy, should help clarify the

relationship existing between the heterotopia and allo- and

neocortex.

AcknowledgementsWe wish to thank Dr Maria Elisa Calcagnotto for her insight-

ful and helpful comments, and Drs Alan Guberman and

Cecile Cieuta-Whalti who referred two of the patients.

References

Barkovich AJ, Kjos BO. Gray matter heterotopia: MR characteristics and

correlation with developmental and neurologic manifestations. Radiology

1992; 182: 493–9.

Barkovich AJ, Kuzniecky RI. Gray matter heterotopia. Neurology 2000;

55: 1603–8.

Baraban SC, Wenzel HJ, Hochman DW, Schwartzkroin PA. Characterization

of heterotopic cell clusters in the hippocampus of rats exposed to

methylazoxymethanol in utero. Epilepsy Res 2000; 39: 87–102.

Bastos AC, Korah IP, Cendes F, Melanson D, Tampieri D, Peters T, et al.

Curvilinear reconstruction of 3D magnetic resonance imaging in

patients with partial epilepsy: a pilot study. Magn Reson Imaging 1995;

13: 1107–12.

Battaglia G, Arcelli P, Granata T, Selvaggio M, Andermann F, Dubeau F, et al.

Neuronal migration disorders and epilepsy: a morphological analysis

of three surgically treated patients. Epilepsy Res 1996; 26: 49–58.

Battaglia G, Granata T, Farina L, D’Incerti L, Franceschetti S, Avanzini G.

Periventricular nodular heterotopia: epileptogenic findings. Epilepsia 1997;

38: 1173–82.

Baulac M, De Grissac N, Hasboun D, Oppenheim C, Adam C, Arzimanoglou

A, et al. Hippocampal developmental changes in patients with partial

epilepsy: magnetic resonance imaging and clinical aspects. Ann Neurol

1998; 44: 223–33.

Bernasconi N, Bernasconi A, Caramanos Z, Antel SB, Andermann F,

Arnold DL. Mesial temporal damage in temporal lobe epilepsy: a

volumetric MRI study of the hippocampus, amygdala and parahippocampal

region. Brain 2003; 126: 462–9.

Calcagnotto ME, Paredes MF, Baraban SC. Heterotopic neurons with

altered inhibitory synaptic function in an animal model of

malformation-associated epilepsy. J Neurosci 2002; 22: 7596–605.

Castro PA, Cooper EC, Lowenstein DH, Baraban SC. Hippocampal hetero-

topia lack functional Kv4.2 potassium channels in the methylazoxy-

methanol model of cortical malformations and epilepsy. J Neurosci

2001; 21: 6626–34.

Cendes F, Li LM, Andermann F, Watson C, Fish DR, Shorvon SD, et al. Dual

pathology and its clinical relevance. Adv Neurol 1999; 81: 153–64.

Chen HX, Roper SN. Reduction of spontaneous inhibitory synaptic activity

in experimental heterotopic gray matter. J Neurophysiol 2003; 89: 150–8.

Chen ZF, Schottler F, Bertram E, Gall CM, Anzivino MJ, Lee KS.

Distribution and initiation of seizure activity in a rat brain with subcortical

band heterotopia. Epilepsia 2000; 41: 493–501.

Colacitti C, Sancini G, Franceschetti S, Cattabeni F, Avanzini G, Spreafico R,

et al. Altered connections between neocortical and heterotopic areas in

methylazoxymethanol-treated rat. Epilepsy Res 1998; 32: 49–62.

Cowan D, Geller LM. Long-term pathological effects of prenatal

X-irradiation on the central nervous system of the rat. J Neuropathol

Exp Neurol 1960; 19: 488–527.

Dalby NO, Mody I. The process of epileptogenesis: a pathophysiological

approach. Curr Opin Neurol 2001; 14: 187–92.

Dubeau F, Tampieri D, Lee N, Andermann E, Carpenter S, Leblanc R, et al.

Periventricular and subcortical nodular heterotopia. A study of 33 patients.

Brain 1995; 118: 1273–87.

Eksioglu YZ, Scheffer IE, Cardenas P, Knoll J, DiMario F, Ramsby G, et al.

Periventricular heterotopia: an X-linked dominant epilepsy locus causing

aberrant cerebral cortical development. Neuron 1996; 16: 77–87.

Francione S, Kahane P, Tassi L, Hoffmann D, Durisotti C, Pasquier B, et al.

Stereo-EEG of interictal and ictal electrical activity of histologically

proved heterotopic gray matter associated with partial epilepsy.

Electroencephalogr Clin Neurophysiol 1994; 90: 284–90.

Friede RL. Developmental neuropathology. 2nd edn. Berlin: Springer-Verlag;

1989.

Gardoni F, Pagliardini S, Setola V, Bassanini S, Cattabeni F, Battaglia G, et al.

The NMDA receptor complex is altered in an animal model of human

cerebral heterotopia. J Neuropathol Exp Neurol 2003; 62: 662–75.

Hannan AJ, Servotte S, Katsnelson A, Sisodiya S, Blakemore C, Squier M,

et al. Characterization of nodular neuronal heterotopia in children. Brain

1999; 122: 219–38.

Harding B, Copp AJ. Malformations. In: Graham DI, Lantos PL,

editors. Greenfield’s neuropathology. 6th edn. London: Arnold; 1997.

p. 397–533.

Kothare SV, VanLandingham K, Armon C, Luther JS, Friedman A,

Radtke RA. Seizure onset from periventricular nodular heterotopias:

depth-electrode study. Neurology 1998; 51: 1723–7.

Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, et al. Decreased

apoptosis in the brain and premature lethality in CPP32-deficient mice.

Nature 1996; 384: 368–72.

Lee KS, Schottler F, Collins JL, Lanzino G, Couture D, Rao A, et al. A genetic

animal model of human neocortical heterotopia associated with seizures.

J Neurosci 1997; 17: 6236–42.

Lehericy S, Dormont D, Semah F, Clemenceau S, Granat O, Marsault C, et al.

Developmental abnormalities of the medial temporal lobe in patients

with temporal lobe epilepsy. AJNR Am J Neuroradiol 1995; 16:

617–26.

Li LM, Dubeau F, Andermann F, Fish DR, Watson C, Cascino GD, et al.

Periventricular nodular heterotopia and intractable temporal lobe

epilepsy: poor outcome after temporal lobe resection. Ann Neurol 1997;

41: 662–8.

Mai R, Tassi L, Cossu M, Francione S, Lo Russo G, Garbelli R, et al. A

neuropathological, stereo-EEG, and MRI study of subcortical band

heterotopia. Neurology 2003; 60: 1834–8.


Dow



Morrell F, Whistler WW, Hoeppner TJ, Smith MC, Kanner AM, Pierre-Louis

C, et al. Electrophysiology of heterotopic gray matter in the double cortex

syndrome. Epilepsia 1992; 33 Suppl 3: 76.

Nagata Y, Matsumoto H. Studies on methylazoxymethanol: methylation

of nucleic acids in the fetal rat brain. Proc Soc Exp Biol Med 1969;

132: 383–5.

Pentney AR, Baraban SC, Colmers WF. NPY sensitivity and postsynaptic

properties of heterotopic neurons in the MAM model of malformation-

associated epilepsy. J Neurophysiol 2002; 88: 2745–54.

Preul MC, Leblanc R, Cendes F, Dubeau F, Reutens D, Spreafico R, Function

and organization in dysgenic cortex. Case report. J Neurosurg 1997; 87:

113–21.

Rakic P. Mechanisms of cortical development: a view from mutations in mice.

Annu Rev Neurosci 1978; 1: 297–326.

Rakic P. The cell in contact: adhesions and junctions as morphogenetic

determinant. In: Edelman G, Thiery J, editors. Contact regulation of

neuronal migration. New York: Neuroscience Research Foundation;

1985. p. 67–91.

Rakic P. Radial versus tangential migration of neuronal clones in

the developing cerebral cortex. Proc Natl Acad Sci USA 1995; 92:

11323–7.

Raymond AA, Fish DR, Stevens JM, Sisodiya SM, Alsanjari N, Shorvon SD.

Subependymal heterotopia: a distinct neuronal migration disorder

associated with epilepsy. J Neurol Neurosurg Psychiatry 1994;

57: 1195–202.

Salanova V, Markand O, Worth R. Temporal lobe epilepsy:

analysis of patients with dual pathology. Acta Neurol Scand 2004; 109:

126–31.

Sancini G, Franceschetti S, Battaglia G, Colacitti C, Di Luca M, Spreafico R,

et al. Dysplastic neocortex and subcortical heterotopias in

methylazoxymethanol-treated rats: an intracellular study of identified

pyramidal neurones. Neurosci Lett 1998; 246: 181–5.

Sarnat HB. Cerebral dysplasias as expressions of altered maturational

processes. Can J Neurol Sci 1991; 18: 196–204.

Schottler F, Couture D, Rao A, Kahn H, Lee KS. Subcortical connections

of normotopic and heterotopic neurons in sensory and motor cortices of

the tish mutant rat. J Comp Neurol 1998; 395: 29–42.

Sisodiya SM, Free SL, Thom M, Everitt AE, Fish DR, Shorvon SD. Evidence

for nodular epileptogenicity and gender differences in periventricular

nodular heterotopia. Neurology 1999; 52: 336–41.

Sisodiya SM, Free SL, Stevens JM, Fish DR, Shorvon SD. Widespread

cerebral structural changes in patients with cortical dysgenesis and

epilepsy. Brain 1995; 118: 1039–50.

Smith BN, Dudek FE, Roper SN. Synaptic responses of neurons in heterotopic

gray matter in an animal model of cortical dysgenesis. Dev Neurosci 1999;

21: 365–73.


Dow



The role of periventricular nodular heterotopia in ...

Documents

Transcript of The role of periventricular nodular heterotopia in ...