Early development destructive brain lesions and their relationship to epilepsy and hippocampal damage

Original article

Early development destructive brain lesions and their relationship to

epilepsy and hippocampal damage

Ricardo A. Teixeiraa, Li M. Lia, Sergio L.M. Santosb, Veronica A. Zanardib,Donizeti C. Honoratoa, Carlos A.M. Guerreiroa, Fernando Cendesa,*

aDepartment of Neurology, University of Campinas (UNICAMP), Campinas, SP, CEP 13083-970, BrazilbDepartment of Radiology, University of Campinas (UNICAMP), Campinas, SP, CEP 13083-970, Brazil

Received 7 August 2002; received in revised form 17 March 2003; accepted 19 March 2003

Abstract

Fifty-one consecutive adult patients with epilepsy and early development destructive brain lesions were divided into three main groups

according to the topographic distribution of the lesion on magnetic resonance imaging: hemispheric (H) ðn ¼ 9Þ; main arterial territory (AT)

ðn ¼ 25Þ and arterial borderzone (Bdz) ðn ¼ 17Þ. Eight (89%) patients from group H presented status epilepticus in the first 5 years of life,

five of them associated with fever. Seventeen of the 25 patients from group AT (76%) had an obvious hemiparesis observed early in life. In

addition, major prenatal events were significantly more common in the group AT compared with the other two groups. Among patients from

group Bdz, prenatal or postnatal events were not identified, except for one patient. Conversely, nine patients from group Bdz (60%) showed a

history of perinatal complications. Hippocampal atrophy (HA) was determined by visual analysis in 74.5% of all patients and by volumetry in

92%. The frequency of HA was comparable among groups, but patients from group H presented the most severe atrophy and more frequent

hyperintense T2 hippocampal signal. In conclusion, these three groups of patients with early destructive lesions and epilepsy (H, AT and

Bdz), appear to have distinct pathogenic mechanisms. Our data show that there is a striking association of HA with different patterns of

neocortical destructive lesions of early development. This association seems to be related to a common and synchronic pathogenic

mechanism. The recognition of the pattern and degree of HA among these patients with intractable seizures may influence the surgical

rationale.

q 2003 Elsevier B.V. All rights reserved.

Keywords: Epilepsy; Hippocampal atrophy; Hemiatrophy; Arterial borderzone; Infarct

1. Introduction

Destructive brain lesions of early development include a

wide variety of congenital, perinatal and postnatal acquired

neuropathological conditions that have in common tissue

necrosis of a previously normally formed brain, and

constitutes one of the most important causes of neurological

morbidity acquired in this period of development [1–3].

Different topographic and morphological patterns of

brain lesions are recognized depending on the nature of the

insult, its severity and the period of development in which it

occurs [4,5]. It has long been known that certain regions of

the brain are more vulnerable than others when the whole

brain is submitted to an insult (e.g. diffuse hypoperfusion,

status epilepticus) and this can be connoted by the term

regional selective vulnerability [6]. The hippocampus is

considered to be one of these vulnerable regions, a concept

very well supported by experimental and clinical data

[7–10].

Epilepsy is a common long-term sequel of those

precocious destructive lesions, often presenting with

intractable seizures [3]. The recognition of hippocampal

atrophy (HA) on the magnetic resonance imaging (MRI) of

Brain & Development 25 (2003) 560–570

www.elsevier.com/locate/braindev

0387-7604/03/$ - see front matter q 2003 Elsevier B.V. All rights reserved.

doi:10.1016/S0387-7604(03)00065-2

* Corresponding author. Fax: þ55-19-3289-3801.

E-mail address: [email protected] (F. Cendes).

Abbreviations: ACA, anterior cerebral artery; AI, asymmetry index;

AT, arterial territory; Bdz, arterial borderzone; EEG,

electroencephalogram; FSE, fast spin-echo; FOV, field of view; GRE,

gradient echo; H, hemispheric; HA, hippocampal atrophy; HS,

hippocampal sclerosis; HV, hippocampal volume; ICVC, intracranial

volume-control group; ICVI, intracranial volume-individual; IR, inversion

recovery; LH, left hippocampus; MCA, middle cerebral artery; MRI,

magnetic resonance imaging; PCA, posterior cerebral artery; RH, right

hippocampus; SE, status epilepticus; TE, time of echo; TI, time of

inversion; TR, time of repetition.

http://www.elsevier.com/locate/braindev

these patients may have major clinical and prognostic

relevance, but only a few studies have addressed this issue

[11–13]. The profile of the hippocampal damage in patients

with ‘pure’ hippocampal sclerosis (HS) has been well

studied but it is not clear among patients with associated

neocortical destructive lesions. This study was designed to

evaluate the frequency and pattern of HA on the MRI of

patients with different kinds of destructive brain lesions of

early development and correlate it with electroclinical data.

2. Patients and methods

We evaluated 51 consecutive adult patients (22 women),

followed in the Epilepsy Clinic of UNICAMP, with the

diagnosis of epilepsy secondary to a destructive brain lesion

of early development (mean age ¼ 31.8 years; range ¼ 15–

55 years) from March 1999 to April 2001. Informed consent

was obtained from all subjects. This study was approved by

the Ethics Committee of the School of Medical Sciences of

UNICAMP.

Detailed histories of prenatal, neonatal and early child-

hood events were systematically reviewed through the

medical records and direct interview with the parents. Data

were only considered significant when the mother had been

interviewed by one of us (R.A.T.). All patients had disease

onset before the fifth year of age. We excluded patients with

foreign tissue lesions detected on MRI as well as those with

history of major traumatic brain injury or with signs of

progressive disease. Seizures were classified according to the

Commission on Classification and Terminology of the

International League Against Epilepsy [14]. Seizure fre-

quency was classified into three groups: (1) daily, (2) weekly

or monthly and (3) controlled or rare seizures (,3 per year).

Previous electroencephalographic (EEG) data were

reviewed and all patients underwent serial routine EEG

studies using the 10–20 system with additional anterior

temporal and zygomatic electrodes.

MRI was performed in a 2.0 T scanner (Elscint Prestige,

Haifa, Israel). Our epilepsy protocol consists of: (a) sagittal

T1 spin-echo, 6 mm thick (TR ¼ 430, TE ¼ 12) for optimal

orientation of the subsequent images; (b) coronal T1

inversion recovery (IR), 3 mm thick (flip angle ¼ 2008;

TR ¼ 2700, TE ¼ 14, TI ¼ 840, matrix ¼ 130 £ 256,

FOV ¼ 16 £ 18 cm) (where FOV refers to field of view);

(c) coronal T2-weighted ‘fast spin-echo’ (FSE), 3–4 mm

thick (flip angle ¼ 1208, TR ¼ 4800, TE ¼ 129, matrix ¼

252 £ 320, FOV ¼ 18 £ 18 cm); (d) axial images parallel to

the long axis of the hippocampus; T1 gradient echo (GRE),

3 mm thick (flip angle ¼ 708, TR ¼ 200, TE ¼ 5, matrix ¼

180 £ 232, FOV ¼ 22 £ 22 cm); (e) axial T2 FSE, 4 mm

thick (flip angle ¼ 1208, TR ¼ 6800, TE ¼ 129, matrix ¼

252 £ 328, FOV ¼ 21 £ 23 cm); (f) volumetric (3D) T1

GRE, acquired in the sagittal plane for multiplanar

reconstruction, 1–1.5 mm thick (flip angle ¼ 358, TR ¼ 22,

TE ¼ 9, matrix ¼ 256 £ 220, FOV ¼ 23 £ 25 cm).

Visual analysis of MRI and multiplanar reconstruction

were systematically performed on a workstation (O2 Silicon

Graphic) using Omnipro software (Elscint Prestige, Haifa,

Israel). Curvilinear reconstruction of 3D volumetric images

was performed for all patients in a Power Macintosh using

the Brainsight software (Rogue Research, Montreal, Que-

bec, Canada). Curvilinear reconstruction was very helpful

for a clear visualization of the extent of cortical involvement

and assisted in the classification of the patients into three

different groups, according to the topographical distribution

of the lesion (Fig. 1): Hemispheric lesions (H) – patients in

this group had homogeneous atrophy of an entire hemi-

sphere without loss of tissue continuity; Arterial territory

lesions (AT) – this group had lesions limited to a main

arterial territory, constituted by cavitations or a localized

retraction of the cerebral tissue with an heterogeneous

appearance suggestive of a substantial gliotic scar; Arterial

borderzone lesions (Bdz) – these patients had lesions

consisting of atrophy between the main cerebral arterial

territories, with the aspect of ulegyria [15,16]. Eleven

patients showed more than one of these lesional patterns and

they were classified according to the most exuberant pattern.

We performed volumetric measurements of the hippo-

campi in all patients using 3 mm thick coronal IR images

with a semiautomatic software developed by the National

Institute of Health (NIH-image). Anatomic boundaries were

as described by a specific protocol [17]. Hippocampal

volumes (HV) were compared with a normal control group

consisting of 25 healthy volunteers. In order to check for

bilateral atrophy, HV were normalized to the individual

intracranial volume and mean intracranial volume of the

control group using the following formula: Corrected

HV ¼ HV £ ICVC=ICVI, where ICVC is the mean intra-

cranial volume of the control group and ICVI is the

individual intracranial volume. To determine the degree of

asymmetry between left and right normalized HV (LH, RH),

we used an asymmetry index (AI) defined by the following

formula: AI ¼ LH 2 RH=½ðLH þ RHÞ=2�. Values more than

2 standard deviations (SD) from the mean of normal

controls were considered abnormal.

In addition, to evaluate the volume distribution along the

major axis of the hippocampus, the mean hippocampal

cross-sectional areas of each group of patients were plotted

in a graph as a function of slice position. In the same graph,

we plotted the mean values of control group and lines

representing 2 SD below these values. The graphs were

analyzed qualitatively by visual assessment and comparison

between the ipsilateral and contralateral hippocampal

graphs. Patients with non-lateralized main destructive

lesions had their atrophic hippocampus assumed as the

‘ipsilateral hippocampus’. The profile of HA was classified

as diffuse or segmental.

We used the Pearson’s chi-square (x 2) or Fisher’s exact

tests for comparing proportions among groups. ANOVA test

and Tukey post hoc pairwise comparisons were applied for

comparison on continuous variables among the three

R.A. Teixeira et al. / Brain & Development 25 (2003) 560–570 561

groups. Pearson’s correlation coefficient (r) was used where

indicated. We considered the significance level of 0.05.

3. Results

Fifty-one patients were distributed as follows: Groups H,

AT and Bdz with 9, 25 and 17 patients, respectively. The

clinical and EEG findings are summarized in Table 1.

3.1. Clinical features

Direct interview with mothers was possible for 48

patients (94.1%). It is worth emphasizing that they could

recall and provide clear detailed histories concerning the

period of gestation and patients’ first years of life.

Among patients from group H, eight (89%) presented

status epilepticus (SE) in the first 5 years of life, five of them

associated with fever. In six patients the SE was the first

manifestation of their disease. Two patients presented SE

after experiencing uncomplicated seizures, one of them

since the neonatal period. The patient without the

antecedent of SE had the first symptoms at the age of 2

years with fever and conscience impairment for 2 days, so

that SE cannot be completely discarded in this case. SE was

by far more common in patients from group H (89%) than in

groups Bdz (6.6%) and AT (4%) (x 2, P , 0:001). All

patients who had SE experienced it only once and developed

Fig. 1. Curvilinear reconstruction of 3D T1-weighted and axial T2-weighted images illustrating the three groups. (A) Diffuse atrophy of the whole right

cerebral hemisphere without loss of tissue continuity. (B) Bilateral atrophy in the borderzone between the three main arterial territories with a left

predominance; a discrete left parasagittal atrophy can also be observed on the borderzone between the anterior cerebral artery and middle cerebral artery

(MCA) (white arrow). (C) Large cavity in the territory of the right MCA. R, right; L, left.

R.A. Teixeira et al. / Brain & Development 25 (2003) 560–570562

Table 1

Clinical and MRI features

Patient/Sex/Age (y) Group Early life events Lesion distribution on MRI S HT2 R HV L HV AI H HT2

1/M/41 H Age 2 y: fever þ conscience alteration for 2 days L Hem þ R Bdz (ACA–MCA) 2 24.5 26 6.0 þ

2/F/39 H Age 2 y: first sz (SE) þ fever þ motor deficit R Hem 2 27.6 21 22.5 þ

3/F/45 H Age 2 y: first sz (SE) R Hem 2 25.9 1.2 18.9 þ

4/M/17 11 Age 6 y: second sz (SE) þ motor deficit R Hem 2 26.8 21.5 17.5 þ

5/F/44 H Age 11 m: first sz (SE) þ exantema þ fever þ motor deficit R Hem þ 29.2 0.4 32.8 þ

6/M/40 H Neonatal sz. Age 6 y: (SE) R Hem þ 29.8 0 36.0 þ

7/F/48 H Age 11 m:first sz (SE) þ fever þ motor deficit R Hem þL Bdz (ACA–MCA) þ 211.7 23.8 50.0 NA

8/M/37 H Age 4 y: first sz (SE) þ fever þ motor deficit R Hem þ bilateral Bdz (ACA–MCA–PCA) þ 21.4 0.8 4.9 þ

9/F/34 H Age 2 y: first sz (SE) þ fever þ motor deficit R Hem þ 28.2 2.9 30.8 þ

10/M/17 Bdz Premature labor Bilateral (ACA–MCA–PCA) þ 21.4 0.1 3.3 2

11/M/19 Bdz Premature labor, fetal distress Bilateral . L (ACA–MCA) þ 20.3 21.8 3.8 þ

12/F/31 Bdz None Bilateral . R (ACA–MCA) þ 22 2.1 8.8 þ

13/M/51 Bdz None R MCA–PCA 2 20.7 22.5 4.4 þ

14/M/21 Bdz Fetal distress Bilateral (ACA–MCA–PCA) þ L trigone leucomalacia 2 0 22.7 6.6 2

15/M/53 Bdz NA Bilateral . L (ACA–MCA) 2 22.1 24.2 6.1 þ

16/M/21 Bdz Fetal distress Bilateral (ACA–MCA–PCA) þ 22.9 21.1 4.5 þ

17/F/39 Bdz Age 1 y 6 m: first sz (SE) þ fever Bilateral (ACA–MCA) 2 0.4 23.8 10.4 þ

18/F/27 Bdz Prolonged rupture of membranes Bilateral . L (ACA–MCA–PCA) þ 0.1 22.6 6.5 þ

19/F/36 Bdz Fetal distress Bilateral . L (ACA–MCA–PCA) þ 20.8 24.5 10.3 þ

20/M/36 Bdz Fetal distress Bilateral (ACA–MCA–PCA) þ 23.1 21.9 3.4 2

21/F/38 Bdz None L ACA–MCA 2 1.6 26.4 21.4 2

22/F/55 Bdz NA Bilateral (ACA–MCA–PCA) 2 1.5 0.6 1.9 2

23/M/20 Bdz Fetal distress Bilateral (ACA–MCA–PCA) þ L MCA clastic lesion þ 22 21.4 1.4 2

24/F/23 Bdz Fetal distress Bilateral . L (ACA–MCA–PCA) þ 0.8 21.4 4.8 þ

25/F/38 Bdz Chronic premature labor, fetal distress Bilateral . L (ACA–MCA–PCA) þ L MCA clastic lesion þ 0.3 22.3 6.1 þ

26/F/40 Bdz Umbilical cord kinking Bilateral . R (ACA–MCA–PCA) þ 25.9 0.4 17.4 þ

27/M/39 AT Age 5 m: first sz (Lhemiconvulsion) þ fever þ motor deficit R MCA (perisylvian) þ 26.9 21.6 18.0 þ

28/M/26 AT None R MCA (perisylvian) þ 0.2 1.5 2.7 þ

29/M/28 AT None L MCA (perisylvian) þ 0.9 23.3 10.0 2

30/M/34 AT Age 6 y: first sz (SE) L MCA (perisylvian) þ 20.9 21.2 0.9 2

31/M/44 AT NA R MCA (perisylvian) þ 23.9 22.4 4.2 2

32/M/20 AT None L MCA (perisylvian) þ 1 20.8 4.0 2

33/F/22 AT None L MCA (perisylvian) þ NA NA NA þ

34/F/27 AT Placental abruption, fetal distress L temporo-occipital þ 20.7 22.1 3.5 þ

35/M/36 AT None L parietal 2 22.4 22.6 0.4 2

36/M/33 AT None R parietal þ 22.1 21.8 0.7 2

37/M/25 AT None R MCA (whole territory) þ L Bdz (ACA–MCA) þ 25 1 15.3 þ

38/M/37 AT Abortion attempt L MCA (whole territory) þ R Bdz (ACA–MCA) 2 21.1 22.4 3.4 þ

39/F/26 AT Repetitive traumas during pregnancy L MCA (whole territory) þ 3.8 23.6 15.6 þ

40/F/50 AT None L MCA (whole territory) 2 24.7 25.9 4.7 þ

41/M/15 AT Fetal distress, falciform anemy R MCA (whole territory) þ bilateral Bdz (ACA–MCA–PCA) þ 24.3 4.8 19.0 þ

42/M/36 AT Fetal distress R MCA (whole territory) þ central bilateral þ 26.1 1 19.4 þ

43/M/28 AT Twin gestation LMCA (whole territory) 2 21.3 23.2 5.0 þ

44/M/27 AT Vaginal bleeding during pregnancy R MCA (whole territory) þ 26 20.8 15.6 þ

(continued on next page)

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a permanent motor deficit, clinically matching the diagnosis

of Hemiconvulsion–Hemiplegia–Epilepsy syndrome [18].

Patients from group AT exhibited quite a different

history. Seventeen of the 25 patients (76%) had an obvious

hemiparesis associated with hemiatrophy, which was

noticed by the parents within the first 2 years of life in all

of them. None of these 17 patients had any evidence of

postnatal events that could be related to the deficit (except

for patient 27 who had a complex febrile convulsion at the

age of 5 months followed by hemiparesis). Five patients

(20%) presented a discrete hemiparesis that was identified

by a neurologist in early childhood (for patient 31 we do not

have this information). Visual field deficits were identified

in five patients (20%). In addition, major prenatal events

such as abortion attempt and severe maternal trauma were

observed in six patients (25%) of group AT and in none from

the other groups, reaching statistical significance (Fisher’s

exact test, P ¼ 0:036).

Among patients from group Bdz, prenatal or postnatal

events were not identified, except for patient 17 who had the

antecedent of SE at the age of 18 months. Conversely, nine

patients (60%) showed a history of perinatal complications,

referred by the mother as fetal distress and neonatal

respiratory problems culminating with delay in hospital

discharge. This antecedent was significantly more frequent

in this group than in group H (11%) and group AT (33.3%)

(x 2, P ¼ 0:043). Four patients exhibited an evident motor

deficit that was detected by the parents in the first 2 years of

life without any postnatal potential precipitating insult. Two

other patients presented a severe visual acuity deficit and

another one had a visual hemifield deficit.

Duration of epilepsy was similar among groups

(ANOVA, P ¼ 0:14) and so was seizure frequency (x 2,

P ¼ 0:82). Epileptiform activity was present in routine

EEGs of 38 patients (74.5%); 26 patients (51%) showed

epileptiform activity restricted to the temporal region while

in eight other patients (15%) it was more widespread but

also involving temporal regions.

3.2. MRI studies

The MRI findings are summarized in Table 1.

Patients from group H revealed a uniform pattern of

atrophy involving the entire cerebral hemisphere. Five

patients (55%) showed a diffuse enhanced subcortical T2

signal in the affected hemisphere, and these were the

patients with the most severe hemiatrophy.

Fourteen patients from group Bdz (82%) exhibited

bilateral lesions, and in nine of them they were asymmetric.

Associated hyperintense T2 signal was present in 11

patients (65%), and it was more diffuse among patients

with the most extensive lesions. In 12 patients (70%), the

lesion was posteriorly distributed on the watershed between

the three main arteries. Five patients had their lesions more

anteriorly, on the watershed between the anterior cerebral

artery (ACA) and middle cerebral artery (MCA).Tab

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Nineteen patients from group AT (76%) presented lesions

on the territory of the MCA, four on the posterior cerebral

artery (PCA) and two on the ACA. Twenty patients (80%)

exhibited hyperintense T2 signal extending beyond the area

of the lesion. Five patients did not exhibit hyperintense T2

signal associated with the lesion, and all these lesions were

of cystic aspect. Other patients with cystic lesions showed

associated enhanced T2 signal, but more discrete when

compared with the patients with non-cystic lesions (Fig. 2).

Thirty-eight patients presented HA (74.5%) on visual

analysis of MRI (Fig. 3). Volumetric study showed HA in 47

patients (92%). All patients from group H, 16/17 (94%) of

group Bdz and 22/25 (88%) of group AT had abnormal

hippocampal volumes with a similar frequency distribution

(x 2, P ¼ 0:48). Moreover, in two patients (patients 7 and

15) who had a visual diagnosis of unilateral HA, the

volumetric study revealed bilateral HA. The HA was

unilateral in 41 patients and it was concordant with the

side of the main lesion, except in two (patients 13 and 46).

The HA was bilateral in six patients and it was more severely

ipsilateral to the main lesion in all six. Hippocampal

hyperintense T2 signal was more frequent among patients

from group H (100%) than from groups AT (54%) and Bdz

(65%) (x 2, P ¼ 0:01). In addition, presence of hyperintense

T2 signal was associated with the severity of atrophy of the

ipsilateral hippocampus (ANOVA, P ¼ 0:023), but not to

the contralateral hippocampus (ANOVA, P ¼ 0:85).

The three groups failed to show any difference in the

frequency distribution of unilateral (x 2, P ¼ 0:53) or

bilateral (x 2, P ¼ 0:48) HA. ANOVA demonstrated that

the normalized mean volume of the hippocampus ipsilateral

to the main lesion was different among the groups

(ANOVA, P , 0:001) and pairwise post hoc comparisons

showed that group H had smaller hippocampal volumes than

groups Bdz and AT. Contralateral normalized hippocampal

volume was not different among the groups (ANOVA,

P ¼ 0:82).

All patients from group H had temporal lobe atrophy

(visually assessed) associated with the HA. In 18 of 22 patients

(82%) of group AT with HA, the atrophy also involved

the temporal lobe. In contrast, only five of 16 patients (31%)

of group Bdz with HA had temporal lobe atrophy, and it

was different from the other two groups (x 2, P ¼ 0:001).

The graphs with the distribution of the hippocampal

cross-sectional areas of the different groups showed some

interesting features. The three groups presented a diffuse

volume loss of the ipsilateral hippocampus but it was

unequivocally more pronounced on the anterior sections.

The long axis of the ipsilateral hippocampus in group H was

shortened in three slices (9 mm) compared with the other

groups (Fig. 4). The patients without HA presented normal

graphs individually.

3.3. Correlation of MRI, clinical, and EEG data

Epilepsy duration was weakly correlated to the volume

of the hippocampus ipsilateral to the main lesion

(r ¼ 20:29, P ¼ 0:046) but no correlation was found with

the contralateral hippocampus (r ¼ 20:23, P ¼ 0:115). In

contrast, hippocampal volumes were not significantly

different among patients with rare seizures, patients with

weekly or monthly seizures and those with daily seizures

ðP . 0:4Þ. History of SE, in turn, was strongly associated

with the severity of the hippocampal volume loss ipsilat-

erally to the main lesion (ANOVA, P , 0:001) but not

contralateral (ANOVA, P ¼ 0:78).

3.4. Surgical results

Nine patients (one H, one Bdz, seven AT), all with HA,

were submitted to a standard anterior temporal lobe removal

including the amygdala and anterior portion of the

hippocampus for control of refractory seizures. This

approach was proposed to the patients as a first step of an

escalated strategy where other interventions could become

necessary. Those patients were selected on the basis that

they presented electroclinical data indicating that the

affected temporal region was the most epileptogenic, and

that a limited temporal resection could have an impact on

seizure control.

Five patients achieved good seizure control with the

temporal resection after a follow-up of at least 12 months. In

two of them (patients 48 and 49), pre-operative MRI

revealed an old infarct lesion with cystic aspect in the PCA

territory (Engel’s classes I and II [19]); one (patient 39) had

an old infarct lesion in the whole territory of the MCA with

a cystic appearance (Engel’s class II); one (patient 3) had

hemiatrophy without hyperintense T2 signal (Engel’s class

II), and the remaining patient (patient 27) had a small non-

cavitated infarct on the MCA territory (Engel’s class I).

The temporal resection was not successful in three

individuals (patients 32, 33 and 44). They presented infarcts

in the MCA territory with a diffuse enhanced T2 signal

extending beyond the area of the lesion. They had

hemiplegia prior to surgery, with neither fine finger

movements nor foot tapping and underwent reoperation

Fig. 2. Coronal fast spin-echo T2-weighted images showing different

degrees of subcortical enhanced signal. Left: Patient 9. Right hemiatrophy

associated with a diffuse subcortical enhanced signal. Right: Patient 49.

Cystic lesion in the territory of the PCA, contiguous to the lateral ventricle.

A discrete area of hyperintense T2 signal can be identified adjacent to the

lesion (arrow). R, right; L, left.


with extension of the initial resection guided by electro-

corticography. After this second procedure, their complex

partial seizures were controlled but the other seizure types

remained unchanged. Patient 44 persisted only with a

monthly discrete sensitive experience over the jaw region

after a follow-up of 20 months (Engel’s class I). A

functional hemispherectomy was performed in patients 32

and 33, and both are seizure-free after a period of 9 and 30

months, respectively.

The ninth patient who underwent surgery (patient 24)

had a bilateral arterial borderzone lesion associated with left

HA and an enhanced T2 signal extending beyond the lesion.

Before surgery, this patient presented daily complex partial

seizures and ictal and interictal EEG activity well localized

over the left temporal region. After surgery, the patient

continued to present monthly seizures (right hemiconvul-

sion) and is now being reevaluated for possible

reintervention.

Fig. 3. Coronal IR T1-weighted images showing unilateral HA (arrows) in patients of the three different groups studied: hemispheric (left), arterial territory

(center) and arterial borderzone on the right (the borderzone lesion is not shown). R, right; L, left.

Fig. 4. Graphs of the hippocampal cross-sectional areas as a function of slice position. Three lines are shown on each plot: (1) the mean of the control group

(broken line); (2) 2 SD below the mean of the control group (dotted line); (3) the mean of the group of interest (continuous line). The unity shown in the Y axis

(0–200) represents the cross-sectional area of each hippocampal slice in mm2. The contralateral hippocampal graphs (not shown here) were very similar to the

graphs of the control group. The three patient groups presented a diffuse hippocampal volume loss ipsilaterally to the main lesion, more pronounced on the

anterior sections. Group H (hemispheric) showed lower ipsilateral hippocampal values and a shortening of its long axis not observed in the other groups,

reflecting a more severe insult rather than a higher frequency of HA in this group.


Enhanced diffuse T2 signal was absent in the five patients

who achieved good seizure control (Engel’s classes I and II)

after temporal resection, and present in all three patients

with poor seizure control (x 2, P ¼ 0:003).

4. Discussion

HS is one of the most frequent neuropathological

substrates associated with epilepsy and is characterized by

hippocampal cell loss and reorganization of the dentate

gyrus [8]. HA on MRI, frequently associated with

hyperintense T2 signal, has been shown to correlate with

HS and to the degree of hippocampal cell loss [8,20–22].

Identification of HA in patients with lesional epilepsies is

important for surgical treatment planning and for prognosis

of postoperative seizure outcome [13,20–22].

The etiology of HS is still a matter of controversy and it

is now assumed that it can be the end result of different

pathogenetic conditions [23,24]. In the present series, all

patients had destructive neocortical brain lesions acquired in

early life and the division into three groups was made on the

basis of the topographical distribution of these lesions.

However, we observed that the natural histories within each

group were also distinct, tending to reflect three different

kinds of insults known to be potential causes of HS.

Most of the patients with cerebral hemiatrophy presented

the SE antecedent in the first years of life. SE is consistently

associated with neuronal necrosis in vulnerable regions of

the brain, as proven by neuropathological studies in humans

and experimental studies in animal models [25–30]. Brain

damage primarily affects the hippocampus (hilus and CA1

and CA3 segments), amygdala, piriform cortex and to a

lesser extent the cerebellar cortex, thalamus and cerebral

cortex [25–28]. It has been well documented that the same

neuropathological patterns can be strictly unilateral when

the SE is lateralized [29,30].

Arterial borderzone lesions were significantly associated

with perinatal complications. There is large clinical and

experimental evidence that perinatal hypoxic–ischemic

insults are strongly related to this pattern of lesion [31,

32]. The end fields of the major cerebral arteries are

expected to be the first regions to experience perfusional

insufficiency after a drop in systemic blood pressure. The

classical borderzone lesion is a bilateral wedge-shaped

infarct at the parasagittal high convexity, between the

territories of the anterior and middle cerebral arteries.

However, the parieto-occipital region is more commonly

involved and it lays at the junction of the territorial

borderzones of the three major arteries; although the lesions

are usually bilateral they can be fairly asymmetric or

unilateral [3,33]. The hippocampus itself is also considered

to be in a watershed region (between the PCA and the MCA)

[34–36]. Experimental studies with primates demonstrated

hippocampal damage commonly associated with arterial

borderzone lesions after hypotension or hypoxia, but there

are many instances where the hippocampi are spared [37,

38]. This inconsistency may reflect different vulnerabilities

of the hippocampi and the parasagittal region to different

insults.

Patients with lesions on a main arterial territory had

histories of risk factors, indicating that the lesions were

presumably of prenatal or perinatal origin. Perinatal

complications, such as prolonged delivery and fetal distress,

were not uncommon among these patients but it is well

known that they can be just a consequence of a prenatal

insult [39]. The arterial supply of the hippocampus is made

by the anterior choroidal artery (MCA branch) and by the

trunk of PCA or its branches with certain variability [40,41].

Thus, insults that lead to damage in the MCA or PCA

territory can also involve the hippocampus. These insults

can represent arterial obstruction, but in the context of an

abnormal or immature anastomotic supply, a systemic

circulatory failure can also lead to localized damage in the

territory of individual arteries [38,42].

There is evidence that the formation of a brain glial scar

in response to a destructive insult is very discrete before the

30th week of gestation, and that insults before this period

usually produce cystic lesions [3,5,43]. Hyperintense T2

signal (suggestive of gliosis) over and around the main

lesion was commonly identified among patients of the three

groups studied. Among patients with lesions in arterial

territories, only patients with cystic lesions did not exhibit

hyperintense T2 signals. However, there were also patients

with cystic lesions who presented hyperintense T2 signal

adjacent to the limits of the cavity, confirming that gliosis

can coexist with cystic lesions of early development.

Pathological studies in humans and animals show that

besides the cavity (which is the result of a complete infarct),

there are neighboring areas in which astroglia survive and

most neurons are selectively destroyed, constituting an

‘incomplete infarct’ [44,45]. Thus, the hyperintense T2

signal discussed earlier could represent areas of incomplete

infarcts, and its extension can be related not only to the time

the lesion occurred but also to the nature and severity of the

insult, as well as the efficiency of the collateral circulation

[4,46]. The relevance of the severity of the insult is well

illustrated in this series by the patients with hemiatrophy

and borderzone lesions, as we observed that the hyper-

intense T2 signal was more evident among patients with the

most severe lesions. This is in agreement with pathological

observations which demonstrated that reactive gliosis is

greater in patients with more severe atrophy [47].

We identified a striking high frequency of HA among the

three groups studied. This coexistence of HA with

extrahippocampal lesions has been referred to as dual

pathology [11,48]. Previous studies have shown that this

association occurs in 5–30% of patients with refractory

epilepsy and that the degree of HA was not affected by the

duration or severity of seizures [11,48]. This suggests that a

common pathogenic mechanism may cause concomitant

HA and extrahippocampal lesions in these patients.


However, studies in animals and in humans have shown that

repetitive seizures can produce pathological and MRI

features of HS [49,50]. Our results suggest that habitual

repetitive seizures (excluding, of course, SE) may have only

a minor role in the progression of HA in these patients, since

severity of HA showed a weak correlation with duration of

epilepsy.

The nature of the extrahippocampal lesion is related to

the frequency of associated HA [12,51,52]. An earlier MRI

volumetric study found that HA was more common in

patients with cortical dysplasias (25%), porencephalic

(31%) and gliotic lesions (23.5%) than in those with tumors

or vascular malformations (2 and 9%) [11,51]. Compared

with the patients in this previous work with destructive

lesions (porencephalic and gliotic lesions), the present series

showed a much higher frequency of HA, probably reflecting

different patient selections. Ho et al. [52] identified HA in

95% of their series of patients with congenital porence-

phaly, a result similar to ours. Thus, HA seems to be much

more associated with large destructive lesions than to other

types of lesions. It is worth emphasizing that all these

studies, including the present one, analyzed highly selected

patients from epilepsy surgery programs, and this can

account for the high frequency of HA.

Most of the patients analyzed by us (particularly

from groups H and AT) had the HA ‘contiguous’ to the

neocortical lesion and one could even suggest that the term

single pathology seems more adequate. However, the

hippocampus and neocortex are anatomically separated

areas and also have distinct embryological origins. More-

over, a good surgical result after temporal resection in some

of these patients indicates that the lesions have at least

different epileptogenic roles. The term dual pathology was

coined and disseminated in the epilepsy literature to denote

that two distinct potential epileptogenic lesions are present

in the same patient. It does not have the connotation that the

two lesions have neuropathologic substrates of distinct

natures, neither does it imply that the lesions occurred at

different times. Thus, we consider the term dual pathology

appropriate in these cases.

The frequency of HA was comparable among the groups,

but patients from group H presented the most severe

hippocampal volume loss, with a shortening of its long axis

and also exhibited T2 hyperintense signal in the atrophic

hippocampus more frequently. This suggests that the

hippocampi of patients from group H were submitted to a

more caustic insult than the ones from groups AT and Bdz.

The antecedent of SE, most commonly identified among

patients from group H, seems to play a major role on the

severity of HA. This is supported by studies of ‘pure’ HA, in

which patients with the antecedent of prolonged febrile

convulsions had smaller hippocampal volumes and more

hippocampal neuron losses than those without [53–55].

Earlier studies have addressed the question of hippo-

campal volume loss along its major axis in patients with

‘pure’ HA. Some studies showed that diffuse atrophy is

the most common pattern identified and that segmental

anterior atrophy is also identified but less frequently

[56–59]. However, other studies found that the majority

of patients had segmental anterior atrophy [60,61]. In the

present series, the HA in the three groups was diffuse but

relatively more severe in the anterior segment. This is in

keeping with pathological studies of HS that show a diffuse

but greater neuronal loss in the anterior segment of

hippocampus [62,63]. The diagnostic sensitivity for HA in

our series was not increased by segmental volumetric

analysis of hippocampus.

The high frequency of interictal epileptiform activity

over the temporal lobe and the striking frequency of

associated HA suggest that the hippocampus can play an

important role in seizure generation in these patients.

Few studies have addressed the problem of surgical

approach for patients with dual pathology. Cascino et al.

[64] reported three patients with temporal lesions (two

with vascular malformation and one with a ganglioglioma)

who achieved seizure control only after a second operation

in which the atrophic hippocampus was removed. Li et al.

[21] compared the results between lesionectomy, resection

of the atrophic hippocampus and the combination of both

procedures in patients with diverse pathologies. Although

the sample was too small, this study [21] suggested that

the combination of the two procedures offers the best

seizure control. The same authors expanded the number of

patients in a second report and confirmed their first

impressions that resection of both lesions should be

considered whenever possible [13]. In selected cases,

however, the removal of the atrophic hippocampus can be

sufficient to achieve seizure control as demonstrated by Ho

et al. [52] and by our study.

All patients operated in the present series exhibited

extensive hemispheric lesions and the HA was presumably

the most epileptogenic lesion, according to electroclinical

data. Resection of the extrahippocampal lesion in these

cases meant hemispherectomy or multilobar resection. In

order to avoid the risks and new deficits potentially

associated with such procedures, we proposed a standard

temporal resection as a first step of an escalated approach.

We could observe that patients with diffuse enhanced T2

signal tended to present poor outcomes after temporal

resection and achieved seizure control only after resection

of the extrahippocampal lesion. These results, albeit

preliminary, led us to begin considering the possibility of

resection of both the atrophied hippocampus and the

extrahippocampal lesion in a single step whenever there

are signs of diffuse gliosis, even if the HA seems to be the

most epileptogenic lesion. The extent of the resection must

naturally be dictated by clinical-EEG findings and the

principle of avoidance of new neurological deficits. On the

other hand, we are encouraged to propose a standard temporal

resection to patients with electroclinical localization over

the temporal lobe and lesions without diffuse gliotic signs,

especially for those with cystic lesions.


In conclusion, our data show that there is a striking

frequency of HA associated with different patterns of

neocortical destructive lesions of early development. This

association seems to be related to a common and synchronic

pathogenic mechanism. The recognition of HA among these

patients is of major importance since it can influence the

surgical rationale in those who present intractable seizures.

Acknowledgements

R.A.T. was supported by a grant from FAPESP

(# 98/13101-8).

The authors are grateful to Dr Susana Mori, Eliane

Kobayashi, Tania Cardoso and Alberto Costa, who assisted

in the management of these patients and to Marcelo

Brunnini, Pablo Rios and Fabricio Ramos for their technical

support.

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