ARTICLE
Auteur(s) : Laura Tassi1, Alessandra
Meroni2, Francesco Deleo2, Flavio
Villani2, Roberto Mai1, Giorgio Lo
Russo1, Nadia Colombo3, Giuliano
Avanzini2, Chiara Falcone4, Manuela
Bramerio5, Alberto Citterio3, Rita
Garbelli2, Roberto
Spreafico2
1Epilepsy Surgery Centre “C. Munari”
2Division of Epilepsy Clinic and Experimental
Neurophysiology, I.R.C.C.S. Foundation Neurological Institute “C.
Besta”
3Department of Neuroradiology, Niguarda
Hospital
4Epidemiology Unit, I.R.C.C.S. Foundation Neurological
Institute “C. Besta”
5Department of Pathology, Niguarda Hospital, Milan,
Italy
Article reçu le 25 Juin 2009, accepté le 22 Septembre 2009
Temporal lobe epilepsy (TLE) is the most common form of focal
epilepsy. In surgical series of patients with drug-resistant
epilepsy, 60-75% of cases are reported to have TLE (Blümcke
et al., 2002; Lahl et al., 2003).
Since the work of Falconer et al. (1964) and Margerison and
Corsellis (1966), hippocampal sclerosis (HS) has been recognized as
a common pathological finding in TLE surgical series. More recent
MRI techniques, such as hippocampal volumetry and
T2 relaxometry, which are able to reliably diagnose HS in vivo
(Bernasconi et al., 2000) have reinforced the idea that the
hippocampus plays a leading role in the genesis of seizures in
patients with drug-refractory TLE. However, pathological studies
show that lesions correlated with TLE may be found well beyond the
hippocampal formation (Margerison and Corsellis, 1966) and
conventional MRI often identifies developmental or vascular
malformations and tumours within the temporal lobe in TLE patients,
which may or may not be associated with HS (Kuzniecky et al.,
1999; Raymond et al., 1994; Lee et al., 1998). More
recently, post-processing MRI techniques, in particular
quantitative volumetric analysis, have identified extrahippocampal
abnormalities such as temporal lobe volume loss and entorhinal
cortex atrophy in TLE patients (Moran et al., 2001; Bernasconi
et al., 2005) suggesting that TLE may depend on either a more
widespread temporal lobe disturbance or is the result of so-called
dual pathology, i.e. HS with alterations in neocortical temporal
structures (Falconer et al., 1964; Lèvesque et al., 1991;
Li et al., 1999).
Evidence that neocortical structures, particularly the temporal
pole, can be involved in the genesis of TLE has been presented by
several other studies dating back to the late 1980s (Kuzniecky
et al., 1987; Kahane et al., 2002; Coste et al.,
2002). Studies that examined the electroclinical features in
patients with TLE (Burgerman et al., 1995; Chabardès
et al., 2005) suggest a pivotal role of the temporo-polar
cortex in many cases, while MRI (Moran et al., 2001),
neuropathological (Mitchell et al., 1999) and metabolic
(Ryvlin et al., 1998) abnormalities have also been identified
in the temporal pole, associated or not with HS. However, there is
no consensus regarding the genesis of neocortical abnormalities,
although gliosis (Falconer et al., 1964), developmental
cortical abnormalities (Hardiman et al., 1988; Thom
et al., 2001), loss of myelin (Meiners et al., 1999) and
non-specific increase in temporal lobe water content (Mitchell
et al., 1999; Concha et al., 2009) have all been
suggested to play a role.
Dual pathology is estimated to occur in 5-30% of TLE cases. The
most common second alteration is a malformation of cortical
development (MCD), most often focal cortical dysplasia (FCD)
(Raymond et al., 1994; Cendes et al., 1995; Lèvesque
et al., 1991; Li et al., 1999). Since an optimal outcome
is obtained when both the HS and FCD are removed (Li et al.,
1999; Salanova et al., 2004; Chabardès et al., 2005) it
seems evident that both contribute to seizure genesis.
Retrospective studies have repeatedly found that a large number
of patients undergoing surgery for intractable TLE have both HS and
a history of febrile seizures (FS) as infants (French et al.,
1993), suggesting that FS may cause injury to mesial temporal
structures causing HS with subsequent development of TLE (Mathern
et al., 1995; VanLandingham et al., 1998). It has also
been suggested that congenital neocortical or hippocampal
abnormalities may render the temporal lobe particularly vulnerable
to prolonged infantile FS and hence TLE (Annegers et al.,
1987; VanLandingham et al., 1998; Blümcke et al., 2002).
In this regard it is noteworthy that induced neuron migration
defects in rat pups result in greater susceptibility to seizures
and greater irreversible hippocampal neuron damage following
hyperthermia than those controls with no neuron migration defects
(Germano et al., 1996). Despite the fact that an association
between dysgenesis and subsequent increase of susceptibility to
hyperthermic seizures and neuronal injury has been documented in
animals, a similar relationship has not been demonstrated in humans
(Lewis, 2005). However, recent MRI and neuropathological data also
provide evidence of a correlation between HS and duration of
epilepsy (Fuerst et al., 2001; Bernasconi et al.,
2005).
The aims of the present retrospective study, performed through
reviewing the neuropathological, MRI and clinical records of
243 patients who received temporal lobe resection for
intractable seizures were to determine: (a) the frequency of
different types of lesion within the temporal lobe, (b) the
frequency of HS isolated or associated with neocortical lesions
(dual pathology), (c) the frequency of risk factors and (d)
surgical outcomes in relation to neuropathological findings.
Methods
Patient selection
Drug resistant epileptic patients were referred to the “C. Munari”
Epilepsy Surgery Centre from different epilepsy units all over
Italy. Eligibility of patients for epilepsy surgery was made only
after a comprehensive discussion among the referring neurologist,
the epileptologists, neurosurgeons and neuroradiologists of the
epilepsy surgery centre. Drug resistance was defined according to
the criteria proposed by Perucca (1998).
Neuropathological data on 291 patients out of
506 operated on between May 1996 and May 2005, with
resection confined to the temporal lobe, were retrospectively
revaluated. Only 243 patients, with surgical specimens
sufficiently preserved to allow a precise evaluation of both
lateral neocortex (including white matter) and hippocampus, were
considered in the present report. The neuropathological data were
classified and related to clinical and MRI findings and
post-surgical outcome.
All patients underwent extensive pre-surgical evaluation
including detailed history with questions about family history of
epilepsy, spontaneous abortions, infections, head trauma, FS and
risk factors for pre- or perinatal brain damage. For these data the
clinical records of each patient were accurately assessed and only
precise descriptions of the pathological events were taken into
account, particularly for FS; when the source of the information
and the description of anamnestic data were not reliable the event
was not considered. Age at seizure onset, mode of presentation,
seizure characteristics and frequency and antiepileptic treatments
up to the time of surgery were also recorded. All patients received
neurological examination, complete neuropsychological work up, MRI
and comprehensive EEG or video-EEG (VEEG) examinations (or both).
When the electroclinical data and MRI findings did not identify the
epileptogenic zone with sufficient precision, invasive pre-surgical
Stereo-EEG (SEEG) was performed to achieve the required accuracy
(Cossu et al., 2005). The description of neuropsychological
and electrophysiological data are beyond the scope of the present
paper and thus have not been presented.
MRI
Preoperative MR imaging was obtained using a 1.5 T machine
(Philips ACS-III-NT) in all patients. The MR protocol (Colombo
et al., 2003) included the following sequences: transverse
spin-echo (SE) double echo images of the entire brain
(2,000-2,500/20-90) [TR msec/TE msec], 1 avg, 128 x
256 matrix, 230 FOV; 4-5 mm thickness; coronal turbo
spin-echo (TSE) TW2 images (2,300/100) [TR msec/TE msec],
4 avgs, 256 x 256 matrix, 230 mm FOV,
3 mm thickness; coronal TSE fluid-attenuated
inversion-recovery (FLAIR) T2W sequence (6,000/100/2,000) [TR
msec/TE msec/inversion time msec], 3 avgs,
238 x 256 matrix, 230 mm FOV, 3 mm
thickness; coronal TSE inversion recovery (IR) T1W images
(3,000/20/400) [TR msec/TE msec/inversion time msec], 3 avgs,
256 x 256 matrix, 230 mm FOV, 3 mm
thickness.
Images, both parallel (transverse) and perpendicular (coronal)
to the major hippocampal axis were acquired. Intravenous contrast
was injected when necessary.
Mass lesions, gyration anomalies, focal thickening of the
cortex, blurring of the grey-white matter junction, areas of
abnormal signal intensity in the cortex and white matter, atrophic
changes and vessel anomalies were all assessed.
Hippocampal alterations were assessed visually with attention to
atrophy, increased signal on TSE-T2W and TSE-FLAIR-T2W images,
decreased signal in TSE-IR-T1W images and loss of definition of the
internal structures.
Surgery and follow-up
Resections were performed for strictly therapeutic reasons after
informed consent. Both the anatomic lesion (where identified) and
the cortical epileptogenic zone, as identified by electroclinical
and MRI examinations, were removed. When MRI was unrevealing, the
resection was planned using electroclinical data. The extent of
resection was planned pre-operatively, in each case considering the
severity of epilepsy and risk of post-surgical deficits. In
42 (17%) patients the surgery was performed after invasive
SEEG. No patient received selective amigdalo-hippocampectomy.
Seizure freedom was monitored periodically and determined
according to Engel’s classification (Engel et al., 1993), with
at least two years of follow-up, in all the recruited patients.
Withdrawal of anti-epileptic drugs (AEDs) was performed only after
24 months of seizure freedom in patients in class I. The
reported data regarding follow-up and anti-epileptic medication
status were compiled through office visits or telephone contact
during the first half of 2008.
Histopathological procedures
Each surgical specimen was fixed in 10% neutral buffered formalin,
embedded in paraffin and processed routinely. Serial 7 μm
sections were stained with haematoxylin and eosin, thionin, Luxol
Fast Blue or Bielschowsky. Other sections were immunostained using
antibodies against glial fibrillary acid protein (GFAP, Boehringer
Mannheim, Germany), neurofilaments (2F11 monoclonal, DAKO,
Germany), microtubule-associated protein-2 (MAP2, Boehringer
Mannheim, Germany) and neuron-specific nuclear protein (NeuN,
Chemicon International, Temecula, CA). The immunoperoxidase
procedure was described elsewhere (Tassi et al., 2001). The
slides were reviewed independently by three neuropathologists, one
of whom had not been involved in the initial diagnoses and was
unaware of the electroclinical data, MRI findings and surgical
outcomes. Disagreements were discussed and a consensus diagnosis
was achieved. Tumours were assigned to histopathological subtypes
following the World Health Organization classification of tumours
(Louis et al., 2007). Hippocampal sclerosis (HS) was diagnosed
in the presence of diffused gliosis associated with pyramidal cell
loss in CA1, CA3 and CA4 (hilus) sectors of the Ammon’s
horn (CA) (Blümcke et al., 2002). Cases with tissue
fragmentation obscuring hippocampal anatomy were excluded. Focal
cortical dysplasia (FCD) was diagnosed according to Tassi
et al. (2002) as refined by Palmini et al. (2004),
recognizing two main morphological types: type I and type II
(Taylor’s type dysplasia). The type II FCD was quite clearly
defined by the presence of profound disruption of cortical layering
coupled with cytological abnormalities characterized by the
occurrence of dysmorphic neurons (FCD type IIA) and the presence of
balloon cells (FCD type IIB). Since only 12 patients presented
this type of dysplasia in the present cohort, the subdivision into
the two subgroups was not considered in the report. Type I FCD was
diagnosed on the basis of cortical dyslamination (figure 1A), frequently
associated with reduction of cortical thickness and with the
presence of numerous heterotopic neurons in the white matter. In
the majority of the patients, laminar alteration was observed
particularly in the supragranular layers (figure 1B), however,
columnar arrangement was also observed in some specimens (figure 1C). In only
eight patients, hypertrophic pyramidal-like neurons, as described
by Tassi et al. (2002), were observed in addition to the
laminar disorganization and thus defined as FCD type IB
(cytoarchitectural dysplasia) (figure 1D). Thus, as was
the case for type II FCD, all the patients were similarly grouped
within category type I. For heterotopic neurons (HN), specimens
from 42 patients with suspected neuronal heterotopia in white
matter were processed for further semi-quantitative estimation of
heterotopic neurons in the white matter from the same anatomical
region for all the specimens. Two temporal autopsy brains obtained
from patients without known neurological disorder and one surgical
specimen of neocortex, adjacent to low-grade glial temporal tumours
from a non-epileptic patient, were used as internal normal
controls. Briefly, 4 μm thick sections were de-waxed in two
changes of xylene and hydrated through graded alcohols.
Pre-treatment with microwave was performed before incubation in 10%
(v/v) normal serum and the following 12 hours incubation in
primary antibody (MAP2, 1:300). The grey-white matter boundaries
were delineated at 2.5 x objective with a fine ink line using
Luxol Fast Blue-stained sections as a reference (Thom et al.,
2001) and only neurons in the deep white matter (at least
500 μm from the grey matter boundary) were measured using a
BX51 microscope (Olympus, Japan) with motorized stage linked
to an image-analysis system (Prior Optic Scan II camera and Image
Pro-Plus 6 software). Cell counting was performed at 20 x
objective in randomly placed visual fields corresponding to a final
surface of 5.54 ± 2.4 mm2/section, according to the
methodological description by Hildebrandt et al. (2005). Using
this methodology, the number of neurons in the white matter in our
control samples was estimated at 8.2 ± 1.4/mm2, thus
below the value of 13.3 ± 0.6/mm2 estimated by
Hildebrandt et al. (2005). However,
15 neurons/mm2 was considered the cut-off for the
diagnosis of HN.
Statistical procedures
The association between HS and familiarity for epilepsy,
miscarriage, risk of spontaneous abortion, pre- and perinatal
infections, neonatal distress, head trauma, and FS was assessed
using Pearson’s chi-square or Fisher exact test (when appropriate).
Association between HS and FS was also evaluated between the two
subgroups with tumours and with MCD.
A logistic regression model was performed to evaluate the
association between duration of epilepsy, age at surgery and HS.
Associations with p ≤ 0.05 were considered significant. All
statistical analysis were performed with STATA for Windows software
version 9.0.
Results
Of the 506 consecutive patients who underwent surgery for
drug-resistant focal epilepsy, 243 (48%) fulfilled the
inclusion criteria and thus were included in the present study
(table 1). There were 114 (47%)
females and 129 (53%) males. Surgery was performed on the
right temporal lobe in 128 (53%) and on the left in
115 (47%) patients. Neurological examination was normal in
219 (90%) patients. Mean age of epilepsy onset was
10 years (SD 9; range 0-53). Mean duration of epilepsy was
20 years (SD 12, range 0-59). Mean age at surgery was
30 years (SD 12, range 1-60). Mean seizure frequency at
surgery was 19 per month (SD 26, range 1-150). General data of
the population are represented in table
1.
MRI was normal in 13 (5%) patients, isolated hippocampal
abnormalities were found in 55 (23%) and dual pathology was
diagnosed in 64 (26%) patients; in the remaining
111 (46%) cases a single lesion (tumour, malformation, etc.)
was identified. However it should be noticed that MRI data could be
biased by the continuous implementation of MRI protocols and
progressive improvement in expertise of neuroradiologists during
the 10 years of patient recruitment. This aspect is especially
relevant for MCD and particularly for FCD, thus the correlation
between neuropathological findings and MRI data will not be further
considered in the following description.
Neuropathological revision showed tumours in 79 (33%)
patients, including 6 (8%) with associated HS. Malformative
lesions were found in 110 (45%) patients and in 77 (70%)
HS was also present. Thus a dual pathology was present in
83 (34%) cases of the total considered cohort. HS was present
with no other lesion in 34 (14%) patients. In 13 (5%)
cases no lesion was found. In the remaining seven (3%) patients
other types of lesion were found (tables 1,
2). Post-surgical follow-up was available for all the
considered patients; 201 (83%) were in Engel class I (64% in
class Ia and Ic), 17 (7%) in class II, 16 (7%) in class
III, and nine (4%) in class IV (table
3). Of the 201 patients in class I, 93 (46%) were
no longer taking AEDs while 87 (43%) were receiving therapy
reduction at last contact (table 4).
No patient died peri-surgically. Unexpected post-surgical
neurological deficits such as mild hemiparesis and hemianopsia
occurred in one patient.
Patients with tumours
In 79 (33%) out of the 243 patients considered,
36 (46%) females and 43 (54%) males, the
neuropathological diagnosis was determined as tumour (table 1). Mean age of epilepsy onset was
10 years (SD 9, range 0-50), mean duration of epilepsy was
15 years (SD 12, range 0-44), mean age at surgery was
25 years (SD 13, range 1-51) and mean seizure frequency was
25 per month (SD 34, range 1-150). Neuronal and mixed
neuronal-glial tumours constituted 76% of all the tumours and these
patients had a mean age of epilepsy onset lower than those with low
grade or meningeal tumours (table 1).
Neurological examination was normal in 71 (90%) patients.
In six (8%) patients preoperative SEEG was performed to determine
the precise localization of the epileptogenic zone to ablate.
In accordance with the WHO classification (Louis et al.,
2007), 23 (29%) patients with dysembryoplastic neuroepithelial
tumours (DNT), 35 (44%) with ganglioglioma and two with
gangliocytoma were included, even though in seven an FCD was found
surrounding these lesions (five with ganglioglioma and two with
DNT).
The outcome in patients with tumours was particularly
favourable; 69 (87%) in Engel class I (75% class Ia-c),
5 (6%) in class II, 3 (4%) in class III and only two (3%)
in class IV (table 3). Pharmacological
therapy was completely withdrawn in 29 (42%) patients and
reduced in 35 (51%) of the patients in class I (table 4).
Table 1 Main clinical characteristics of 243
patients.
|
Neuropathology
|
N. of patients (%)
|
Males (%)
|
Females (%)
|
Mean age at epilepsy onset (SD)
|
Mean duration of epilepsy (SD)
|
Mean age at surgery (SD)
|
Mean n. of seizures per month (SD)
|
|
Glial and meningeal tumoursa
|
19 (8)
|
12 (63)
|
7 (37)
|
16 (13)
|
12 (11)
|
27 (13)
|
18 (26)
|
|
Mixed neuronal-glial tumoursb
|
60 (25)
|
31 (52)
|
29 (48)
|
8 (7)
|
16 (12)
|
24 (14)
|
27 (35)
|
|
Tot. tumours
|
79 (33)
|
43 (54)
|
36 (46)
|
10 (9)
|
15 (12)
|
25 (13)
|
25 (34)
|
|
FCD I
|
60 (25)
|
31 (52)
|
29 (48)
|
10 (10)
|
22 (11)
|
32 (12)
|
13 (15)
|
|
FCD II
|
12 (5)
|
7 (58)
|
5 (42)
|
8 (7)
|
22 (9)
|
30 (10)
|
20 (19)
|
|
Heterotopic neurons
|
23 (9)
|
15 (65)
|
8 (35)
|
8 (8)
|
23 (11)
|
31 (9)
|
18 (23)
|
|
Other MCD c
|
15 (6)
|
9 (60)
|
6 (40)
|
9 (7)
|
23 (13)
|
32 (11)
|
20 (29)
|
|
Tot. malformations
|
110 (45)
|
62 (56)
|
48 (44)
|
9 (9)
|
23 (11)
|
32 (11)
|
16 (20)
|
|
HS Only
|
34 (14)
|
18 (53)
|
16 (47)
|
7 (6)
|
26 (10)
|
34 (11)
|
12 (13)
|
|
Other d
|
7 (3)
|
2 (29)
|
5 (71)
|
17 (9)
|
16 (8)
|
34 (10)
|
23 (36)
|
|
No pathology found
|
13 (5)
|
4 (31)
|
9 (69)
|
11 (9)
|
19 (10)
|
30 (10)
|
19 (28)
|
|
Totals
|
243
|
129 (53)
|
114 (47)
|
10 (9)
|
20 (12)
|
30 (12)
|
19 (26)
|
Table 2 History of febrile seizure and presence/absence
of hippocampal sclerosis.
|
Neuropathology
|
N. of patients
|
HS (%)
|
FS (%)
|
FS and HS (%)
|
|
Glial and meningeal tumours
|
19
|
2 (11)
|
2 (11)
|
1 (5)
|
|
Mixed neuronal-glial tumours
|
60
|
4 (7)
|
6 (10)
|
0
|
|
Tot. tumours
|
79
|
6 (8)
|
8 (10)
|
1 (1)
|
|
FCD I
|
60
|
50 (83)
|
29 (48)
|
27 (45)
|
|
FCD II
|
12
|
6 (50)
|
3 (25)
|
3 (25)
|
|
Heterotopic neurons
|
23
|
16 (70)
|
13 (57)
|
12 (52)
|
|
Other MCD
|
15
|
5 (33)
|
5 (33)
|
3 (20)
|
|
Tot. malformations
|
110
|
77 (70)
|
50 (45)
|
45 (41)
|
|
HS Only
|
34
|
34 (100)
|
15 (44)
|
15 (44)
|
|
Other
|
7
|
0
|
1 (14)
|
0
|
|
No pathology found
|
13
|
0
|
3 (23)
|
0
|
|
Totals
|
243
|
117 (48)
|
77 (32)
|
61 (25)
|
Table 3 Surgical outcome according to the
histopathological subtypes.
|
Neuropathology
|
Ia-c (%)
|
Ib (%)
|
Id (%)
|
Tot. I (%)
|
II (%)
|
III (%)
|
IV (%)
|
|
Glial and meningeal tumours
|
16 (84)
|
0
|
0
|
16 (84)
|
0
|
1 (5)
|
2 (11)
|
|
Mixed neuronal-glial tumours
|
43 (72)
|
5 (8)
|
5 (8)
|
53 (88)
|
5 (8)
|
2 (3)
|
0
|
|
Tot. tumours
|
59 (75)
|
5 (6)
|
5 (6)
|
69 (87)
|
5 (6)
|
3 (4)
|
2 (3)
|
|
FCD I
|
37 (62)
|
5 (8)
|
7 (12)
|
49 (82)
|
3 (5)
|
4 (7)
|
4 (7)
|
|
FCD II
|
9 (75)
|
2 (17)
|
0
|
11 (92)
|
0
|
1 (8)
|
0
|
|
Heterotopic neurons
|
12 (52)
|
3 (13)
|
1 (4)
|
16 (70)
|
5 (22)
|
2 (9)
|
0
|
|
Other MCD
|
7 (47)
|
4 (27)
|
0
|
11 (73)
|
2 (13)
|
2 (13)
|
0
|
|
Tot. malformations
|
65 (59)
|
14 (13)
|
8 (7)
|
87 (79)
|
10 (9)
|
9 (8)
|
4 (4)
|
|
HS Only
|
22 (65)
|
4 (12)
|
6 (18)
|
32 (94)
|
1 (3)
|
0
|
1 (3)
|
|
Other
|
3 (43)
|
1 (14)
|
0
|
4 (57)
|
0
|
1 (14)
|
2 (29)
|
|
No pathology found
|
7 (54)
|
2 (15)
|
0
|
9 (69)
|
1 (8)
|
3 (23)
|
0
|
|
Totals
|
156 (64)
|
26 (11)
|
19 (8)
|
201 (83)
|
17 (7)
|
16 (7)
|
9 (4)
|
Table 4 Withdrawal of therapy in patients in Engel
class I.
|
Neuropathology
|
N. patients in class I (%)
|
Therapy stopped (%)
|
Therapy in reduction (%)
|
|
Glial and meningeal tumours
|
16 (84)
|
7 (44)
|
9 (56)
|
|
Mixed neuronal-glial tumours
|
53 (88)
|
22 (42)
|
26 (49)
|
|
Tot. tumours
|
69 (87)
|
29 (42)
|
35 (51)
|
|
FCD I
|
49 (82)
|
20 (41)
|
21 (43)
|
|
FCD II
|
11 (92)
|
6 (55)
|
4 (36)
|
|
Heterotopic neurons
|
16 (70)
|
11 (69)
|
5 (31)
|
|
Other MCD
|
11 (73)
|
5 (45)
|
6 (55)
|
|
Tot. malformations
|
87 (79)
|
42 (48)
|
36 (41)
|
|
HS Only
|
32 (94)
|
16 (50)
|
12 (38)
|
|
Other
|
4 (57)
|
1 (25)
|
3 (75)
|
|
No pathology found
|
9 (69)
|
5 (56)
|
1 (11)
|
|
Totals
|
201 (83)
|
93 (46)
|
87 (43)
|
Malformation of cortical development (MCD)
MCD was found in 110 (45%) of patients, 48 (44%) females
and 62 (56%) males (table 1). Mean
age of epilepsy onset in this group was nine years (SD 9, range
0-53), mean duration of epilepsy was 23 years (SD 11, range
1-59), mean age at surgery was 32 years (SD 11, range 4-60)
and mean seizure frequency was 16 per month (SD 20, range
1-120). No significant differences were observed among the
categories of MCD with respect to the mean age at epilepsy onset,
mean duration of epilepsy mean age at surgery and number of
seizures per month (table 1). The
outcome in this group of patients are shown in table 3; 87 (79%) patients were in class I
with 65 (59%) in class Ia-c. In this group of patients, AEDs
were withdrawn in 42 (48%) and reduced in 36 (41%).
Focal Cortical Dysplasias (FCD) were the most common
malformations, recognized in 72 (65%) patients representing
the 30% of the total population. Among the 72 patients with
FCD, type I was most frequently observed at the neuropathological
investigation accounting for the 55% (60/110) of all malformative
lesions and the 83% (60/72) of FCD (table
1). Of the FCD patients, 60 (83%) were in class I with
46 (64%) in class Ia-c (table 3).
No statistical difference in outcome was present between patients
with isolated FCD I and those with FCD I plus HS. Of the entire
cohort of FCD patients, AEDs were withdrawn in 26 (43%) and
reduced in 25 (42%) (table 4).
A total of 23 (9%) cases (15 males, 8 females)
were judged to have only heterotopic neurons (HN) in the deep white
matter of the temporal lobe (table 1).
Histological and immunocytochemical findings demonstrated numerous
medium-size neurons, often arranged in small clusters, most of them
showing pyramidal morphology (figure 1E, F). Within this
group, 16 (70%) patients were in class I with 12 (52%) in
class Ia-c (table 3). AEDs were
completely withdrawn in 11 (69%) patients and were in a phase
of reduction for 5 (31%) (table
4).
Hippocampal sclerosis (HS)
Of the entire cohort of 243 patients, HS was
neuropathologically ascertained in 117 (48%). HS was the only
pathology found in 34 (29%) patients while in the remaining
83 (71%) it was associated with another pathology (dual
pathology).
In the group with HS only, represented by 18 (53%) males
and 16 (47%) females, mean age at epilepsy onset was seven
years (SD 6, range 1-23), mean duration of epilepsy was
26 years (SD 10, range 6-43), mean age at surgery was
34 years (SD 11, range 7-55) and mean seizure frequency was
12 per month (SD 13, range 1-60) (table
1). Follow-up revealed that 32 (94%) were in class I
with 22 (65%) in class Ia-c (table
3). For 16 (50%) patients, the AEDs were completely
withdrawn and were in a phase of reduction for 12 (38%) (table 4).
Among the 83 (71%) patients with dual pathology, HS was
associated with tumours in only 6 (7%). Of the
110 patients with MCD, HS was found in 77 (70%). The
highest incidence of dual pathology was present in association with
type I FCD with 50 cases out of 60 (83%) and in
16 out of 23 (70%) patients with HN (table 2).
Absence of neuropathology (cryptogenic)
In 13 (5%) cases, four males and nine females, no
neuropathological abnormalities were found (table 1). Mean age of epilepsy onset was
11 years (SD 9, range 0-28), mean duration of epilepsy was
19 years (SD 10, range 7-43), mean age at surgery was
30 years (SD 10, range 12-46) and mean seizure frequency was
19 per month (SD 28, range 1-90). Nine patients (69%) had an
Engel class I outcome, with seven (54%) in class Ia-c (table 3). For five (56%) patients the AED were
withdrawn and were in a phase of reduction for one (table 4).
Febrile seizures and HS
The frequency of familiarity for epilepsy, miscarriage, risk of
spontaneous abortion, pre- and perinatal infections, neonatal
distress and head trauma were not significantly associated with the
different neuropathological entities observed in the present
cohort.
History of febrile seizures was present in 77 (32%)
patients (table 2) and the presence of
HS in patients with FS was revealed in 61 (25% of the whole
population and 52% of the patients with HS). A chi-square
analysis between the presence of FS and HS was performed and a
strong association (p < 0.01) was found. A history of FS
was present particularly in patients with either a
neuropathological diagnosis of MCD (50 out of 110; 45%) or HS
only (15 out of 34; 44%). The highest prevalence of FS was
found in 29/60 (48%) patients with FCD type I and
13/23 (57%) patients with HN.
In patients not presenting either MCD or HS, FS were less
common; in particular among the 79 patients with tumour, only
eight (10%) had FS and only one with meningioma had HS. The
association in the whole cohort of 243 patients between HS and
FS remains significant in the subgroup of MCD (Pearson’s chi-square
p < 0.01) but not in the subgroup of tumours (p = 0.48, Fisher
exact test).
Within the MCD group (110 patients) two subgroups can be
recognized: I) patients with a history of FS (FS+ = 50; 45%) that
also showed HS in 45 (90%) of the patients; II) patients
without documented FS (FS- = 60; 55%) with HS present in
32 (53%). A logistic regression model was performed on
these subgroups to evaluate the association of HS and two other
parameters: duration of epilepsy and age at surgery.
A significant association between HS and duration of epilepsy
(p = 0.019; OR: 1.086; CI 95%: 1.013-1.163), but not with age at
surgery (p = 0.62), was found only in the subgroup of patients
without a history of FS (figure 2).
Discussion
Of the 243 patients, with at least two years of follow-up, 83%
were classified in Engel class I and only nine (4%) did not benefit
from surgery (class IV). A class I outcome was obtained in 87%
in patients with tumours and 79% of patients with malformative
lesions (92% and 82% in type II and I FCD respectively),
irrespective of the presence of HS. These data support the findings
of the only randomized trial of surgery for refractory TLE so far
published (Wiebe et al., 2001) and highlight the low
frequency of post-surgical morbidity and the absence of mortality.
In many studies associated with TLE, HS is primarily
investigated, giving the misleading impression that the two
entities are the same (Zhang et al., 2002). However HS cannot
be regarded as the unique cause of TLE since in recent
neuropathological data, HS was found in about 65% of patients that
underwent surgery for intractable TLE (Blümcke et al., 2002).
In our cohort the presence of HS was observed in 48% of the
patients, and in most of these, in association with other
pathologies; mainly MCD. Despite the role of HS in TLE, dual
pathology is increasingly recognized in these patients and recent
electroclinical and imaging findings indicate that
extra-hippocampal structures may play an important role (Chabardès
et al., 2005).
Tumours and TLE
The reported frequency of tumours that are believed to be a cause
of intractable TLE ranges widely (11-56%), in part due to
difficulties in assessing different histopathological subtypes,
mainly due to the fragmented nature of tissue available for
neuropathological diagnosis (Pasquier et al., 2002). In our
series, 33% of the patients had tumours that were believed to be a
cause of TLE. This number is unlikely to be representative of
refractory TLE in general, because patients were only referred to
our centre with a long history of epilepsy.
Although HS is present with other major neuropathological
findings in around 30% of TLE surgical cases, the association of HS
with tumours is variable (Wolf et al., 1993; Lee et al.,
1998; Blümcke et al., 1999; Li et al., 1999; Pasquier
et al., 2002). In our series, HS was coupled with a tumour in
only 8% of cases showing that the association is rare. Wolf
et al. (1993) and Blümcke et al. (1999) have noticed that
tumours, particularly ganglioglioma and DNT, in patients with HS
are also associated with the presence of malformative lesions in
the temporal lobe, suggesting a maldevelopmental origin of these
neuropathological entities. In our series, four of the six tumour
plus HS cases had gangliogliomas, and two of them were associated
with cortical dysplasia. A history of FS was present in eight
(10%) patients and only one with HS.
Malformations of cortical development and TLE
MCDs were identified in 110 (45%) patients most of which (29%
of total population) were FCDs. Reported frequencies of FCD in TLE
range from 9% to 16% (Raymond et al., 1994; Lee et al.,
1998; Pasquier et al., 2002; Salanova et al., 2004). The
high frequency of FCD in our series, in accordance with proportions
in other recent studies (Srikijvilaikul et al., 2003; Fauser
et al., 2004), is almost certainly due to refinement of
diagnostic neuropathological observations and to the common
classification system (Palmini et al., 2004).
Among the patients with malformative lesions, 21% appeared to
have an excess number of scattered neurons (HN) in the white
matter. Isolated white matter neurons are a feature of normal
brains and may be remnants of subplate neurons or an anatomical
extension of layer VI (Hardiman et al., 1988; McConnell
et al., 1989; Rojiani et al., 1996). It has also been
suggested that heterotopic white matter neurons are those that
failed to reach their cortical target due to migrational arrest
during development and that this disruption can result in altered
cortical circuitry (Sarnat, 1991). However the cut-off between
normal and excessive white matter neurons is ill-defined. Using a
stereological cell counting technique, Thom et al. (2001,
2005) demonstrated significantly greater neuronal density in
surgical epilepsy cases than in controls, although an overlap
between the two groups was noted. These authors also found, in
agreement with Kasper et al. (1999), that white matter
neuronal density was independent of the extent of secondary
gliosis. These data have been confirmed by Hildebrandt et al.
(2005) showing that the number of solitary neurons within white
matter sites was significantly increased in the epilepsy patient
cohort, compared to age-matched controls, and these authors suggest
that “this anatomical feature associates with chronic epileptic
activity, i.e. seizure-induced neurogenesis, or point to early
disturbances in the architectural development of the cortex and
white matter”.
In patients with pathologically proven HS, Choi et al.
(1999) found that white matter neuronal density was greater in
patients with MRI white matter changes in the anterior temporal
lobe than in those without white matter changes. These findings
indicate that HN is a characteristic feature of malformations of
cortical development included in the recent classification by
Palmini et al. (2004).
We also found that the heterotopic neurons were arranged
abnormally, with numerous incorrectly oriented pyramidal cells and
frequent clusters of 5-10 cells. These morphological
abnormalities, not evident on thionin-stained sections, were
clearly revealed on MAP2-, neurofilaments- and NeuN-immunostained
sections. We have included these patients within the group of
malformative lesions, in agreement with the data present in the
current literature (Fauser et al., 2004).
Isolated HS and dual pathology
Only 34 (14%) of our cases had isolated HS, 32 (94%) of
which had a class I outcome and 16 (50%) were no longer
receiving AEDs.
Dual pathology is generally referred to as the presence of HS
associated with an additional extra-hippocampal lesion. In the
literature, the frequency of dual pathology in cases of refractory
TLE ranges from 5% to 30%, the commonest extra-hippocampal lesion
being developmental abnormality (Lèvesque et al., 1991;
Raymond et al., 1994; Cendes et al., 1995; Li
et al., 1999). This wide range is largely due to variations in
patient selection. However, it should be considered that routine
neuropathological and MRI examinations are unlikely to detect
subtle extra-hippocampal abnormalities (Sloviter and Pedley, 1998).
Quantitative MRI studies generally report a dual pathology
frequency at around 15% (Raymond et al., 1994; Cendes
et al., 1995); however many developmental abnormalities,
particularly minor malformations of cortical development (Palmini
et al., 2004) and type I FCD, cannot be detected even with
high resolution MRI (Colombo et al., 2003).
In the present series, dual pathology was present in 34% of the
patients. While the number of cases of HS associated with tumours
was negligible (8%), the number of patients presenting HS
associated with FCD increased from 70% to 83% in those with type I
FCD. These data are in agreement with those reported by Eriksson
et al. (2005) and further support the concept by Mathern
et al. (1995) that tumours are less likely than malformations
to produce HS. The high proportion of malformative lesion cases
with HS has led to speculation that there may be a common pathway
for the development of the two lesions.
In a recent paper, Thom et al. (2009) identified 11% of
their cohort of surgically treated patients, presenting temporal
lobe sclerosis. On the basis of neuropathological findings, they
suggested that the hallmark features were represented by areas of
neuronal loss in supragranular layers (layers II-III), indicating
that this aspect may represent an acquired non-developmental
process. These neuropathological features have been also identified
in some of our patients but have been incorporated into FCD type I
and justify the large number of FCD in our population. Whether
these specific neuropathological findings, restricted to the
temporal lobe and almost exclusively associated with HS, should be
separated by the other type of FCD would require further data and a
revaluation of the present classification of FCD.
Febrile seizures and HS
The presence of FS in our cohort is biased, like any other report
on adult patients, by the reliability of anamnestic data. Taking
into account this aspect that could not be ruled out in
retrospective studies, our data show that FS were present in 32% of
the entire cohort but significantly increased (p < 0.001) when
the MCD group was considered (45%). These data suggest that
patients with MCD and particularly with FCD are more prone to FS
than the other patients.
In patients with MCD there is a significant association with FS
and HS. In patients with MCD without FS a strong association
between HS and duration of epilepsy is revealed. Thus we can
speculate that in MCD patients, HS is the result of either FS or
duration of the epilepsy. In this respect it should be noticed that
Fuerst et al. (2001) demonstrated in their neuropathologic
study, a correlation between the degree of HS and duration of
epilepsy.
As noted by Raymond et al. (1994) and Fisher and Blum
(1999), three explanations to correlate malformative lesions, HS
and FS can be formulated: (a) malformations of cortical development
predispose to prolonged FS in childhood leading to HS, (b)
malformations of cortical development are responsible for repeated
seizures that cause secondary hippocampal damage and (c)
malformations of cortical development and HS share a common
embryonic damage.
Statistical analysis of antecedents in our patients leads to the
conclusion that only FS are relevant in epilepsy history, and that
FS are statistically relevant only in patients with malformative
lesions (not tumours) plus HS.
A relationship between developmental malformations FS and HS has
been suggested through experimental animals (Germano et al.,
1996) and clinical studies (Wolf et al., 1993; Raymond
et al., 1994; Kuzniecky et al., 1999; Fauser et al.,
2004). The nature of this relationship has been reviewed by
Sloviter and Pedley (1998), and Velisek and Moshé (2003).
Our data showing a strong association between extrahippocampal
malformative lesions, FS and HS suggest that malformative lesions
predisposes to FS and seizures leading to HS. However the
hypothesis that malformative lesions and HS share a common
embryonic damage (Vernet et al., 2000; Blümcke et al.,
2002) cannot be ruled out, since sophisticated methodologies such
as those used by these authors were not performed.
With regard to surgery it is controversial whether the lateral
temporal neocortex should be removed or selective surgery on mesial
regions should be performed on patients whose MRI reveals only HS.
However, in patients with dual pathology diagnosed pre-operatively,
both the lesion and the sclerotic hippocampus should be removed
whenever possible, since hippocampectomy alone and lesionectomy
alone give unsatisfactory results (Li et al., 1999; Wieser,
2004).
Seizure outcome
Although methods to report seizure outcome are quite heterogeneous
among different papers, the most well defined, widely accepted and
clinically useful scale is that proposed by Engel et al.
(1993). According to this scale, 83% of the 243 patients were
in class I and optimal results were obtained in patients with HS
only (94%) and with type II FCD (92%). A very favourable
outcome was also obtained in patients with tumour (87%) and with
Type I FCD (82%). It should be noted also that in this later group,
no statistical difference with respect to the outcome was observed
between isolated FCD I and FCD I associated with HS.
Despite the wide use of the Engel scale, antiepileptic
medication status is not considered. Thus, although systematic
reviews suggest that 66-70% of patients are seizure-free at short
term, most papers report difficulties in separating patients that
are either taking or not taking AEDs (Spencer and Huh, 2008). This
aspect should be taken into consideration in order to evaluate
whether the surgical procedure, particularly in temporal lobe
epilepsies, is effective in the cure or care of seizures. In the
present report, we considered only patients with at least two years
of follow-up and, in addition to the usual classification scale, we
also reported those patients who did not receive medication and
were thus considered to be cured by epilepsy surgery. In the total
population of 243 patients, 201 (83%) patients were in
class I and of those 93 (46%) were, at last contact,
medication free while another 43% were in a phase of therapy
reduction.
Acknowledgments
This work was supported by: FIRB the Italian Ministry of Health
(grant No. RBNE01NR34-008 and I35-RF2003-RF38), MIUR-Prot-
2003068749-001, Fondazione Banca del Monte di Lombardia,
Associazione Paolo Zorzi per le Neuroscienze and EU grant
“Functional Genomics and Neurobiology of Epilepsy” (EPICURE,
contract N° LSHM-CT-2006-0373315). We wish to thank Dr G. Bertini
for his expert technical assistance and Ms Carol Rodes for help
with English.
Disclosure.
None of the authors has any conflict of interest to
disclose.
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