Epilepsia, 53(Suppl. 6):31–36, 2012doi: 10.1111/j.1528-1167.2012.03700.x
Blood–brain barrier, epileptogenesis, and treatment
*Mehmet Kaya, yAlbert J. Becker, and zCandan Gu¨rses
*Department of Physiology, Istanbul Faculty of Medicine, Epilepsy Center (EPIMER), Istanbul University, Istanbul,
Turkey; yDepartment of Neuropathology, University of Bonn Medical Center, Bonn, Germany; and zDepartment
of Neurology, Istanbul Faculty of Medicine, Epilepsy Center (EPIMER) Istanbul University, Istanbul, Turkey
and EM revealed no BBB impairment in any of
the treatment groups. In a second set of experi-
Cortical dysplasia (CD) is one of the most impor-
ments, we assessed the relationship between dis-
tant causes of intractable epilepsy. The precise
mechanisms of epileptogenesis in CD are not
epileptogenesis. Astrocytic albumin uptake in
known. Using CD animal models, we attempted
focal epileptogenic lesions with vascular compo-
to understand the mechanisms and efficacy of
nents suggested that dysfunction of the BBB con-
various antiepileptic drugs. In two separate stud-
tributes immediately to epileptogenesis, rather
ies, we assessed (1) the effects of levetiracetam
than simply resulting from seizure activity. He-
(LEV) and vagus nerve stimulation (VNS) on pen-
mosiderin deposits were seen as potential epilep-
tylenetetrazol (PTZ)–kindled rats, and (2) the
togenic triggers in vascular malformations (e.g.,
effects of LEV and topiramate (TPM) on rats with
cavernomas [CA] or arteriovenous malforma-
CD and hyperthermia (HT). In the HT-induced
tions [AVMs] with or without a dysplastic cortical
rats with CD study, LEV and TPM decreased both
component). However, we found strikingly high
the intensity of seizures and the number of rats
accumulation of astrocytic albumin deposits in
with seizure. In these studies, we used immunocy-
surgically removed brain parenchyma in the vicin-
tochemistry (occludin, glial fibrillary acidic pro-
ity of CAs and AVMs from patients with pharma-
tein [GFAP], and P-glycoprotein [Pgp antibodies]
coresistant epilepsy, which suggests different
and electron microscopy (EM) (sodium fluores-
pathophysiologic dispersion pathways for hemo-
cein [NaFlu]) and horseradish peroxidase [HRP])
siderin and albumin in vascular lesions.
to assess blood–brain barrier (BBB) integrity.
KEY WORDS: Cortical dysplasia, Epilepsy, Blood–
Both LEV and TPM protected BBB. In PTZ- kin-
brain barrier, Electron microscopy, Immunohisto-
dled rats with CD, both LEV and VNS reduced
chemistry, Lesion with vascular component.
the duration of seizures. Immunocytochemistry
This article presents the results of two separate studies
on the involvement of blood–brain barrier (BBB) in epi-
lepsy. The first focuses on the effects of antiepilepticdrugs in animal models of cortical dysplasia, to examine if
Cortical dysplasia (CD), first described by Taylor et al.
these drugs influence BBB integrity. The second part
(1971), is one of the most important causes of intractable
deals with breakdown of vascular components as a con-
epilepsy. Although the precise mechanisms linking CD to
tributing factor in epileptogenesis.
epileptogenesis remain unknown, pathogenetic mecha-nisms of epileptogenesis in the setting of CD are revealedto be multifactorial. Among the variable clinical manifes-
Address correspondence to Candan Gürses, Department of Neurol-
tations of CD are seizures, developmental delay, and per-
ogy, Istanbul Faculty of Medicine, Epilepsy Center (EPIMER), Istanbul
sistent neurologic deficits. Seizures are often medically
University, Capa/Fatih 34093 Istanbul, Turkey. E-mail: candangrss@gmail.com
refractory and disabling. The exact incidence of CD isunknown, since we examine only case reports or small
Wiley Periodicals, Inc. ª 2012 International League Against Epilepsy
series, but there may be a higher prevalence of CD that
eludes detection due to lack of clinical manifestation.
vided us with invaluable observations and solutions. We
Hence, a great amount of invaluable data remains unrav-
previously reported morphologic changes in cortical lay-
eled. The size of the lesion and the severity of epilepsy
ers of rats exposed to 145-cGy irradiation in utero (Kaya
may not be correlated in some cases. Therefore, some
et al., 2008; Gürses et al., 2009; Ahishali et al., 2010). Our
patients with significantly small lesions or magnetic reso-
data showed that in utero irradiation caused histologic
nance (MR)–negative (biopsy-proven CD) may have
abnormalities in cerebral cortex and hippocampus, and in
severely disabling seizures. These patients may continue
vivo epileptogenicity increased in the setting of CD.
to have seizures after the operation.
We have carried out experiments with three treatment
Patients with refractory epilepsy due to CD are a
approaches, previously used for patients with epilepsy, on
challenge for clinicians. There is still a long distance
animal models with CD, namely topiramate (TPM), lev-
to be covered to achieve complete freedom from sei-
etiracetam (LEV), and vagus nerve stimulation (VNS).
zures (Regis et al., 2011; Chassoux et al., 2012). With
TPM is known to have at least five different mechanisms
the development of neuroimaging technology, the post-
of antiseizure effects. Neuroprotective effects against neu-
operative outcomes convey better results in terms of
ronal injury from hypoxia (Koh & Jensen, 2001) and status
epilepticus (Niebauer & Gruenthal, 1999) have been dem-
There are studies that suggest a vascular component of
onstrated in animal models. TPM is also effective in both
CD. Microvascular anomaly was noted in the dysplastic
partial and generalized seizures. Double-blind random-
cerebral cortex, and ultrastructurally, endothelial cells
ized placebo-controlled studies showed its efficacy in both
with relatively pale nuclei bounding the lumen and some
children and adults (Ben-Menachem et al., 1996; Elterman
pericytes with elongated, dark nuclei were also observed
in a human case (Kakita et al., 2002). Moreover, it is
As for LEV, it is an effective monotherapy and adjunc-
reported that heterotopia-supplying vessels were abnor-
tive treatment for partial and also generalized seizures. It
mal and the number of anastomotic capillaries increased
shows its antiepileptic effect through binding at the synap-
in in utero irradiation–induced CD (Marin-Padilla et al.,
tic vesicle SV2A receptors (Lynch et al., 2004). Random-
2003). The size and organization of the heterotopia’s cap-
ized controlled trials showed its efficacy particularly on
illary plexus often mimicked that of its neurons, suggest-
median seizure frequency, with 50% responder rate
ing a developmental response to its functional demands
(Cereghino et al., 2000; Boon et al., 2002). Another study
(Smith et al., 1999; Marin-Padilla et al., 2003). Alterations
showed no long-term efficacy of LEV tolerance in 1,422
in microvasculature as well as in neurons in CD have been
patients (Ben-Menachem & Gilland, 2003).
suggested to play a possible role in the pathogenesis of sei-
The effects of VNS, on the other hand, have not been
demonstrated fully, although VNS is effective in patients
In human CD, N-methyl-D-aspartate (NMDA) impair-
with partial epilepsies. Because VNS was approved for
ment was associated with altered molecular structure of
epilepsy, clinicians have debated its role (Ben-Menachem
the postsynaptic membrane (Finardi et al., 2006). In addi-
& French, 2005). Seizure control is maintained in long-
tion, a relative reduction in the number of inhibitory inter-
term studies of VNS, including catastrophic childhood
neurons has been observed (Calcagnotto et al., 2005;
epilepsy (DeGiorgio et al., 2000; Henry, 2002).
Battaglia et al., 2009). Up-regulation of NMDA receptor
In two separate studies, we experimented with two
subunits 2A/B (NR2A/B) in the cortical dysplastic neu-
groups of rats, one pentylenetetrazol (PTZ) kindled with
rons suggests the involvement of glutamate receptors in
CD and the other hyperthermia (HT) induced with CD.
the cellular mechanism of epileptogenesis in CD. There
We fashioned our HT group to evaluate febrile convul-
are animal models of CD with similar electrophysiologic,
sions. Febrile convulsions are common among children,
functional, and histopathologic properties of human CD
and 31% of the MR imaging (MRI) studies of children
such as in utero alkylating, focal freeze lesion, in utero
with febrile status epilepticus have shown anomalies
irradiation, ethanol, and genetically mutant models
(Yoong et al., 2012). Other studies also asserted that the
(Roper et al., 1995; Wenzel et al., 2001; Marchi et al.,
presence of an underlying focal CD leads to a prolongation
2006; Kaya et al., 2008; Wong, 2009; Aronne et al.,
of febrile seizures (Bocti et al., 2003; Scantlebury & He-
2011). In the in utero irradiation model, the offspring
ida, 2010) as well as higher mortality rates (Pujar et al.,
develops cortical malformation, which is characterized
2011). In addition, we used the double-hit approach in our
by the loss of the normal six-layered cortex leading to
study to verify the findings of such studies. We evaluated
cortical dyslamination (Roper et al., 1995; Marin-Padilla
our findings with immunohistochemical and electron
et al., 2003; Kaya et al., 2008; Gürses et al., 2009; Ahis-
microscopy (EM) analysis, and demonstrated the validity
To better evaluate data on CD, understand epileptogen-
Although PTZ-kindled rats with CD were receiving
esis, and investigate the efficacy of antiepileptic drugs
LEV and VNS, in the experiments on HT-induced rats
(AEDs) on seizures, animal epilepsy models have pro-
with CD, LEV and TPM were used. In the PTZ-kindled
Epilepsia, 53(Suppl. 6):31–36, 2012doi: 10.1111/j.1528-1167.2012.03700.x
rats with CD, VNS at 1 mA suppressed seizures com-
these changes were exacerbated during pilocarpine-
pletely, whereas PTZ administration to kindled rats with
induced seizures (Marchi et al., 2006). The disrupted BBB
CD exhibited seizures with mean Racine’s scores of
may contribute to increased neuronal excitability in the het-
3.57 € 1.2. In the HT-induced rats with CD, LEV and
erotopic areas by allowing the entry of blood-borne sub-
TPM were observed to decrease both the intensity of sei-
stances (Seiffert et al., 2004). Cerebral blood flow–single
zures and the number of rats exhibiting seizures. The mean
photon emission computed tomography (SPECT) studies
seizure score was 3.92 € 1.2 (standard error of mean) in
on focal CD have shown hyperperfusion in lesional tissues
rats with CD during hyperthermia. Pretreatment with
during ictal events, suggesting that this hemodynamic com-
TPM significantly inhibited the occurrence of seizures in
ponent may contribute to increased albumin extravasation
rats with CD during HT, and the mean Racine score of the
to brain parenchyma (Roch et al., 2002). Our recent unpub-
seizures in these animals was 2.4 € 0.6, except for one rat,
lished study has demonstrated that the responsible mecha-
which exhibited seizures with a Racine score of 4.
nism for the increase in BBB permeability in CD plus
Immunohistochemically, occludin showed no signifi-
epileptic seizures is via a transcellular pathway, as indi-
cant difference for LEV or VNS in the PTZ-kindled rats
cated by an increased number of caveolar vesicles in the
with CD group. Glial fibrillary acidic protein (GFAP)
groups that received no AEDs or VNS (Fig. 1). In our pub-
showed decrease with LEV but increase with VNS. Pgp,
lished and unpublished studies, tight junctions were seen
used only in the VNS study, yielded almost no staining in
not to be disrupted except for the transcellular route. In
the CD group, but color intensity was prominent in
addition, the transcellular pathway remained intact in treat-
HT-induced rats with CD and VNS-treated groups. There
seems to be a conflict between the unexpected overexpres-
In our experiment with PTZ-kindled rats with CD,
sion of Pgp in the VNS group and lack of seizures, which
electron microscopy results revealed no distinct HRP
requires further studies to account for. In the HT-induced
products in the endothelial cells of brain microvessels of
group, immunohistochemically, a tight junction protein,
rats in one VNS (1 mA) and LEV groups. In these ani-
occludin, showed no significant difference for either LEV
mals, only occasional transport vesicles containing HRP-
or TPM. GFAP, which was used only in LEV study but not
reaction products were observed following 1-mA VNS
TPM, showed no change. P-gp, used only in the TPM
treatment in the brain capillary endothelial cells in both
study, yielded almost no staining in the CD group, but
cerebral cortex and hippocampus. The results of this
color intensity was prominent in HT-induced rats with CD.
study suggest that 1-mA VNS application inhibits seizure
Under normal physiologic conditions, the BBB protects
activity and maintains BBB integrity in kindled animals
brain to blood-borne, potentially toxic molecules by
with CD. Its effects on BBB were the same as the other
controlling both paracellular and also transcellular
two drugs: LEV and TPM. Hence, it can be concluded
‘‘transendothelial’’ routes. Transcellular routes are highly
that LEV and VNS showed no BBB impairment in PTZ-
selective, and the rate of transcytosis of solutes is also
restricted at the barrier type of brain capillary endothelial
To show the functional and morphologic alterations in
cells. The presence of tight junctions between adjacent
BBB integrity, sodium fluorescein (NaFlu) and horserad-
endothelial cells limits the action of paracellular pathway
ish peroxidase (HRP) were used in the experiment with
of hydrophilic molecules across the BBB. However, theextravasation of blood-borne substances associated withBBB disruption may occur through a paracellular and/or anumber of different transcellular routes. In CD studies,BBB integrity is underevaluated as a significant compo-nent. BBB integrity becomes more vulnerable or isimpaired as a result of alterations in functional and struc-tural BBB characteristics in the malformed brain tissues(Marchi et al., 2006; Kaya et al., 2008; Gürses et al., 2009;Ahishali et al., 2010). On the other hand, the overexpres-sion of multidrug transporter proteins in the capillaryendothelium of BBB, astrocytic end-feet, microglia, and
neurons has been suggested as the major mechanism
Electron micrographs of capillaries in the hippocampus
responsible for multidrug resistance in epilepsy (Golden
of rats with CD plus PTZ-induced kindling. Note that
& Pardridge, 2000; Sisodiya et al., 2002; Aronica et al.,
the brain capillary endothelial cells reveal frequent vesi-
2003; Lçscher et al., 2011). Morphologically aberrant
cles containing HRP-reaction products in their cyto-
vessels, increased BBB permeability, and the expression
of endothelial Pgp were shown in the heterotopic
hippocampus in methylazoxymethanol-treated rats, and
LEV and TPM on HT-induced rats with CD, respectively.
Hemosiderin deposits have been repeatedly discussed
NaFlu extravasation was seen to decrease in LEV group,
as potential epileptogenic triggers in patients with focal
and likewise, no distinct HRP products were seen in the
epilepsy due to epileptogenic lesions with vascular com-
vessels of rats in the TPM group. Therefore, both LEV and
ponents such as vascular malformations, for example,
TPM are shown to protect BBB integrity by reducing
transcellular route in rats with HT-induced rats with CD.
(AVMs) with or without a dysplastic cortical component.
All in all, because experimental models share the
However, immediate evidence for this suggestion is rare.
majority of cortical abnormalities observed in humans,
Perilesional intracranial hemorrhages have been sug-
they not only provide invaluable means of understanding
gested to be associated with a worse outcome of seizures
the cellular and molecular mechanisms of epileptogenesis,
(Stefan & Hammen, 2004). Despite significantly higher
predisposition, and occurrence of BBB impairment in the
amounts of hemosiderin deposits in patients with CAs
setting of CD but also enable us to develop new therapeu-
than in patients with AVMs, no differences in either post-
tic strategies against CD, epileptogenesis, and BBB dis-
operative seizure outcome or preoperative seizure fre-
ruption. Hence, knowing the presence of an underlying
quency was present (Raabe et al., 2012). However, we
anomaly will contribute to our understanding of etiopatho-
found strikingly high accumulation of astrocytic albumin
genesis and to plan treatment protocols accordingly. Fur-
deposits in surgically removed brain parenchyma in the
ther studies on the subject are needed for a better
vicinity of CAs and AVMs from patients with pharmaco-
understanding of the emergence and control of seizures.
resistant epilepsy, which suggest different pathophysio-logic dispersion pathways for hemosiderin and albumin in
vascular lesions. On the other hand, the extent of albumin
deposits was not statistically different in either vascularlesion groups (Raabe et al., 2012). Intriguingly, substan-
tial albumin immunoreactivity was not only observed
The revised International League Against Epilepsy
within the vascular lesion but also in perilesional astro-
(ILAE) classification of cortical dysplasias brought about
cytes in both CAs and AVMs. We found a varying pattern
a new approach with specific emphasis on combined
of albumin distribution with preferential membranous
pathologies, for instance type III focal cortical dysplasia
accumulation but also diffuse cytoplasmic immunoreac-
(FCD). In addition to dysmorphic cells, several chronic
tivity in samples from all patients with focal epilepsy and
epilepsy associated lesions contain a prominent vascular
vascular malformations. The absence of such specific
component (Blumcke et al., 2011). We have therefore
astrocytic accumulation in vascular lesions not associated
addressed the question of whether there is evidence for
with epilepsy and FCD type II, for example, epileptic
activity of BBB dysfunction and subsequent astrocytic
lesions without vascular component, rules out a nonspe-
albumin uptake as described below in focal epileptogenic
cific surgical artifact or seizures as the underlying cause
It has been suggested that the dysfunction of the BBB
FCD type IIIc, that is, combination of FCD with
contributes immediately to epileptogenesis, rather than
vascular malformations according to the new ILAE
simply results from seizure activity (Seiffert et al., 2004;
classification system (Blumcke et al., 2011), did not
Ivens et al., 2007). Application of albumin on the neocorti-
show significant differences with respect to albumin
cal surface generated an epileptic focus in rats (Seiffert
distribution in reactive astrocytes adjacent to the vas-
et al., 2004). Furthermore, hippocampal release of albu-
cular lesion. In our view, these data underscore the
min was reported in patients with temporal lobe epilepsy,
multifactorial character of epilepsies associated with
whereas no significant albumin was present in autopsy
focal malformations, that is, there is a broad spectrum
controls (van Vliet et al., 2007). In a rat model of temporal
of lesions which (1) lack a substantial vascular com-
lobe epilepsy, transient dysfunction of the BBB following
ponent and BBB disruption plays no obvious role in
status epilepticus with parenchymal accumulation of
their pathogenesis, for example, FCD IIa; (2) combine
serum proteins potentially aggravates epileptic seizures.
a vascular lesion with BBB dysfunction and reactive
The intracellular accumulation of albumin, however, may
astroglial albumin uptake with adjacent dysplastic cor-
be protective as it may reduce the acute edema that fol-
tex, for which the epileptogenic mechanisms of the
lows BBB dysfunction and extravasation of proteins into
individual pathogenetic components need to be care-
the brain extracellular areas. Furthermore, recent studies
fully dissected, for example, FCD IIIc; (3) are purely
have demonstrated that albumin, via transforming growth
vascular lesions (CA, AVM), for which recent evi-
factor b (TGFb) signaling, induces the transformation of
dence points to the ‘‘BBB-disruption astrocyte albumin
astrocytes from a ‘‘resting’’ to a ‘‘reactive’’ state (Ivens
uptake’’ cascade as a putatively epileptogenic mecha-
et al., 2007; Cacheaux et al., 2009).
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5. PRESENTATION DES RESULTATS DRAMES 2010 L’enquête DRAMES (Décès en Relation avec l’Abus de Médicaments ET de Substances) a pour objectifs de recueillir les cas de décès liés à l’usage abusif de substances psychoactives, d’identifier celles qui sont impliquées (qu’il s’agisse de médicaments ou de drogues illicites), d’évaluer leur dangerosité et d’estimer l’évol