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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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