Brain Advance Access originally published online on June 12, 2007
Brain 2007 130(8):e78; doi:10.1093/brain/awm120
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Reply: Complexities in the association of human blood–brain barrier disruption with seizures: importance of patient population and method of disruption
1Epilepsy Institute of The Netherlands (SEIN), Achterweg 5, 2103 SW, Heemstede, The Netherlands and 2Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Kruislaan 320, 1098 SM, Amsterdam, The Netherlands
Correspondence to: Dr J.A. Gorter, Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Kruislaan 320, 1098 SM Amsterdam, The Netherlands E-mail: gorter{at}science.uva.nl
We recently reported that epileptic seizures might be facilitated through the action of blood–proteins that leak into the CNS during the chronic epileptic phase in rats (Van Vliet et al., 2007
). This was further supported by our mannitol experiments in epileptic rats which showed increased seizure progression in a subgroup of rats. Mannitol can be used to open the blood–brain barrier (BBB) by producing osmotic shrinking of the endothelial cells and mechanical separation of the tight junctions that form the BBB. Therefore mannitol can be used to deliver various drugs directly to the brain. Previous studies by Neuwelt et al. (Neuwelt et al., 1983, 1986; Roman-Goldstein et al., 1994) pointed to the fact that seizures could be one of the complicating factors when patients with brain tumours were treated with mannitol. Since these patients were also treated with chemotherapeutic and contrast agents, seizures might have occurred through the pro-epileptogenic action of these agents. On the other hand, blood proteins that leak into the CNS might also facilitate seizure activity especially when potentially epileptogenic tumours are present. Many brain tumours are highly epileptogenic: epilepsy has been reported in >80% of low-grade gliomas (Vertosick et al., 1991), in 30–60% of high-grade gliomas (Scott and Gibberd, 1980), in 30% of meningiomas (Lieu and Howng, 2000) and in 20% of primary CNS lymphomas (Hochberg and Miller, 1988). Marchi and colleagues recently reported that leakage of blood proteins into the CNS via mannitol treatment might induce seizures. This treatment was performed in brain tumour patients (with CNS lymphomas), but they substantiated their conclusion by findings in two normal pigs in which seizures occurred after mannitol injection that was accompanied by BBB leakage. It is tempting to speculate that these acute seizures were caused by blood-borne substances that have entered the brain after the BBB is compromised (Marchi et al., 2007). We need to be cautious however not to overestimate the role of a leaking BBB in acute seizure activity. After all, (1) we did not observe acute seizures after mannitol treatment in control rats and (2) an epileptogenic focus only develops several days after cortical BBB disruption in control rats (Seiffert et al., 2004; Ivens et al., 2007; Tomkins et al., 2007). Thus the pro-epileptogenic action of mannitol in normal pig brain could reflect methodological differences or species specificity. Moreover it is very likely that other mechanisms play a role in the manifestation of the acute seizures versus the development of an epileptogenic focus or the increased excitability on an already epileptogenic ‘background’.
There are anecdotal data that suggest that mechanical BBB disruption by electrode placement in the brain, decreases seizure activity, which would argue against the pro-epileptogenic role of BBB leakage. The fact that these patients receive AEDs and other perioperative drugs (such as corticosteroids) makes it rather difficult to estimate the contribution of the BBB disruption itself. Controlled animal studies might resolve this issue.
The evidence is accumulating that blood-borne substances contribute to the maturation of an epileptogenic focus (Seiffert et al., 2004; Ivens et al., 2007; Tomkins et al., 2007) and/or the worsening of the epileptic condition (Van Vliet et al., 2007). Although it is not fully elucidated which factors contribute to increased excitability, a recent study elegantly demonstrated that BBB opening resulted in brain exposure to albumin, followed by downregulation of inward rectifying potassium channels in astrocytes. This, in turn, led to reduced buffering of extracellular potassium and facilitated N-methyl-D-aspartate receptor mediated neuronal hyperexcitability and epileptiform activity (Ivens et al., 2007). Another pro-epileptogenic factor may be local brain inflammation that occurs after the entry of serum-derived proteins. Inflammation is permanently increased in a chronic epileptic rat model (Gorter et al., 2006) and inflammatory responses such as leucocyte recruitment, cytokine- and interleukin-production can be pro-convulsive and contribute to the sustained BBB leakage by disrupting tight junctions. Future studies should be focused on whether restoration of BBB function (e.g. by inhibition of the inflammatory process) will affect seizure susceptibility.
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