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Keywords:

  • Blood-brain barrier;
  • Antiepileptic drugs;
  • Glucocorticosteroids;
  • Seizures

Summary

  1. Top of page
  2. Summary
  3. Acknowledgments
  4. Disclosure
  5. References

A significant number of patients with epilepsy fail to respond to currently available antiepileptic drugs. This suggests a need for alternative approaches to reduce the occurrence of seizures in these patients. Recent data have shown that in addition to well-known neuronal mechanism, seizures may be a consequence of misguided inflammatory response and blood–brain barrier disruption. Both peripheral and brain proinflammatory events have been demonstrated to govern the onset of status epilepticus. Evidence deriving from the experimental and clinical realms supports the notion that a role for proinflammatory and cerebrovascular events in seizure disorders is broader than previously suspected. As a result, methods to pharmacologically reduce blood–brain barrier permeability and reduce inflammation have emerged as means to reduce seizure burden. For instance, corticosteroids have been shown to be beneficial and the same agents may be able to further reduce seizure burden in conjunction with currently prescribed antiepileptic drugs.

The current direction of epilepsy research has substantially changed from the conventional focus. In the past, the traditional approach based on a neurocentric view of seizure generation promoted understanding of the neuronal mechanisms of seizures. These efforts resulted in the development of potent antiepileptic drugs (AEDs) and triggered refined surgical approaches to treat multiple drug-resistant seizures. However, the fact that a significant number of epileptics still fail to respond to available AEDs restates the need for an alternative approach.

Two emerging players hold the lion's share of “unconventional” epilepsy research. On one hand, inflammation is becoming an essential topic linking the immune system to neuronal dysfunction. On the other, altered blood–brain barrier (BBB) permeability plays an important etiologic role in seizure generation. The BBB has recently been targeted to develop new pharmacologic approaches aimed at restoring homeostasis and normal function. Combination therapies utilizing an AED in conjunction with BBB-stabilizing corticosteroid therapy may control seizures better than AED therapy alone (Marchi et al., 2011). Experimental and clinical evidence supports the use of antiinflammatory drugs to treat seizures; these results have been published and reviewed (e.g., Vezzani & Granata, 2005; Janigro, 2012). This short article uses an indirect approach in an attempt to further the notion that seizures can be prevented or treated by targeting inflammation and its gate keeper, the BBB. In particular, we will focus on status epilepticus (SE) and its management.

In status epilepticus the role of BBB–immune interactions is poorly understood but if one considers the therapeutic approaches to treat SE, a surprising overlap with antiinflammatory maneuvers becomes apparent (Shorvon & Ferlisi, 2011; Marchi et al., 2012). These therapeutic options span from drugs acting on γ-aminobutyric acid (GABA) receptors (benzodiazepines, anesthetics, and barbiturates), to antiinflammatory drugs (corticosteroids) and to other maneuvers with direct or indirect, documented or unknown, mechanisms of action on neurons.

One extreme of the spectrum of treatments for SE are GABAergic drugs or anesthetics, which quickly (<1 h) achieve the desired anti-SE effect. For these, a direct effect on neurons and modulation of inhibitory synapses is the unquestionable modus operandi. However, anesthetic drugs also have immunomodulatory effects partially overlapping with those of corticosteroids. For instance, propofol or thiopental exert potent antiinflammatory effects mediated by decreased nuclear factor-κB expression (Roesslein et al., 2008; Sanchez-Conde et al., 2008). Sevoflurane, which has similar anesthetic potency but lacks antiinflammatory action, is not the first choice among halogenated anesthetics for SE. Furthermore, sevoflurane may actually have an epileptogenic effect (Jaaskelainen et al., 2003). These antiinflammatory mechanisms are comparable to what is observed with corticosteroids and aid in the prevention, or recovery, of BBB integrity (Verhelst et al., 2005; Marchi et al., 2009, 2011 ).

An emerging therapeutic approach to refractory SE (reviewed by (Shorvon & Ferlisi, 2011) is the use of intravenous infusion of magnesium sulfate. Magnesium has negligible BBB permeability and, in healthy individuals, brain levels exceed serum concentrations (Amtorp & Sorensen, 1974). When the BBB is disrupted (e.g., during seizures), brain Mg2+ may decrease owing to brain-to-blood leakage. This causes a partial, seizure-promoting N-methyl-d-aspartate (NMDA) receptor disinhibition. Therefore, systemic administration to achieve high magnesium levels in blood may prevent leakage or restore brain levels of this ion, with a pronounced effect on excitatory synapses and thus on neuronal excitability.

Last but not least, traditional AEDs exert immunologic effects. Although an ample array of contradictory data exist, AEDs interfere with normal immunologic responses, thereby leading to the activation of proinflammatory pathways that may lead to or exacerbate seizure activity (Beghi & Shorvon, 2011).

There are several issues that need to be clarified before our understanding of inflammation and seizures translates into meaningful drug or therapeutic development. For example, it is not known if “fixing the barrier,” as with corticosteroids (Cucullo et al., 2004; Hoheisel et al., 1998), is sufficient to treat SE or other forms of seizures, or whether a full-blown antiinflammatory action is necessary. It is our opinion that BBB repair alone may be sufficient in SE when the initiating trigger consists of a permeability change leading to acute neuronal synchronization (as for example after iatrogenic BBB disruption (Marchi et al., 2007, 2010a,b) or BBB loss by noniatrogenic means (Ivens et al., 2007). When the cascade of events leading to seizures is more complex, as in encephalopathies or other panencephalic disease forms, it is likely that a broader antiinflammatory action is needed, perhaps consisting of use of more than one therapeutic modality (e.g., steroids and hypothermia or magnesium supplementation). An impediment to the development of these new combination therapies is the lack of recognized animal models. Pilocarpine has gained ground on systemic/intraparenchymal kainic acid, or electrical kindling, as a model of TLE; given the involvement of the brain–inflammatory axis in this model, we suggest that the pilocarpine model, or its variant Li-pilocarpine (Marchi et al., 2009), should be used as a paradigm for exploratory studies on SE treatments based on antiinflammatory agents. In the case of acute, provoked seizures, osmotic BBB disruption with intrarterial mannitol has the advantage of being readily available in many species, and the undisputed advantage of having been tested in human subjects.

In addition, BBB repair may lead to a beneficial “pharmacokinetic” effect. Several AEDs are, in blood, bound to serum proteins; the AED–protein complex does not permeate across the BBB and only the dissociated, “free” AED creates the gradient for concentration-driven accumulation into the brain. In the case of BBB disruption, this equilibrium is perturbed, resulting in the accumulation of AED and plasma proteins into the brain, altering the level of interstitial free AED. Reestablishing a proper blood-to-brain separation could counterbalance this phenomenon. “Fixing” the BBB could have a two-pronged effect; it would reestablish the proper brain interstitial ionic homeostasis (Janigro, 2012) and allow for AED passage across the BBB according to the drug chemical and physical proprieties (e.g., molecular weight and lipophilicity). The latter hypothesis further supports therapeutic approaches where an AED and a cerebrovascular/antiinflammatory drug are concomitantly administered.

In conclusion, these are exciting times for the epilepsy research community, with many new approaches, forms of disease, and disease models being developed (see for example (Ivens et al., 2007; van Vliet et al., 2007; Fabene et al., 2008; Maroso et al., 2010; Nabbout et al., 2011). A combined approach including neurologists, neuroscientists, and immunologists will likely leapfrog the field of treatment of SE and perhaps other epilepsies.

Acknowledgments

  1. Top of page
  2. Summary
  3. Acknowledgments
  4. Disclosure
  5. References

Supported by R01NS43284, R41MH093302, R21NS077236, R42MH093302, R21HD057256, and UH2TR000491.

Disclosure

  1. Top of page
  2. Summary
  3. Acknowledgments
  4. Disclosure
  5. References

The authors have no conflict of interest to declare.

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Acknowledgments
  4. Disclosure
  5. References
  • Amtorp O, Sorensen SC. (1974) The ontogenetic development of concentration differences for protein and ions between plasma and cerebrospinal fluid in rabbits and rats. J Physiol 243:387400.
  • Beghi E, Shorvon S. (2011) Antiepileptic drugs and the immune system. Epilepsia 52:4044.
  • Cucullo L, Hallene K, Dini G, Dal Toso R, Janigro D. (2004) Glycerophosphoinositol and dexamethasone improve transendothelial electrical resistance in an in vitro study of the blood-brain barrier. Brain Res 997:147151.
  • Fabene PF, Navarro MG, Martinello M, Rossi B, Merigo F, Ottoboni L, Bach S, Angiari S, Benati D, Chakir A, Zanetti L, Schio F, Osculati A, Marzola P, Nicolato E, Homeister JW, Xia L, Lowe JB, McEver RP, Osculati F, Sbarbati A, Butcher EC, Constantin G. (2008) A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 14:13771383.
  • Hoheisel D, Nitz T, Franke H, Wegener J, Hakvoort A, Tilling T, Galla HJ. (1998) Hydrocortisone reinforces the blood-brain properties in a serum free cell culture system. Biochem Biophys Res Commun 247:312315.
  • Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O, Seiffert E, Heinemann U, Friedman A. (2007) TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130:535547.
  • Jaaskelainen SK, Kaisti K, Suni L, Hinkka S, Scheinin H. (2003) Sevoflurane is epileptogenic in healthy subjects at surgical levels of anesthesia. Neurology 61:10731078.
  • Janigro D. (2012) Are you in or out? Leukocyte, ion, and neurotransmitter permeability across the epileptic blood-brain barrier. Epilepsia 53(Suppl. 1):2634.
  • Marchi N, Angelov L, Masaryk T, Fazio V, Granata T, Hernandez N, Hallene K, Diglaw T, Franic L, Najm I, Janigro D. (2007) Seizure-Promoting Effect of Blood-Brain Barrier Disruption. Epilepsia 48(4):732742.
  • Marchi N, Fan Q, Ghosh C, Fazio V, Bertolini F, Betto G, Batra A, Carlton E, Najm I, Granata T, Janigro D. (2009) Antagonism of peripheral inflammation reduces the severity of status epilepticus. Neurobiol Dis 33:171181.
  • Marchi N, Teng Q, Ghosh C, Fan Q, Nguyen MT, Desai NK, Bawa H, Rasmussen P, Masaryk TK, Janigro D. (2010a) Blood-brain barrier damage, but not parenchymal white blood cells, is a hallmark of seizure activity. Brain Res 1353:176186.
  • Marchi N, Teng QS, Nguyen MT, Franic L, Desai NK, Masaryk T, Rasmussen P, Trasciatti S, Janigro D. (2010b) Multimodal investigations of trans-endothelial cell trafficking under condition of disrupted blood-brain barrier integrity. Bmc Neurosci 11:34.
  • Marchi N, Granata T, Freri E, Ciusani E, Ragona F, Puvenna V, Teng Q, Alexopolous A, Janigro D. (2011) Efficacy of anti-inflammatory therapy in a model of acute seizures and in a population of pediatric drug resistant epileptics. PLoS ONE 6:e18200.
  • Marchi N, Granata T, Alexopoulos A, Janigro D. (2012) The blood-brain barrier hypothesis in drug resistant epilepsy. Brain 135(Pt 4):e211.
  • Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM, Rossetti C, Molteni M, Casalgrandi M, Manfredi AA, Bianchi ME, Vezzani A. (2010) Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 16:413419.
  • Nabbout R, Vezzani A, Dulac O, Chiron C. (2011) Acute encephalopathy with inflammation-mediated status epilepticus. Lancet Neurol 10:99108.
  • Roesslein M, Schibilsky D, Muller L, Goebel U, Schwer C, Humar M, Schmidt R, Geiger KK, Pahl HL, Pannen BH, Loop T. (2008) Thiopental protects human T lymphocytes from apoptosis in vitro via the expression of heat shock protein 70. J Pharmacol Exp Ther 325:217225.
  • Sanchez-Conde P, Rodriguez-Lopez JM, Nicolas JL, Lozano FS, Garcia-Criado FJ, Cascajo C, Gonzalez-Sarmiento R, Muriel C. (2008) The comparative abilities of propofol and sevoflurane to modulate inflammation and oxidative stress in the kidney after aortic cross-clamping. Anesth Analg 106:371378, table.
  • Shorvon S, Ferlisi M. (2011) The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 134:28022818.
  • van Vliet EA, da Costa AS, Redeker S, van Schaik R, Aronica E, Gorter JA. (2007) Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130:521534.
  • Verhelst H, Boon P, Buyse G, Ceulemans B, D'Hooghe M, De Meirleir L, Hasaerts D, Jansen A, Lagae L, Meurs A, Van Coster R, Vonck K. (2005) Steroids in intractable childhood epilepsy: clinical experience and review of the literature. Seizure 14:412421.
  • Vezzani A, Granata T. (2005) Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46:17241743.