Pharmaco-Resistant Epilepsy: Underlying Mechanisms & Treatment Options
ACVIM 2008
Holger A. Volk, DVM, Ph.D., MRCVS
London, UK

Introduction

Epilepsy is the most common chronic neurological disorder in both humans and dogs (Chandler, 2006). Most epileptic dogs are treated successfully for life, with the standard seizure suppressing drugs ("antiepileptic drugs", AEDs) phenobarbitone (PB) and/or potassium bromide (KBr). However, in about 20-30% of treated dogs, seizures are poorly responsive to treatment with a combination of PB and KBr (Schwartz-Porsche et al., 1985; Podell and Fenner, 1993; Trepanier et al., 1998). Increasing the dosage of PB and KBr may improve seizure control but this is not always possible due to side-effects and toxicity (e.g., polyuria/polydipsia, polyphagia, ataxia, lethargy and hepatotoxicity) (Dewey, 2006). In human medicine there has been progress in developing better tolerated epilepsy treatment over recent decades (Beghi, 2004; Rogawski and Löscher, 2004). Conversely, in veterinary medicine there is still a lack of data concerning new treatment options for epileptic patients, especially for pharmacoresistant patients. Many of the newer AEDs that show some effect and are well tolerated in humans (Beghi, 2004), are not efficacious in small animals due to inappropriate pharmacokinetics or life-threatening side-effects; these include vigabatrin, lamotrigine, tiagabine, oxcarbazepine (Podell, 1998). There are few alternative AEDs to use in canine pharmacoresistant patients. The human AEDs felbamate, gabapentin, levetiracetam, and zonisamide have been successfully used as additional drugs in some dogs with pharmacoresistant epilepsy (Podell, 1998; Dewey et al., 2004; Govendir et al., 2005; von Klopmann et al., 2005; Dewey, 2006; Platt et al., 2007; Volk et al., 2007). However, even if gabapentin, levetiracetam, and zonisamide have been shown to provide good short-term seizure control (Dewey et al., 2004; Govendir et al., 2005; Platt et al., 2007), their long-term efficacy is questionable (Govendir et al., 2005; Volk et al., 2007; von Klopmann et al., 2005). Drug-resistant epilepsy continues to be a major clinical problem in around one third of patients with epilepsy in human and veterinary medicine. Thus, new treatment options with a high long-term efficacy and without risk of toxicity in dogs are urgently needed.

This abstract will review the three major theories leading to drug refractoriness: 1) change in the neuronal network properties, 2) reduced drug-target sensitivity in epileptogenic brain tissue--"drug-target hypothesis", and 3) removal of antiepileptic drugs from the epileptogenic tissue through excessive expression of multidrug transporters--"multidrug transporter hypothesis".

Change in the Neuronal Network Properties

The neuronal network properties change in patients with recurrent seizures. This has been most intensively studied in humans with mesial temporal lobe epilepsy (TLE) and animal models of TLE. TLE is the most common form of human epilepsy and is characterized by recurrent complex partial seizures. The complex partial seizures are most often refractory to AEDs. The mechanisms underlying the pharmacoresistance of TLE are only poorly understood. Factors which have been discussed are the aetiology of the syndrome, disease progression, alterations in AED targets in the epileptogenic brain tissue, reduced AED penetration to the seizure focus, and structural brain alterations, hippocampal sclerosis (Regesta and Tanganelli, 1999; Kwan and Brodie, 2002). Hippocampal sclerosis is the most frequent pathological finding in patients with TLE, which have a temporal lobe resection for pharmacoresistant seizures. Hippocampal sclerosis is characterized by marked (typically >50%) neuronal loss in the CA1 and CA3 region of the hippocampus formation and the hilus of the dentate gyrus (Engel, 1996). Associated with the neuronal loss in the hippocampus are circuit rearrangements such as mossy fiber sprouting, which is characterised by sprouting of dentate granule cell axons back onto the inner molecular layer of the dentate gyrus. The question about the hippocampal formation being the cause or consequence of TLE remains under discussion. But a perhaps the more important question might be whether and how hippocampal sclerosis is involved in the medical refractoriness of TLE (Schmidt and Löscher, 2005). Interestingly, surgical resection of the epileptogenic hippocampus can turn a pharmacoresistant patient with TLE into a drug-sensitive patient assuming that the structural and functional changes in the epileptogenic hippocampus alter the response to AEDs (Schmidt and Löscher, 2005). In a rodent model for pharmacoresistant epilepsy we found significant loss of neurons in the CA1, CA3c/CA4 and dentate hilus of rats with drug-resistant epilepsy (Volk et al. 2006). We have suggested that the altered network properties could have lead to the observed refractoriness.

TLE is associated with complex partial seizures which have been considered unusual in dogs. Partial seizures have historically been considered rare in dogs, and it is thought that most dogs with idiopathic epilepsy exhibit generalised tonic-clonic seizures (Schwartz-Porsche, 1994). On the other hand, a few studies have recently questioned this, and it is being increasingly recognised that partial seizures are more common in dogs than was previously thought (Berendt and Gram, 1999; Jaggy and Bernardini,1998; Licht et al., 2002). Also in veterinary medicine it is generally believed that partial seizures can be more challenging to treat. Volk et al. (2007) showed in a recent study on pharmacoresistant epileptic dogs that 79% of the dogs' seizures were classified as complex-partial. However, the origin of the complex-partial seizures was not determined. In general, there is a lack of data if canine TLE exists. If surgical resection of pharmacoresistant epileptogenic tissue would be considered as a treatment option, further work needs to be done to characterise partial seizures in dogs.

Drug-Target Hypothesis

The drug target hypothesis is based on data of pharmacoresistant patients and animal models which have shown a reduction in sensitivity of drug targets such as receptors or ion channels to AEDs (Remy et al., 2003; Volk et al., 2006). This hypothesis is mainly based on findings which show that in the hippocampus of patients with pharmacoresistant TLE the use-dependent inhibition of sodium channels by carbamazepine was lost (Remy et al., 2003a). In addition, in a rodent TLE model, Remy et al. (2003b) found a loss of use-dependent blocking effects of carbamazepine identical to that observed in pharmacoresistant patients. Based on these findings, Remy et al. (2003a,b) suggested that reduced pharmacosensitivity of Na+ channels may contribute to the development of drug resistance. Further evidence to the drug-target hypothesis delivered a more recent study. In the aforementioned rodent model for pharmacoresistant epilepsy there was not only evidence of hippocampal sclerosis in the nonresponders, there was also a shift from GABA-A diazepam-sensitive to GABA-A diazepam-insensitive receptors in the hippocampus of nonresponders (Volk et al., 2007).However, most humans with refractory TLE are resistant to multiple AEDs with diverse mechanisms of action, so that alterations in other brain targets or additional resistance mechanisms must be involved (Löscher, 2007).

Multi drug transporter Hypothesis

In contrast to the aforementioned hypotheses, the multidrug transporter hypothesis is based on the assumption that it is not the brain target itself but the reduced AED concentration at the target that causes pharmacoresistance (Löscher, 2007). Indeed, an increased expression of multidrug transporters in brain capillary endothelial cells that form the blood-brain barrier (BBB) has been demonstrated both in epileptogenic brain tissue of human pharmacoresistant patients (Löscher, 2007) and in animal models of pharmacoresistant epilepsy (Löscher, 2007; Potschka et al., 2004; Volk and Löscher, 2005). Multidrug transporters such as P-glycoprotein (P-gp) act as drug efflux transporters in the BBB, limiting the penetration of various lipophilic drugs into the brain. An increased expression of such transporters in the BBB is thus likely to reduce brain drug levels of AEDs (Löscher, 2007).

Figure 1.
Figure 1.

The schematic shows the expression of P-gp in the normal blood brain barrier and the overexpression of P-gp in the epileptic focus.
In the epileptic focus P-gp is not only expressed in the luminal side of endothelial cells, but also in astrocytes and neurones. This leads to an increased efflux of AEDs into the blood, lowering the AED level in the epileptic focus.
 

In humans with pharmacoresistant epilepsy a variety of multidrug transporters have been described such as the multidrug-resistance proteins (MRPs), breast cancer resistance protein (BCRP) and the aforementioned P-gp. Currently, data suggests that P-gp plays the major role for drug refractoriness. Human P-gp actively transports the AEDs carbamazepine, felbamate, gabapentin, lamotrigine, phenobarbital, phenytoin, and topiramate. Interestingly, there is increasing evidence that P-gp substrates differ between species. A recent study showed that canine P-gp transports diazepam, gabapentin, lamotrigine, levetiracetam, and phenobarbital, however carbamazepine, felbamate, phenytoin, topirimate, and zonisamide were not substrates for canine P-gp (West and Mealey, 2007). Despite the fact that most AEDs are weak P-gp substrates, it is generally believed that the marked overexpression of P-gp in the epileptic focus is sufficient to explain the clinical experienced drug-refractoriness. Also in normal rats, using a microdialysis technique in which P-gp was inhibited has shown a significant increase in phenytoin brain tissue concentration (Potschka and Löscher, 2001). Similarly, the brain concentration of phenytoin was increased in mdr1 knockout mice that lack the gene encoding for P-gp in comparison with wild-type controls (Rizzi et al., 2002).

In two animal models for pharmacoresistant epilepsy, it was shown that P-gp was overexpressed in the rats which did not respond to treatment either with phenytoin (Potschka et al., 2004) or phenobarbital (Volk et al., 2005). Considering the fact that P-gp is overexpressed in patients with pharmacoresistant epilepsy and that a great variety of AEDs are P-gp substrates, the proof of principles reversing the drug refractoriness would be the next step.

Single case reports in the human literature have already suggested that verapamil could be used to reverse the drug-refractoriness of seizure activity (Summers et al., 2004; Iannetti et al. 2005). Large clinical trials are currently planned in Germany and Austria to confirm these findings (Löscher, 2007). In animal models, using verapamil or the more selective P-gp inhibitor Tariquidar did reverse the pharmacoresistance to oxcarbazepine, phenytoin, and phenobarbital (Clinckers et al., 2005; van Vliet et al., 2006; Brandt et al., 2006). Verapamil was also used in dogs with pharmacoresistant epilepsy as add on to phenobarbital, but this did not reverse the drug refractoriness (Jambroszyk et al. 2007). Further studies are needed to proof a benefit of P-gp inhibitors in pharmacoresistant epilepsy.

Conclusions

Convergent human clinical and experimental data support the three hypothesis of drug refractoriness: 1) change in the neuronal network properties, 2) drug-target hypothesis, and 3) multidrug transporter hypothesis--and offer novel therapeutic approaches for the treatment of drug-resistant epilepsy. However, further research is needed to evaluate the significance of the aforementioned hypotheses for canine epilepsy and for us to develop a more target approach to the problem of pharmacoresistant canine epilepsy.

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Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Holger Volk, DVM, PhD, MRCVS
The Queen Mother Hosp. for Animals
Hatfield, United Kingdom


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