Update on Advanced Treatment Options for Epilepsy

Michael Podell MSc, DVM, DACVIM (Neurology)

Over the past two decades, the number of antiepileptic drugs (AEDs) available to veterinarians has expanded exponentially. Coupled with this increase is the ability to rapidly and accurately diagnose underlying brain disease with readily accessible MRI scanning. As a result, the veterinary community is attuned to the need for early treatment intervention. As more treatment choices become available, the unrelenting questions that still arise are when should treatment begin, which initial drug therapy is best for our patients, when should treatment changes be considered, and finally, what advantages do newer drugs provide for our patients.

DECISION MAKING STRATEGIES FOR AED THERAPY

When To Start Treatment
The decision to start AED treatment is based on a number of factors, including etiology, risk of recurrence, seizure type and effect on patient, and risk of treatment. Risk factors for seizure recurrence are not well-established for cats and dogs. A number of relative risk factors have been identified in epileptic people, to include a diagnosis of current or previous defined cerebral lesions or trauma, presence of interictal EEG epileptic discharges (up to 90 % recurrence rate) and a history of marked post-ictal adverse effects (Todd’s paralysis).1 Evidence-based guidelines through several international groups are well established for people based on risk: benefit ratio and predictability factors of drug effect.1,2 From these guidelines, several commonalities exist in guiding clinical practice to include confirmation of an epileptic seizure event and seizure type, obtaining a definitive diagnosis, knowledge that recurrent seizure activity is correlated with poorer long term treatment success, and the influence of treatment on quality of life factors.3 Thus, the decision to treat is a reflection of the treatment goals to reduce or eliminate epileptic events, reduce seizure severity, avoid adverse effects, and reduce seizure-related mortality and morbidity.4
While similar information is not as readily available in our patient population, extrapolation is possible to provide rationale treatment guidelines. Overwhelming evidence exists in people that there is no benefit to start treatment after a single unprovoked event.5 The earlier AED therapy is started, however, the better the potential outcome may be for seizure control. Reasons to start AED include: 1) Identifiable structural lesion present or prior history of brain disease or injury; 2) Status epilepticus has occurred (ictal event > 10 minutes; 3) Two or more generalized seizures occur within a 24 hour period; 4) Two or more isolated seizure events occur within a 6 month period; and 5) Prolonged, severe, or unusual post-ictal periods occur.

Drug Selection
AED selection is based on a number of factors, including seizure type, efficacy, and tolerability. Again, evidence-based guidelines established by the International League Against Epilepsy (ILAE), American Academy of Neurology, and Standard and New AED Trials (SANAD) provide probability based recommendations.1,2,5 Despite these guidelines, no evidence exists that any single AED provides a better outcome for adults with unprovoked epilepsy when early treatment is started.3 Drug selection, therefore, is often based on tolerability. Adverse effects can be divided into transient, persistent and life-threatening categories (idiosyncratic or predictable). Most transient adverse effects are avoidable with titration dosing and dissipate within several weeks. Persistent effects are either CNS dose dependent effects associated with sedation, ataxia, vertigo or cognitive impairment or metabolic related with hormonal imbalances, metabolic syndromes and degenerative effects (e.g., osteoporosis). Severe life-threatening effects are mainly associated with either idiosyncratic bone marrow disease (e.g., aplastic anemia) or predictable organ damage over time (e.g., hepatotoxicity).

Success Parameters
Epilepsy treatment should be goal-oriented and approached in an objective fashion. Seizure elimination or significant seizure reduction, reducing seizure severity and maintaining normal lifestyle for patient and owner are all important considerations. While many drugs may provide initial improvement in seizure control, long-term efficacy is dependent on many factors. With only approximately 60 – 80% of both human and canine epileptic patients responsive to treatment, 6, 7 evaluation of reasons for recurrent seizure activity (refractory epilepsy) is important. These factors can be broken down into three main dependent variables: disease related, drug-related, and patient-related problems. Disease related factors include presence of an undiagnosed underlying brain disease, such as cortical malformation, prior trauma, or active disease process. Occult conditions can lead to localization related epilepsy where epileptic foci develop drug resistance due to architectural brain changes. Drug-related mechanisms include ineffective mechanism of action, development of tolerance, and alteration of drug target or uptake over time.8 Seizure specific therapy targets a drug for a specific seizure type, and inappropriate drug selection may result in poor control. Patient-related issues are now being discovered in relation to gene polymorphisms that affect AED pharmacokinetic or pharmacodynamic properties. As a result, altered drug metabolism or action is no longer predictable as compared to the general patient population.

Drug-Resistant Epilepsy
The ILAE recently developed a consensus statement on defining drug-resistant epilepsy based on a 2 level structure. In level 1, a patient is either classified as seizure free, undetermined outcome, or a treatment failure based on a standard monotherapy approach. Undetermined outcome is reserved for situations where an inadequate time period or drug level was documented as cause for failure. In level 2, patients have recurrent seizures on 2 or more appropriately chosen and used AED.23 Moreover, definitive evidence exists that a third AED is unlikely to provide further benefit in people.24 A variety of mechanisms of drug resistant have been postulated, to include altered neuronal membrane ion channels, enhanced drug efflux through the blood-brain barrier, and other immune-related interactions.25,26

THE GENERATION GAP

History of AED Development
From the introduction of bromide in 1857 by Sir Charles Locock to treat “hysterical” epileptic fits in women, to the development of phenobarbital in early 1900’s and the introduction of phenytoin, valproate and carbamazepine in the early 1970s, the use of these first generation AEDs was limited by mechanism, benefit, and adverse effects. Not until the early 1990’s did a revolution in drug development occur with the introduction of felbamate. The enhancement of rodent models for drug discovery screening was a driving factor in this expansion. The succession of the second generation drugs over the next two decades resulted in greater treatment success with significant improvement in tolerability. As the second decade of the 21st century starts, a third generation of AED therapy enters with more advances in improving seizure control and patient quality of life. (Table 1)

Mechanisms of Action
Antiepileptic drugs can be classified into three broad mechanistic categories (Table 2):

• Enhancement of inhibitory processes via facilitated action of gamma amino-butyric acid (GABA)
• Reduction of excitatory transmission
• Modulation of membrane cation (sodium or calcium) conductance

Unfortunately, several limitations exist in the selection of AEDs for use in veterinary medicine.9 In the past, many of the AEDs useful in people could not be prescribed to small animals either due to inappropriate pharmacokinetics (too rapid of an elimination), ineffectiveness, or the potential hepatotoxicity. The result was that the most commonly used AEDs in veterinary medicine were from the same mechanistic category of enhancing brain inhibition. The advent of new AEDs with alternative mechanisms of action is now available to allow a broader selection of treatment options.

Table 1. Categorization of Antiepileptic Drugs by Generation of Drug Development

FIRST GENERATION	SECOND GENERATION	THIRD GENERATION	NEXT GENERATION
Bromide Phenobarbital Benzodiazepines Phenytoin Carbamazepine Valproate	Felbamate Gabapentin Oxcarbazine Zonisamide Lamotrigine Levetiracetam Pregabalin Topiramate	Lacosamide Rufinamide	Flurofelbamate Brivacetam Carisbamate Retigabine Tiagabine Losigamone Remacemide Seletracetam

Clinical AED Pharmacology
The efficacy and safety profiles of AEDs are determined in large part by their pharmacokinetic properties. Drugs that are the easiest to use by the general population are ones that have the most favorable pharmacokinetic properties. For this reason, phenobarbital (PB) has been widely used in veterinary medicine for generations. Ultimately, the most desirable pharmacokinetic profile of an AED is one that has complete bioavailability, availability as a parenteral formulation, an elimination half-life suitable for daily or twice daily dosing, linear elimination kinetics, no autoinduction of enzymatic biotransformation, no pharmacokinetic interactions with other drugs, rapid brain penetration, a volume of distribution with a single compartment, low and nonsaturable protein binding, and no active metabolites. Unfortunately, the ideal AED has not been formulated for any species.

Table 2. Summary of the Mechanism of Actions of Currently Available Antiepileptic Drugs

	MECHANISM OF ACTION
	Decrease seizure onset		Decrease seizure spread
Drug	Enhanced Na+ channel inactivation	Enhanced GABA activated Cl- conductance	Reduced Ca+2 channel current	Reduced glutamate excitation	Novel mech- anism
Phenobarbital		++	+	?
Bromide		++*
Felbamate	+	+		+
Benzodiazepines		++
Gabapentin	?	+	++
Topiramate	+	+		+
Zonisamide	+		++
Levetiracetam		?	?	?	SV2a receptor
Pregabalin			++
Lacosamide	+				CRMP
Rufinamide	++

*Competitive displacement of Cl- through activated GABA receptors; ? = Possible mechanism; SV2a=synaptic vesicle 2A binding; CRMP=collapsin response mediator protein 2 binding.

First Generation AEDs
Phenobarbital is well-tolerated and is still the standard of care for first generation AED use in the cat and dog, as it is highly efficacious and well tolerated. The drug has high bioavailability, is over 50% protein bound, has a long elimination half-life, with predominant hepatic metabolism and autoinduction of hepatic microsomal enzymes (p-450 system), which can progressively reduce the elimination half-life with chronic dosing. Bromide is an inorganic salt with a prolonged elimination half-life (15-20 days), is solely renal excreted unchanged, has proven efficacy, but does have greater dose-dependent adverse effects.10

Second Generation AEDs
Felbamate is believed to increase seizure threshold and prevent seizure spreading by reducing excitatory neurotransmission in the brain and increasing GABA activity. Felbamate is most useful as monotherapy in the treatment of uncontrolled partial epilepsy and Lennox-Gastaut syndrome with atonic seizures. In dogs, the drug has a high bioavailability and protein binding capability and is metabolized by the hepatic microsomal p450 enzymes.11 Effective control of focal seizure activity (automatisms) with documented therapeutic serum concentrations has been shown with felbamate therapy in dogs.12 Felbamate is a non-sedating drug, but has been correlated with a higher incidence of idiosyncratic aplastic anemia and liver toxicity in people. Similar, but rare and reversible blood cytopenias and hepatotoxcity have been observed in the dog. Serial monitoring of the complete blood count and chemistry panel is recommended at 1 month and every 3 months during treatment. Initial dose is 5-10 mg/kg q 12 hours with titration to q 8 hr dosing. Trough serum drug concentration is typically done 1 –2 weeks after initiation of treatment, with a therapeutic range between 25-100 mg/L.
Topiramate is a sulphamate-substituted monosaccaride with multiple mechanisms of action of rapidly potentiated GABA activity, sodium channel blockade and post-synaptic glutamate receptor blockage that is efficacious against a wide variety of seizure types.12 In people, topiramate is well-absorbed, is primarily renal excreted as an unchanged drug and has a relatively long-half life of 20-30 hours. In the dog, however, topiramate has a relatively short elimination half-life in the dog of 2-4 hours,13 but may exhibit prolonged pharmacodynamic activity in the brain due to high affinity receptor binding. Initial dosing is 2- 5 mg/kg q 12 hours with gradual adaption to 10 mg/kg q 12 hr. Loss of appetite, irritability, GI upset and sedation are potential adverse effects.
Zonisamide is a substituted 1,2-benzisoxazole derivative that works via multiple mechanisms to block the propagation of epileptic discharges and suppress focal epileptogenic activity through sodium and calcium channel blockade and GABA activity potentiaion.14 In the dog, zonisamide is well-absorbed, has a relatively long-half life (15-20 hours), has high protein-binding affinity and has both hepatic and renal metabolism.15 The drug is highly concentrated in red blood cells due to high binding to carbonic anhydrase and other red cell protein components. Broad-spectrum antiepileptic activity has been reported against a variety of seizure types, with particular improvement in the treatment of adult myoclonus epilepsy.16. Since serum drug levels are lowered by phenobarbital, phenobarbital doses should be decreased by 25%. Initial dose is 5 mg/kg q 12 hr with a therapeutic range of 10-40 mcg/ml, with greater efficacy at 20 mcg/ml.17 Major adverse effects include a higher incidence of sedation, GI upset, metabolic acidosis and renal calculi formation.
Levetiracetam is the S-enantiomer of the ethyl analogue of piracetam with a unique mechanism of action mediated by binding to the synaptic vesicular protein, SV2A, which decreases neurotransmitter release. In dogs, the drug is well-absorbed, is rapidly metabolized with an elimination half-life estimate of 4-8 hours and is predominantly renal excreted (> 80%).18 Wide fluctuations of drug metabolism, however, occur in the dog. Initial dose is 10- 20 mg/kg q 12 hours with gradual increment to 20 or higher mg/kg q 8 hour dosing. The therapeutic range is not well-defined and drug monitoring is recommended only to establish individual patient pharmacokinetic pattern. The drug is well-tolerated, with sedation noted as the most common adverse effect. Parenteral formulation is available for IV loading at 40-60 mg/kg over 10 minutes.
Lamotrigine is a novel drug that is chemically unrelated to current AEDs. Although efficacious in human epileptic patients, the drug is converted to a cardiotoxic 2-N methyl metabolite in dogs, 19 not found in people, and is not recommended for use in dogs.
Pregabalin is a structural analogue of GABA with a mechanism of action of voltage-gated calcium channel modulation that decreases depolarization induced calcium influx at nerve terminals, ultimately, to reduce excitatory neurotransmitter release. The mean elimination half-life is estimated at 7 hours in dogs.20 Metabolism appears to be predominantly renal excretion with minimal protein binding and drug interaction. Efficacy as an add-on for refractory partial seizures was found in several studies in people and in a recent study in dogs.21 A definitive therapeutic range has yet to be determined for people or dogs. Initial dose recommendation is 4 mg/kg q 8 to 12 hours. Adverse effects appear limited to sedation and ataxia.

Third Generation AEDs
Lacosamide (Vimpat®) is a functionalized amino acid proven to decrease neuronal discharge frequency and synaptic excitability.22 The postulated mechanisms of action includes selective slow inactivation of sodium channels and novel binding to collapsin response mediator protein-2. In people, the drug is well-absorbed, has minimal first pass effect with predominant renal excretion, low protein binding, favorable drug-drug interactions with other AEDs, and is well-tolerated. Clinical trials demonstrate comparable decrease in seizure frequency as that of levetiracetam and zonisamide at a dose of 100-200 mg q 12 hours. A parenteral formulation is available for IV loading. No data was found regarding clinical use in dogs or cats.
Rufinamide (Banzel®) is a novel AED that is structurally unrelated to any other AED. The main mechanism of action is related to prolongation of the inactive state of the sodium channel to prevent neuronal depolarization. In people, the drug is slowly absorbed with low bioavailability. Renal excretion is high and no induction of the hepatic p450 system was found, although other hepatic metabolized drugs decrease serum concentration. Of a total of 9 double-blinded studies in people, 5 revealed a positive effect of rufinamide to treat refractory partial seizures but not generalized seizures.23 Initial dosing ranged from 10 to 40 mg/kg/day, with dose dependent adverse effects of sedation, fatigue and dizziness noted. A parenteral formulation is not available. No data was found regarding clinical use in dogs or cats.

THE NEXT GENERATION

The future of epilepsy treatment is undergoing a multifaceted, exponential growth. Over 15 new AEDs are currently in clinical trials throughout the world. A common denominator for drug development is the ability to define pharmacoresistant therapy by both drug action and patient pharmacogenomics. With the advent of more advanced diagnostic capabilities to map localization epilepsy, conventional surgical and radiosurgical intervention can provide curative outcomes previously never imagined. Vagal and brain stimulators introduce physiologic methods of altering the brain’s baseline seizure threshold. While veterinarians may not incorporate all of these modalities into our clinical practice yet, the future potential to help our patients grows every day as well.

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