Clinical Topics & News

Modern Treatment of Drug-Resistant Epilepsy

Andrew Wilner, MD
Dr. Wilner is a neurologist, epileptologist, and author of Bullets and Brains.
He is affiliated with Angels Neurological Centers in Abington, Massachusetts.



Approximately two-thirds of people with new-onset seizures become seizure free with antiepileptic drug treatment.The initial medication choice must be individualized and take into account many factors, including the patient’s seizure type, syndrome, comorbidities, associated medications, hepatic and renal function, childbearing potential, antiepileptic drug adverse event profile, and cost.

Drug-Resistant Epilepsy
Conversely, approximately one-third of people with epilepsy fail to respond to the first, second, or even third antiepileptic drug.1 Poor prognostic factors include multiple seizures before the initiation of treatment, as well as the presence of a structural cerebral abnormality.1

The International League Against Epilepsy (ILAE) has recently proffered the following definition of drug-resistant epilepsy:

“… failure of adequate trials of two (or more) tolerated, appropriately chosen, and appropriately used antiepileptic drug regimens (whether administered as monotherapies or in combination) to achieve freedom from seizures.” 2

Other, less precise terms to describe drug resistant epilepsy include “intractable,” “refractory,” “treatment-resistant,” and “uncontrolled.” While it may seem surprising that the ILAE definition requires only two drug failures before declaring a patient “drug-resistant,” the definition contains three strict stipulations. First, the patient must tolerate the drug. If, for example, a patient takes one or two doses of a new drug, complains of dizziness, and stops taking the medication, that does not count as an “adequate trial.” Second, the medication must be appropriate for the seizure type. For example, if ethosuximide were prescribed for partial-onset seizures, it would not be an “appropriately chosen” drug. Third, the definition requires adherence to the chosen regimen, as the medication must be “appropriately used.”

Poor medication adherence often contributes to suboptimal seizure control and may mimic drug resistance.3 Once-a-day therapies such as eslicarbazepine (Aptiom), perampanel (Fycompa), and extended-release preparations should be considered in patients who struggle to remember to take their medication.

The treatment of drug-resistant patients requires empiric trials of antiepileptic drugs used in monotherapy or in combination. Even after failing three antiepileptic drugs, some patients become seizure free when additional drugs are tried.4 Additional strategies for drug-resistant patients include neuromodulating devices such as the vagus nerve stimulator and responsive neurostimulation; the ketogenic, modified Atkins, or other diets; and epilepsy surgery. Cannabinoids are not yet proven safe or effective.

Expanding Medical Armamentarium
The US Food and Drug Administration (FDA) has granted approval to multiple medications for the treatment of seizures. These include older drugs, many of which are still commonly used (Table 1), and a plethora of new drugs that have received FDA approval since 1993 (Table 2). Clinicians can choose from these medications with the dual goals of improving seizure control and decreasing adverse events. This army of antiepileptic drugs exhibits the following mechanisms of action that may decrease or eliminate seizures:

• AMPA receptor noncompetitive blockade

• Carbonic anhydrase inhibition

• GABA enhancement

• Potassium channel opening

• Sodium channel blockade

• Synaptic vesical glycoprotein 2A binding

• Voltage dependent calcium channels effects

• α2δ calcium channel subunit binding.5

Table 1

Carbamazepine (Tegretol)

Divalproex sodium (Depakote)

Ethosuximide (Zarontin)

Phenobarbital (Luminal)

Phenytoin (Dilantin)

Primidone (Mysoline)

Valproic acid (Depakene)

Table 2

Clobazam (Onfi)

Eslicarbazepine (Aptiom)

Ezogabine (Potiga)

Felbamate (Felbatol)

Gabapentin (Neurontin)

Lacosamide (Vimpat)

Lamotrigine (Lamictal)

Levetiracetam (Keppra)

Oxcarbazepine (Trileptal)

Perampanel (Fycompa)

Pregabalin (Lyrica)

Rufinimide (Banzel)

Tiagabine (Gabitril)

Topiramate (Topamax)

Vigabatrin (Sabril)

Zonisamide (Zonegran)

Rational Polytherapy
Advantages of monotherapy include improved compliance, fewer drug–drug interactions, decreased toxicity, and lower cost. However, some patients only achieve seizure control with the combination of two or more drugs (adjunctive therapy). Rational polytherapy is the practice of combining drugs that complement each other in terms of mechanism of action and side effect profiles. Limited evidence supports this concept.6 For example, in one study, the combination of a sodium channel drug plus a drug with multiple mechanisms of action resulted in significantly more seizure-free patients than any other combination.7 The combination of lamotrigine and valproate may be particularly effective.8,9Prescribing two drugs that both block sodium channels may result in additive toxicity, constituting an additional argument to combine drugs with different mechanisms of action.10

While approximately two-thirds of people with epilepsy achieve seizure control, the remaining one-third are drug-resistant. Drug-resistant patients are challenging to treat, but repeated empiric trials with novel antiepileptic drugs may result in improved seizure control and sometimes even seizure freedom. While the simplicity of monotherapy is preferred, some patients require adjunctive therapy. Once-a-day therapy may improve adherence. The availability of many new drugs with different mechanisms of action and side-effect profiles offers the potential to eliminate seizures and reduce side effects in people with drug-resistant epilepsy.

Recommended Reading

Can Cerebral Oxygenation Predict Generalized Tonic–Clonic Seizures?
Epilepsy Resource Center
New Guideline Offers Advice for First Unprovoked Seizure
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Seizure Onset Is Delayed After Intracranial Electrode Implantation
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Does Deep Brain Stimulation of ANT Provide Sustained Efficacy and Safety?
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AAN/AES Guideline on Management of Unprovoked First Seizure in Adults
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Medical Marijuana Liquid Extract May Help Children With Severe Epilepsy
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Pediatric Epilepsy Surgeries Have Increased in the Past Decade
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Elinor Ben-Menachem, MD
Epilepsy Resource Center
Allan Krumholz, MD
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Nikesh Ardeshna, MD
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