Pharmacoresistant epilepsy: From pathogenesis to current and emerging therapies
ABSTRACTAlmost one-third of people with epilepsy continue to have seizures despite appropriate antiepileptic drug treatment, placing them at considerable risk of cognitive and psychosocial dysfunction and death. We recommend early referral to an epilepsy center when seizures are difficult to control.
KEY POINTS
- When seizures have failed to respond to two or three appropriate antiepileptic drugs, the chance of significant benefit from other drugs is 10% or less.
- The biologic basis of pharmacoresistance is multifactorial and varies from one patient to another.
- Social and lifestyle factors, including alcohol misuse and nonadherence to prescribed antiepileptic drugs, can contribute to or masquerade as pharmacoresistance.
- Current options for patients with pharmacoresistant epilepsy are surgery (the best option when feasible), vagus nerve stimulation, investigational drugs or devices, and aggressive combination treatment with available antiepileptic drugs.
AN APPROACH TO PHARMACORESISTANT EPILEPSY FOR THE NONSPECIALIST
Review and confirm the diagnosis of epilepsy with the help of a careful history, video-EEG, and imaging.
When seizures cannot be controlled with drugs, it is important to verify that the events in question are indeed epileptic. Continuous video-EEG monitoring may be necessary to capture and characterize the clinical manifestations and corresponding EEG changes.14 When a typical spell is not associated with an EEG change, one can often make the diagnosis of nonepileptic events, which commonly are psychogenic nonepileptic seizures. Of note, however: scalp EEG may fail to pick up ictal EEG changes in focal seizures arising from a small or deeply situated focus: for example, as in focal sensorimotor seizures from restricted perirolandic cortex.15,16
Identify the cause, type of seizure or seizures, and syndromic classification, if any.
Review past and present medications, doses, efficacy, and side effects. Consider the possibility of drug interactions.
Different drugs may have different pharmacokinetic and dose-efficacy curves. With most of the newer-generation antiepileptic compounds such as lamotrigine (Lamictal), levetiracetam (Keppra), pregabalin (Lyrica), and topiramate (Topamax), efficacy may continue to increase in some patients as the dose is increased without reaching toxicity. An important exception is phenytoin (Dilantin): due to its nonlinear and saturable pharmacokinetics, even minor dose increases may lead to a large increase in phenytoin concentration (the drug accumulates as elimination becomes saturated). A high degree of individual variability exists, which is determined by factors that include the patient’s age, genetic and enzymatic profile, comorbidities, and concurrent medications.17 Understanding these relationships in individual patients facilitates dose selection and titration and enhances compliance. Testing serum drug levels may help when compliance is questionable.
Choose antiepileptic drugs primarily on the basis of the type of seizures and the individual clinical scenario: Which drug is likely to be most efficacious with the fewest side effects, and which one is appropriate for the patient’s comorbidities and concomitant medications?
When changing the dosage, withdrawing a drug, or adding a second antiepileptic drug, always do it in a systematic way, one step at a time. Reassess the response to the change before moving to the next step.
Discuss issues such as seizure precautions, lifestyle modifications, psychosocial dysfunction, and sudden unexpected death. Offer access to epilepsy-specialist nurses and epilepsy support groups such as those offered by the Epilepsy Foundation of America, the agency dedicated to the welfare of individuals with epilepsy in the United States (https://epilepsyfoundation.ning.com/).
PATTERNS OF DRUG RESISTANCE
Epidemiologic studies suggest three different patterns of drug resistance in epilepsy: de novo, progressive, and waxing-and-waning.
De novo drug resistance
In some patients, resistance is present from the time of onset of the very first seizure, before any antiepileptic drug is even started. One landmark study showed that patients with newly diagnosed epilepsy for whom the first drug was ineffective had only an 11% probability of future success, compared with 41% to 55% in patients who had had to stop taking the drug because of intolerable side effects or idiosyncratic reactions.10 Most patients for whom the first drug fails will be resistant to most and often all antiepileptic drugs.18 These results suggest that seizures in newly diagnosed patients are either easy to control or difficult to control right from the start.
Progressive drug resistance
In some patients, epilepsy is initially controlled but then gradually becomes refractory. This pattern may be seen, for example, in childhood epilepsies or in patients with hippocampal sclerosis.19,20
Waxing and waning resistance
In some patients, epilepsy has a waxing-and-waning pattern: ie, it alternates between a remitting (pharmacoresponsive) and relapsing (pharmacoresistant) course. Patients thought to have drug-resistant epilepsy may become seizure-free when other drugs are tried. Changes in drug bioavailability, local concentration of the drug in the brain, receptor changes, the development of tolerance, and interactions with new medications may be implicated, though the exact mechanism is not understood.21
BIOLOGIC BASIS OF PHARMACORESISTANT EPILEPSY
Pharmacoresistance is not unique to epilepsy: it is now recognized in diverse brain disorders, including depression and schizophrenia,22 and in other diseases affecting the brain, such as human immunodeficiency virus infection and many forms of cancer.23
Multiple drug resistance is characterized by insensitivity to a broad spectrum of drugs that presumably act on different receptors and by different mechanisms.24
Conceptually, the variable response to antiepileptic drugs can be attributed to factors related to the disease, the patient, and the drugs, or to other unknown factors. These factors are not mutually exclusive and may be either constitutive or acquired during the course of the disease.
