Distinguishing Drug Resistance From Pseudoresistance in Epilepsy

PHILADELPHIA—Between 60% and 65% of patients with new-onset epilepsy become seizure-free with medications, according to an overview presented at the 69th Annual Meeting of the American Epilepsy Society. A patient whose seizures are uncontrolled by medication may have drug-resistant epilepsy, but the neurologist must take care to rule out pseudoresistance, said Patrick Kwan, MD, PhD, Chair of Neurology at the University of Melbourne in Australia. “A substantial proportion of these patients with seemingly uncontrolled epilepsy could become seizure-free with further drug adjustment, and the early data we’ve seen … would suggest that dose increase alone might be just as effective as substitution or add-on.”

What Is Drug Resistance?

In 2010, the International League Against Epilepsy (ILAE) defined drug-resistant epilepsy as the failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug (AED) schedules to achieve sustained seizure freedom. Longitudinal research by Brodie and colleagues appears to provide evidence to support this definition. In 2015, the researchers presented the latest analysis of the outcomes of a cohort of adults and adolescents with newly diagnosed epilepsy. The analysis included more than 1,800 patients who had been followed up for more than 30 years. Most of the patients became seizure-free on their first (45%) or second (12%) drug schedule. Less than 7% of patients who failed two AEDs subsequently became seizure-free. The latest results are consistent with the investigators’ previous analyses of the cohort.

A 2007 study by Callaghan et al also appears to support the ILAE definition of drug resistance. For three years, the researchers followed 246 patients with epilepsy who had failed to respond to at least two AEDs and who continued to receive medical therapy. Approximately 14% of patients treated only with medication became seizure-free for six months. “Clearly, these patients had a much lower chance of becoming seizure-free,” said Dr. Kwan.

Thus, if a patient fails two AED schedules, “that is enough to suspect … underlying drug-resistant epilepsy,” he added. At that point, the neurologist should review the patient’s diagnosis and the classification of the epilepsy before considering new drug therapies or drug combinations.

Ruling Out Pseudoresistance

Ruling out pseudoresistance is an important part of the re-evaluation of a patient with apparent drug-resistant epilepsy. A patient who has received an incorrect diagnosis may have pseudoresistance. One 40-year-old male patient had recurrent seizures despite a history of resective surgery, said Dr. Kwan. An EKG revealed that the patient had asystole and needed a pacemaker rather than medical or surgical treatment.

Pseudoresistance also may apply to a patient who takes an inappropriate AED for his or her epilepsy syndrome. A 34-year-old woman with limb twitches and convulsion successively initiated and discontinued lamotrigine and levetiracetam after developing side effects, said Dr. Kwan. Carbamazepine also failed to stop the seizures. Although the woman had received a diagnosis of mesial temporal sclerosis, a review of her MRI revealed a malrotation of the hippocampus. After the woman discontinued carbamazepine and initiated a low dose of valproate, “she became seizure-free almost immediately and has remained seizure-free for the last two years,” said Dr. Kwan.

An incorrect dose of therapy also may result in pseudoresistance. A 52-year-old man continued to have seizures despite treatment with high doses of valproate and levetiracetam and began to develop sensitivity to valproate. A neurologist added 100 mg/day of topiramate to the patient’s regimen and reduced his dose of valproate. After the patient had another seizure five months later, the neurologist increased his dose of topiramate to 150 mg/day. The patient became seizure-free and remained so for two years, said Dr. Kwan.

Identifying an Adequate Dose

Drug resistance cannot be established unless the patient has received adequate doses of therapy. One way of identifying an adequate dose relies on the World Health Organization’s definition of the defined daily dose: the assumed average maintenance dose per day for a drug used for its main indication in adults. Examples of the defined daily dose include 1,000 mg/day of carbamazepine and 1,500 mg/day of valproate.

Dr. Kwan and colleagues followed patients with newly diagnosed epilepsy to determine whether the dose at which the first drug failed predicted patients’ response to the second drug. Doses of the first regimen were stratified according to whether they were above or below the 25%, 50%, or 75% cutoffs for the defined daily dose of the given AED. The investigators found that when the first drug failed at a dose above the 50% and 75% cutoffs of its defined daily dose, the patient was less likely to respond to the second drug. “In particular, the 50% defined daily dose cutoff had a high sensitivity and specificity,” said Dr. Kwan. “This will be perhaps a reasonable dose to use.”

Another researcher recruited more than 300 patients with seemingly uncontrolled epilepsy into an observational study. Approximately 10% of the cohort fulfilled the ILAE definition of drug resistance. Among patients who were not drug-resistant and not seizure-free, the most common reason for their outcome was an inadequate dose of AED (ie, less than 50% of the defined daily dose). For some of the patients, treating neurologists increased the AED dose or changed or added an AED. During a three-year period, 17% of patients whose treatment was modified became seizure-free. In contrast, none of the patients in the drug-resistant group became seizure-free. The proportion of seizure-free patients was similar for patients who received an increased dose of the same AED and patients who received a different AED.

“The patient seizure-free rate was significantly lower in patients who had failed at least one AED at an adequate dose,” said Dr. Kwan. “This reinforces the concept that … failure of an adequate dose of at least one AED has a very strong prediction of subsequent outcome,” Dr. Kwan concluded.

—Erik Greb

PHILADELPHIA—Between 60% and 65% of patients with new-onset epilepsy become seizure-free with medications, according to an overview presented at the 69th Annual Meeting of the American Epilepsy Society. A patient whose seizures are uncontrolled by medication may have drug-resistant epilepsy, but the neurologist must take care to rule out pseudoresistance, said Patrick Kwan, MD, PhD, Chair of Neurology at the University of Melbourne in Australia. “A substantial proportion of these patients with seemingly uncontrolled epilepsy could become seizure-free with further drug adjustment, and the early data we’ve seen … would suggest that dose increase alone might be just as effective as substitution or add-on.”

What Is Drug Resistance?

In 2010, the International League Against Epilepsy (ILAE) defined drug-resistant epilepsy as the failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug (AED) schedules to achieve sustained seizure freedom. Longitudinal research by Brodie and colleagues appears to provide evidence to support this definition. In 2015, the researchers presented the latest analysis of the outcomes of a cohort of adults and adolescents with newly diagnosed epilepsy. The analysis included more than 1,800 patients who had been followed up for more than 30 years. Most of the patients became seizure-free on their first (45%) or second (12%) drug schedule. Less than 7% of patients who failed two AEDs subsequently became seizure-free. The latest results are consistent with the investigators’ previous analyses of the cohort.

A 2007 study by Callaghan et al also appears to support the ILAE definition of drug resistance. For three years, the researchers followed 246 patients with epilepsy who had failed to respond to at least two AEDs and who continued to receive medical therapy. Approximately 14% of patients treated only with medication became seizure-free for six months. “Clearly, these patients had a much lower chance of becoming seizure-free,” said Dr. Kwan.

Thus, if a patient fails two AED schedules, “that is enough to suspect … underlying drug-resistant epilepsy,” he added. At that point, the neurologist should review the patient’s diagnosis and the classification of the epilepsy before considering new drug therapies or drug combinations.

Ruling Out Pseudoresistance

Ruling out pseudoresistance is an important part of the re-evaluation of a patient with apparent drug-resistant epilepsy. A patient who has received an incorrect diagnosis may have pseudoresistance. One 40-year-old male patient had recurrent seizures despite a history of resective surgery, said Dr. Kwan. An EKG revealed that the patient had asystole and needed a pacemaker rather than medical or surgical treatment.

Pseudoresistance also may apply to a patient who takes an inappropriate AED for his or her epilepsy syndrome. A 34-year-old woman with limb twitches and convulsion successively initiated and discontinued lamotrigine and levetiracetam after developing side effects, said Dr. Kwan. Carbamazepine also failed to stop the seizures. Although the woman had received a diagnosis of mesial temporal sclerosis, a review of her MRI revealed a malrotation of the hippocampus. After the woman discontinued carbamazepine and initiated a low dose of valproate, “she became seizure-free almost immediately and has remained seizure-free for the last two years,” said Dr. Kwan.

An incorrect dose of therapy also may result in pseudoresistance. A 52-year-old man continued to have seizures despite treatment with high doses of valproate and levetiracetam and began to develop sensitivity to valproate. A neurologist added 100 mg/day of topiramate to the patient’s regimen and reduced his dose of valproate. After the patient had another seizure five months later, the neurologist increased his dose of topiramate to 150 mg/day. The patient became seizure-free and remained so for two years, said Dr. Kwan.

Identifying an Adequate Dose

Drug resistance cannot be established unless the patient has received adequate doses of therapy. One way of identifying an adequate dose relies on the World Health Organization’s definition of the defined daily dose: the assumed average maintenance dose per day for a drug used for its main indication in adults. Examples of the defined daily dose include 1,000 mg/day of carbamazepine and 1,500 mg/day of valproate.

Dr. Kwan and colleagues followed patients with newly diagnosed epilepsy to determine whether the dose at which the first drug failed predicted patients’ response to the second drug. Doses of the first regimen were stratified according to whether they were above or below the 25%, 50%, or 75% cutoffs for the defined daily dose of the given AED. The investigators found that when the first drug failed at a dose above the 50% and 75% cutoffs of its defined daily dose, the patient was less likely to respond to the second drug. “In particular, the 50% defined daily dose cutoff had a high sensitivity and specificity,” said Dr. Kwan. “This will be perhaps a reasonable dose to use.”

Another researcher recruited more than 300 patients with seemingly uncontrolled epilepsy into an observational study. Approximately 10% of the cohort fulfilled the ILAE definition of drug resistance. Among patients who were not drug-resistant and not seizure-free, the most common reason for their outcome was an inadequate dose of AED (ie, less than 50% of the defined daily dose). For some of the patients, treating neurologists increased the AED dose or changed or added an AED. During a three-year period, 17% of patients whose treatment was modified became seizure-free. In contrast, none of the patients in the drug-resistant group became seizure-free. The proportion of seizure-free patients was similar for patients who received an increased dose of the same AED and patients who received a different AED.

“The patient seizure-free rate was significantly lower in patients who had failed at least one AED at an adequate dose,” said Dr. Kwan. “This reinforces the concept that … failure of an adequate dose of at least one AED has a very strong prediction of subsequent outcome,” Dr. Kwan concluded.

—Erik Greb

PHILADELPHIA—Between 60% and 65% of patients with new-onset epilepsy become seizure-free with medications, according to an overview presented at the 69th Annual Meeting of the American Epilepsy Society. A patient whose seizures are uncontrolled by medication may have drug-resistant epilepsy, but the neurologist must take care to rule out pseudoresistance, said Patrick Kwan, MD, PhD, Chair of Neurology at the University of Melbourne in Australia. “A substantial proportion of these patients with seemingly uncontrolled epilepsy could become seizure-free with further drug adjustment, and the early data we’ve seen … would suggest that dose increase alone might be just as effective as substitution or add-on.”

What Is Drug Resistance?

In 2010, the International League Against Epilepsy (ILAE) defined drug-resistant epilepsy as the failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug (AED) schedules to achieve sustained seizure freedom. Longitudinal research by Brodie and colleagues appears to provide evidence to support this definition. In 2015, the researchers presented the latest analysis of the outcomes of a cohort of adults and adolescents with newly diagnosed epilepsy. The analysis included more than 1,800 patients who had been followed up for more than 30 years. Most of the patients became seizure-free on their first (45%) or second (12%) drug schedule. Less than 7% of patients who failed two AEDs subsequently became seizure-free. The latest results are consistent with the investigators’ previous analyses of the cohort.

A 2007 study by Callaghan et al also appears to support the ILAE definition of drug resistance. For three years, the researchers followed 246 patients with epilepsy who had failed to respond to at least two AEDs and who continued to receive medical therapy. Approximately 14% of patients treated only with medication became seizure-free for six months. “Clearly, these patients had a much lower chance of becoming seizure-free,” said Dr. Kwan.

Thus, if a patient fails two AED schedules, “that is enough to suspect … underlying drug-resistant epilepsy,” he added. At that point, the neurologist should review the patient’s diagnosis and the classification of the epilepsy before considering new drug therapies or drug combinations.

Ruling Out Pseudoresistance

Ruling out pseudoresistance is an important part of the re-evaluation of a patient with apparent drug-resistant epilepsy. A patient who has received an incorrect diagnosis may have pseudoresistance. One 40-year-old male patient had recurrent seizures despite a history of resective surgery, said Dr. Kwan. An EKG revealed that the patient had asystole and needed a pacemaker rather than medical or surgical treatment.

Pseudoresistance also may apply to a patient who takes an inappropriate AED for his or her epilepsy syndrome. A 34-year-old woman with limb twitches and convulsion successively initiated and discontinued lamotrigine and levetiracetam after developing side effects, said Dr. Kwan. Carbamazepine also failed to stop the seizures. Although the woman had received a diagnosis of mesial temporal sclerosis, a review of her MRI revealed a malrotation of the hippocampus. After the woman discontinued carbamazepine and initiated a low dose of valproate, “she became seizure-free almost immediately and has remained seizure-free for the last two years,” said Dr. Kwan.

An incorrect dose of therapy also may result in pseudoresistance. A 52-year-old man continued to have seizures despite treatment with high doses of valproate and levetiracetam and began to develop sensitivity to valproate. A neurologist added 100 mg/day of topiramate to the patient’s regimen and reduced his dose of valproate. After the patient had another seizure five months later, the neurologist increased his dose of topiramate to 150 mg/day. The patient became seizure-free and remained so for two years, said Dr. Kwan.

Identifying an Adequate Dose

Drug resistance cannot be established unless the patient has received adequate doses of therapy. One way of identifying an adequate dose relies on the World Health Organization’s definition of the defined daily dose: the assumed average maintenance dose per day for a drug used for its main indication in adults. Examples of the defined daily dose include 1,000 mg/day of carbamazepine and 1,500 mg/day of valproate.

Dr. Kwan and colleagues followed patients with newly diagnosed epilepsy to determine whether the dose at which the first drug failed predicted patients’ response to the second drug. Doses of the first regimen were stratified according to whether they were above or below the 25%, 50%, or 75% cutoffs for the defined daily dose of the given AED. The investigators found that when the first drug failed at a dose above the 50% and 75% cutoffs of its defined daily dose, the patient was less likely to respond to the second drug. “In particular, the 50% defined daily dose cutoff had a high sensitivity and specificity,” said Dr. Kwan. “This will be perhaps a reasonable dose to use.”

Another researcher recruited more than 300 patients with seemingly uncontrolled epilepsy into an observational study. Approximately 10% of the cohort fulfilled the ILAE definition of drug resistance. Among patients who were not drug-resistant and not seizure-free, the most common reason for their outcome was an inadequate dose of AED (ie, less than 50% of the defined daily dose). For some of the patients, treating neurologists increased the AED dose or changed or added an AED. During a three-year period, 17% of patients whose treatment was modified became seizure-free. In contrast, none of the patients in the drug-resistant group became seizure-free. The proportion of seizure-free patients was similar for patients who received an increased dose of the same AED and patients who received a different AED.

“The patient seizure-free rate was significantly lower in patients who had failed at least one AED at an adequate dose,” said Dr. Kwan. “This reinforces the concept that … failure of an adequate dose of at least one AED has a very strong prediction of subsequent outcome,” Dr. Kwan concluded.

—Erik Greb