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The development of new antiepileptic drugs (AEDs) with novel mechanisms of action has not improved overall outcomes for patients with epilepsy, according to an analysis published online ahead of print December 26, 2017, in JAMA Neurology.
“A paradigm shift in treatment and research strategies is needed to improve the long-term outcomes of newly diagnosed epilepsy. Patients with drug-resistant epilepsy should be considered early for nonpharmacologic therapies, such as resective surgery and brain stimulation techniques,” said Patrick Kwan, MD, PhD, Chair of Neurology at the University of Melbourne and Head of Epilepsy at the Royal Melbourne Hospital, and colleagues. 
The analysis suggests that contemporary AEDs suppress seizures, but do not affect the underlying disease. “Future research should focus on novel treatments that can modify the development or progression of epilepsy, ideally guided by biomarkers,” said the authors.
Investigators Examined an Expanded Cohort
In an oft-cited study published in 2000, Dr. Kwan and Martin J. Brodie, MD, followed 470 patients with newly diagnosed epilepsy who presented to the Epilepsy Unit at the Western Infirmary in Glasgow from 1982 to 1998. They observed that seizures persisted despite AED treatment for more than one-third of patients. Participants with an inadequate response to their first or second treatment regimens were likely to develop refractory epilepsy.
To study whether newer AEDs have changed treatment outcomes, Dr. Kwan and colleagues followed 1,795 patients with newly diagnosed epilepsy who presented to the Western Infirmary between July 1, 1982, and October 31, 2012. The investigators followed patients until October 31, 2014, or until their deaths. Patients with poor adherence for reasons unrelated to drug efficacy or tolerability, those whose seizures resulted from drug use, and those with nonepileptic seizures were excluded from the analysis.
Patients visited the clinic every two to six weeks for the first six months after treatment initiation. After month six, participants had follow-up visits at least every four months. Physicians collected data routinely during standard clinical care. Patients recorded seizure descriptions and the number of seizures that occurred between visits.
Nearly Two-Thirds Became Seizure-Free
Of the 1,795 study participants, 969 (53.7%) were male. Patients’ median age at referral was 33. In all, 386 patients (21.5%) had generalized epilepsy, and 1,409 patients (78.5%) had focal epilepsy. Follow-up lasted for a median of 11 years.
As of the final follow-up visit, 1,440 patients (80.2%) were receiving AED monotherapy, and 355 (19.8%) were receiving two or more AEDs. In all, 1,144 participants (63.7%) had been seizure-free for the previous 12 months or longer, of whom 993 (55.3%) had attained this outcome by taking a single AED. The remaining 151 seizure-free patients had achieved this outcome by taking two or more AEDs.
In all, 816 participants (45.4%) achieved at least one year of seizure freedom while taking their first AED, and 212 patients (28.6%) achieved this outcome while taking the second regimen, which was either monotherapy or polytherapy. The first and second regimens together accounted for 1,028 of the 1,144 patients (89.9%) who achieved at least one year of seizure freedom. At the last follow-up, seizure freedom was more common among patients with generalized epilepsy (68.1%) than among those with focal epilepsy (62.5%).
Although the use of newer AEDs increased significantly during the study, the proportion of patients who were seizure-free at the last follow-up was similar in the three time-period subgroups that the investigators examined. The cumulative probability of one year of seizure freedom also was similar in these periods. Adjustment for patient characteristics did not alter these findings.
Number of AEDs Affected Likelihood of Seizure Freedom
For patients who did not achieve one year of seizure freedom with their first AED, the likelihood of uncontrolled epilepsy increased with each subsequent AED tried (odds ratio [OR], 1.73). Dr. Kwan and colleagues found a significant difference in the probability of seizure freedom between patients treated with the first and second AED regimens (hazard ratio [HR], 0.52). The difference in this outcome between participants treated with their second and third AED regimen was also significant (HR, 0.71). Whether epilepsy was focal or generalized did not affect these findings.
When the investigators adjusted their data for sex and epilepsy classification, they found that a high number of seizures in the year before treatment initiation, a history of smoking, a history of recreational drug use, a family history of epilepsy in first-degree relatives, previous brain injury, and psychiatric comorbidity were significantly associated with an adverse prognosis. Each increase in the number of seizures in the year before treatment was associated with a 6% decrease in the chance of seizure freedom at the last follow-up.
Is Better Seizure Control Possible?
“The observation that newer drugs have not increased the percentage of people who are rendered seizure-free is not new and should not be surprising,” said W. Allen Hauser, MD, Special Lecturer in the Gertrude H. Sergievsky Center at Columbia University in New York, in an accompanying editorial. “Even though mechanisms of action of specific drugs may differ, the same animal models have been used to predict successful suppression of seizures in preclinical studies for the last 80 years, and successful response has been the basis for clinical drug development for both old and new therapeutic agents.”
Nevertheless, the data “are sobering and somewhat disconcerting,” Dr. Hauser added. “In 1881, pioneering neurologist Sir William Gowers reported that he could not control seizures in 36% of the patients to whom he prescribed bromide compounds. It seems that we might not have improved our initial management results for a much longer period than the 30 years covered in the current study. While biologically unlikely, it is possible that a two-thirds proportion represents a ceiling for the initial control of epilepsy.”
—Erik Greb
Suggested Reading
Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].
Hauser WA. Questioning the effectiveness of newer antiseizure medications. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].
The development of new antiepileptic drugs (AEDs) with novel mechanisms of action has not improved overall outcomes for patients with epilepsy, according to an analysis published online ahead of print December 26, 2017, in JAMA Neurology.
“A paradigm shift in treatment and research strategies is needed to improve the long-term outcomes of newly diagnosed epilepsy. Patients with drug-resistant epilepsy should be considered early for nonpharmacologic therapies, such as resective surgery and brain stimulation techniques,” said Patrick Kwan, MD, PhD, Chair of Neurology at the University of Melbourne and Head of Epilepsy at the Royal Melbourne Hospital, and colleagues.
The analysis suggests that contemporary AEDs suppress seizures, but do not affect the underlying disease. “Future research should focus on novel treatments that can modify the development or progression of epilepsy, ideally guided by biomarkers,” said the authors.
Investigators Examined an Expanded Cohort
In an oft-cited study published in 2000, Dr. Kwan and Martin J. Brodie, MD, followed 470 patients with newly diagnosed epilepsy who presented to the Epilepsy Unit at the Western Infirmary in Glasgow from 1982 to 1998. They observed that seizures persisted despite AED treatment for more than one-third of patients. Participants with an inadequate response to their first or second treatment regimens were likely to develop refractory epilepsy.
To study whether newer AEDs have changed treatment outcomes, Dr. Kwan and colleagues followed 1,795 patients with newly diagnosed epilepsy who presented to the Western Infirmary between July 1, 1982, and October 31, 2012. The investigators followed patients until October 31, 2014, or until their deaths. Patients with poor adherence for reasons unrelated to drug efficacy or tolerability, those whose seizures resulted from drug use, and those with nonepileptic seizures were excluded from the analysis.
Patients visited the clinic every two to six weeks for the first six months after treatment initiation. After month six, participants had follow-up visits at least every four months. Physicians collected data routinely during standard clinical care. Patients recorded seizure descriptions and the number of seizures that occurred between visits.
Nearly Two-Thirds Became Seizure-Free
Of the 1,795 study participants, 969 (53.7%) were male. Patients’ median age at referral was 33. In all, 386 patients (21.5%) had generalized epilepsy, and 1,409 patients (78.5%) had focal epilepsy. Follow-up lasted for a median of 11 years.
As of the final follow-up visit, 1,440 patients (80.2%) were receiving AED monotherapy, and 355 (19.8%) were receiving two or more AEDs. In all, 1,144 participants (63.7%) had been seizure-free for the previous 12 months or longer, of whom 993 (55.3%) had attained this outcome by taking a single AED. The remaining 151 seizure-free patients had achieved this outcome by taking two or more AEDs.
In all, 816 participants (45.4%) achieved at least one year of seizure freedom while taking their first AED, and 212 patients (28.6%) achieved this outcome while taking the second regimen, which was either monotherapy or polytherapy. The first and second regimens together accounted for 1,028 of the 1,144 patients (89.9%) who achieved at least one year of seizure freedom. At the last follow-up, seizure freedom was more common among patients with generalized epilepsy (68.1%) than among those with focal epilepsy (62.5%).
Although the use of newer AEDs increased significantly during the study, the proportion of patients who were seizure-free at the last follow-up was similar in the three time-period subgroups that the investigators examined. The cumulative probability of one year of seizure freedom also was similar in these periods. Adjustment for patient characteristics did not alter these findings.
Number of AEDs Affected Likelihood of Seizure Freedom
For patients who did not achieve one year of seizure freedom with their first AED, the likelihood of uncontrolled epilepsy increased with each subsequent AED tried (odds ratio [OR], 1.73). Dr. Kwan and colleagues found a significant difference in the probability of seizure freedom between patients treated with the first and second AED regimens (hazard ratio [HR], 0.52). The difference in this outcome between participants treated with their second and third AED regimen was also significant (HR, 0.71). Whether epilepsy was focal or generalized did not affect these findings.
When the investigators adjusted their data for sex and epilepsy classification, they found that a high number of seizures in the year before treatment initiation, a history of smoking, a history of recreational drug use, a family history of epilepsy in first-degree relatives, previous brain injury, and psychiatric comorbidity were significantly associated with an adverse prognosis. Each increase in the number of seizures in the year before treatment was associated with a 6% decrease in the chance of seizure freedom at the last follow-up.
Is Better Seizure Control Possible?
“The observation that newer drugs have not increased the percentage of people who are rendered seizure-free is not new and should not be surprising,” said W. Allen Hauser, MD, Special Lecturer in the Gertrude H. Sergievsky Center at Columbia University in New York, in an accompanying editorial. “Even though mechanisms of action of specific drugs may differ, the same animal models have been used to predict successful suppression of seizures in preclinical studies for the last 80 years, and successful response has been the basis for clinical drug development for both old and new therapeutic agents.”
Nevertheless, the data “are sobering and somewhat disconcerting,” Dr. Hauser added. “In 1881, pioneering neurologist Sir William Gowers reported that he could not control seizures in 36% of the patients to whom he prescribed bromide compounds. It seems that we might not have improved our initial management results for a much longer period than the 30 years covered in the current study. While biologically unlikely, it is possible that a two-thirds proportion represents a ceiling for the initial control of epilepsy.”
—Erik Greb
Suggested Reading
Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].
Hauser WA. Questioning the effectiveness of newer antiseizure medications. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].
The development of new antiepileptic drugs (AEDs) with novel mechanisms of action has not improved overall outcomes for patients with epilepsy, according to an analysis published online ahead of print December 26, 2017, in JAMA Neurology.
“A paradigm shift in treatment and research strategies is needed to improve the long-term outcomes of newly diagnosed epilepsy. Patients with drug-resistant epilepsy should be considered early for nonpharmacologic therapies, such as resective surgery and brain stimulation techniques,” said Patrick Kwan, MD, PhD, Chair of Neurology at the University of Melbourne and Head of Epilepsy at the Royal Melbourne Hospital, and colleagues.
The analysis suggests that contemporary AEDs suppress seizures, but do not affect the underlying disease. “Future research should focus on novel treatments that can modify the development or progression of epilepsy, ideally guided by biomarkers,” said the authors.
Investigators Examined an Expanded Cohort
In an oft-cited study published in 2000, Dr. Kwan and Martin J. Brodie, MD, followed 470 patients with newly diagnosed epilepsy who presented to the Epilepsy Unit at the Western Infirmary in Glasgow from 1982 to 1998. They observed that seizures persisted despite AED treatment for more than one-third of patients. Participants with an inadequate response to their first or second treatment regimens were likely to develop refractory epilepsy.
To study whether newer AEDs have changed treatment outcomes, Dr. Kwan and colleagues followed 1,795 patients with newly diagnosed epilepsy who presented to the Western Infirmary between July 1, 1982, and October 31, 2012. The investigators followed patients until October 31, 2014, or until their deaths. Patients with poor adherence for reasons unrelated to drug efficacy or tolerability, those whose seizures resulted from drug use, and those with nonepileptic seizures were excluded from the analysis.
Patients visited the clinic every two to six weeks for the first six months after treatment initiation. After month six, participants had follow-up visits at least every four months. Physicians collected data routinely during standard clinical care. Patients recorded seizure descriptions and the number of seizures that occurred between visits.
Nearly Two-Thirds Became Seizure-Free
Of the 1,795 study participants, 969 (53.7%) were male. Patients’ median age at referral was 33. In all, 386 patients (21.5%) had generalized epilepsy, and 1,409 patients (78.5%) had focal epilepsy. Follow-up lasted for a median of 11 years.
As of the final follow-up visit, 1,440 patients (80.2%) were receiving AED monotherapy, and 355 (19.8%) were receiving two or more AEDs. In all, 1,144 participants (63.7%) had been seizure-free for the previous 12 months or longer, of whom 993 (55.3%) had attained this outcome by taking a single AED. The remaining 151 seizure-free patients had achieved this outcome by taking two or more AEDs.
In all, 816 participants (45.4%) achieved at least one year of seizure freedom while taking their first AED, and 212 patients (28.6%) achieved this outcome while taking the second regimen, which was either monotherapy or polytherapy. The first and second regimens together accounted for 1,028 of the 1,144 patients (89.9%) who achieved at least one year of seizure freedom. At the last follow-up, seizure freedom was more common among patients with generalized epilepsy (68.1%) than among those with focal epilepsy (62.5%).
Although the use of newer AEDs increased significantly during the study, the proportion of patients who were seizure-free at the last follow-up was similar in the three time-period subgroups that the investigators examined. The cumulative probability of one year of seizure freedom also was similar in these periods. Adjustment for patient characteristics did not alter these findings.
Number of AEDs Affected Likelihood of Seizure Freedom
For patients who did not achieve one year of seizure freedom with their first AED, the likelihood of uncontrolled epilepsy increased with each subsequent AED tried (odds ratio [OR], 1.73). Dr. Kwan and colleagues found a significant difference in the probability of seizure freedom between patients treated with the first and second AED regimens (hazard ratio [HR], 0.52). The difference in this outcome between participants treated with their second and third AED regimen was also significant (HR, 0.71). Whether epilepsy was focal or generalized did not affect these findings.
When the investigators adjusted their data for sex and epilepsy classification, they found that a high number of seizures in the year before treatment initiation, a history of smoking, a history of recreational drug use, a family history of epilepsy in first-degree relatives, previous brain injury, and psychiatric comorbidity were significantly associated with an adverse prognosis. Each increase in the number of seizures in the year before treatment was associated with a 6% decrease in the chance of seizure freedom at the last follow-up.
Is Better Seizure Control Possible?
“The observation that newer drugs have not increased the percentage of people who are rendered seizure-free is not new and should not be surprising,” said W. Allen Hauser, MD, Special Lecturer in the Gertrude H. Sergievsky Center at Columbia University in New York, in an accompanying editorial. “Even though mechanisms of action of specific drugs may differ, the same animal models have been used to predict successful suppression of seizures in preclinical studies for the last 80 years, and successful response has been the basis for clinical drug development for both old and new therapeutic agents.”
Nevertheless, the data “are sobering and somewhat disconcerting,” Dr. Hauser added. “In 1881, pioneering neurologist Sir William Gowers reported that he could not control seizures in 36% of the patients to whom he prescribed bromide compounds. It seems that we might not have improved our initial management results for a much longer period than the 30 years covered in the current study. While biologically unlikely, it is possible that a two-thirds proportion represents a ceiling for the initial control of epilepsy.”
—Erik Greb
Suggested Reading
Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].
Hauser WA. Questioning the effectiveness of newer antiseizure medications. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].