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BANGKOK – Since founding the Epilepsy Unit at Glasgow’s Western Infirmary 37 years ago, Martin J. Brodie, MD, has seen many changes in the field, including the introduction of more than a dozen new antiepileptic drugs (AEDs) in the past 2 decades.
And based upon this vast clinical experience coupled with his leadership of landmark studies, he has a message for his physician colleagues and their epilepsy patients. And it’s not pretty.
“Has the probability of achieving seizure freedom increased significantly in the last 3 decades? Regrettably, the answer is no,” he declared at the International Epilepsy Congress.
“Over all these years, in terms of seizure freedom there has been no real difference in outcome. There’s really quite a long way to go before we can say that we are doing all that well for people,” he said at the congress sponsored by the International League Against Epilepsy.
In the year 2000, he and his coinvestigators published a prospective, longitudinal, observational cohort study of 470 newly diagnosed patients with epilepsy treated at the Western Infirmary during 1982-1997, all with a minimum of 2 years’ follow-up. Sixty-one percent achieved complete freedom from seizures for at least 1 year on monotherapy, and another 3% did so on polytherapy, for a total rate of 64% (N Engl J Med. 2000 Feb 3;342[5]:314-19).
But these were patients who by and large were treated with older AEDs such as carbamazepine, which has since fallen by the wayside because of toxicities. Scottish neurologists now generally turn to lamotrigine (Lamictal), levetiracetam (Spritam), and other, newer AEDs. So Dr. Brodie and his coworkers recently published a follow-up study, this one featuring 30 years of longitudinal follow-up of 1,795 patients newly treated for epilepsy with AEDs, new and old, during 1982-2012. The investigators demonstrated that the seizure-free survival curves over time were virtually superimposable. In the larger, more recent study, remission was achieved in 55% of patients with AED monotherapy and in another 9% with polytherapy, for a total rate of 64%, identical to the rate in the 2000 study, and as was the case in the earlier study, 36% of patients remained uncontrolled (JAMA Neurol. 2018 Mar 1;75[3]:279-86).
“Overall, the way this population behaves, there’s no difference in efficacy and no difference in tolerability whether you’re using old drugs used properly or new drugs used properly,” said Dr. Brodie, professor of neurology at the University of Glasgow (Scotland).
It’s noteworthy that Sir William R. Gowers, the Londoner who has been called the greatest neurologist of all time, reported a 70% seizure-free rate in 1881, while Dr. Brodie and workers achieved a 64% rate in their 30-year study. “It’s interesting that the numbers are so bad, really, I suppose,” Dr. Brodie commented.
How about outcomes in pediatric epilepsy?
Dr. Brodie and coworkers recently published a 30-year prospective cohort study of 332 adolescent epilepsy patients newly diagnosed and treated at the Western Infirmary during 1982-2012. At the end of the study, 67% were seizure-free for at least the past year, a feat accomplished via monotherapy in 83% of cases. The seizure-free rate was 72% in those with generalized epilepsy, significantly better than the 60% figure in those with focal epilepsy. The efficacy rate was 74% with newer AED monotherapy and similar at 77% with monotherapy older drugs. Adverse event rates ranged from a low of 12% with lamotrigine to 56% with topiramate (Topamax), according to the findings published in Epilepsia (2019 Jun;60[6]:1083-90).
Roughly similar outcomes have been reported from Norway in a study of 600 children with epilepsy, median age 7 years, with a median follow-up of 5.8 years that is considerably shorter than that in the Glasgow pediatric study. Overall, 59% of the Norwegian children remained seizure free for at least 1 year, 30% developed drug-resistant epilepsy, and 11% followed an intermediate remitting/relapsing course (Pediatrics. 2018 Jun. doi: 10.1542/peds.2017-4016).
Why the decades of flat pharmacologic outcomes?
The consistently suboptimal seizure-free outcomes obtained over the past 30 years shouldn’t really be surprising, according to Dr. Brodie.
“Although we think we have lots of mechanisms of action and lots of differences between the drugs, they’re arguably all antiseizure drugs and not antiepilepsy drugs. We don’t treat the whale; we treat the spout. We don’t treat what we cannot see; we treat what we can see, which is the seizures, but we’re not influencing the long-term outcome,” the neurologist explained.
The compelling case for early epilepsy surgery
Epilepsy surgery remains underutilized, according to Dr. Brodie and other experts.
The International League Against Epilepsy defines drug-resistant epilepsy as failure to achieve sustained seizure freedom after adequate trials of two tolerated and appropriately chosen and used AED schedules. Dr. Brodie’s work was influential in creating that definition because his data demonstrated the sharply diminishing returns of additional drug trials.
“When do we consider epilepsy surgery? Arguably, the earlier, the better. After two drugs have failed appropriately, I don’t think anybody in this room would argue about that, although people in some of the other rooms might,” he said at the congress.
Influential in his thinking on this score were the impressive results of an early study, the first-ever randomized trial of surgery for epilepsy. In 80 patients with a 21-year history of drug-refractory temporal lobe epilepsy who were randomized to surgery or 1 year of AED therapy, at 1 year of follow-up blinded epileptologists rated 58% of surgically treated patients as free from seizures that impair awareness of self and surroundings, compared with just 8% in the AED group (N Engl J Med. 2001 Aug 2;345[5]:311-8).
“That’s a big outcome, and I’m very keen to ensure that my data continue to drive the push for early surgery,” according to the neurologist.
A Cochrane review of 177 studies totaling more than 16,000 patients concluded that 65% of epilepsy patients had good outcomes following surgery. Prognostic factors associated with better surgical outcomes included complete surgical resection of the epileptogenic focus, the presence of mesial temporal sclerosis, concordance of MRI and EEG findings, and an absence of cortical dysplasia (Cochrane Database Syst Rev. 2019;6:CD010541. doi: 10.1002/14651858.CD010541.pub3).
In addition, a systematic review and meta-analysis by Canadian investigators found that 72% of adults with lesional epilepsy identified by MRI or histopathology were seizure-free after surgery, compared with 36% of those with nonlesional epilepsy. The disparity in outcomes was similar in pediatric epilepsy patients, with seizure freedom after surgery in 74% of those with lesional disease versus 45% with nonlesional epilepsy (Epilepsy Res. 2010 May;89[2-3]:310-8).
Whither are neurostimulatory device therapies headed?
Dr. Brodie was quick to admit that as a pharmacologic researcher, device modalities including vagus nerve stimulation, responsive neurostimulation, and deep brain stimulation are outside his area of expertise. But he’s been following developments in the field with interest.
“These device therapies have shown efficacy in short-term randomized trials, but very few patients attain long-term seizure freedom. I think these are largely palliative techniques. I gave up on these techniques a long time ago because I felt it was a very costly way of reducing seizures by a relatively small margin, and really we need to go a little bit further than that. But I know there’s a lot of work going on at the moment,” he said.
Dr. Brodie reported serving on the scientific advisory boards of more than a half dozen pharmaceutical companies.
BANGKOK – Since founding the Epilepsy Unit at Glasgow’s Western Infirmary 37 years ago, Martin J. Brodie, MD, has seen many changes in the field, including the introduction of more than a dozen new antiepileptic drugs (AEDs) in the past 2 decades.
And based upon this vast clinical experience coupled with his leadership of landmark studies, he has a message for his physician colleagues and their epilepsy patients. And it’s not pretty.
“Has the probability of achieving seizure freedom increased significantly in the last 3 decades? Regrettably, the answer is no,” he declared at the International Epilepsy Congress.
“Over all these years, in terms of seizure freedom there has been no real difference in outcome. There’s really quite a long way to go before we can say that we are doing all that well for people,” he said at the congress sponsored by the International League Against Epilepsy.
In the year 2000, he and his coinvestigators published a prospective, longitudinal, observational cohort study of 470 newly diagnosed patients with epilepsy treated at the Western Infirmary during 1982-1997, all with a minimum of 2 years’ follow-up. Sixty-one percent achieved complete freedom from seizures for at least 1 year on monotherapy, and another 3% did so on polytherapy, for a total rate of 64% (N Engl J Med. 2000 Feb 3;342[5]:314-19).
But these were patients who by and large were treated with older AEDs such as carbamazepine, which has since fallen by the wayside because of toxicities. Scottish neurologists now generally turn to lamotrigine (Lamictal), levetiracetam (Spritam), and other, newer AEDs. So Dr. Brodie and his coworkers recently published a follow-up study, this one featuring 30 years of longitudinal follow-up of 1,795 patients newly treated for epilepsy with AEDs, new and old, during 1982-2012. The investigators demonstrated that the seizure-free survival curves over time were virtually superimposable. In the larger, more recent study, remission was achieved in 55% of patients with AED monotherapy and in another 9% with polytherapy, for a total rate of 64%, identical to the rate in the 2000 study, and as was the case in the earlier study, 36% of patients remained uncontrolled (JAMA Neurol. 2018 Mar 1;75[3]:279-86).
“Overall, the way this population behaves, there’s no difference in efficacy and no difference in tolerability whether you’re using old drugs used properly or new drugs used properly,” said Dr. Brodie, professor of neurology at the University of Glasgow (Scotland).
It’s noteworthy that Sir William R. Gowers, the Londoner who has been called the greatest neurologist of all time, reported a 70% seizure-free rate in 1881, while Dr. Brodie and workers achieved a 64% rate in their 30-year study. “It’s interesting that the numbers are so bad, really, I suppose,” Dr. Brodie commented.
How about outcomes in pediatric epilepsy?
Dr. Brodie and coworkers recently published a 30-year prospective cohort study of 332 adolescent epilepsy patients newly diagnosed and treated at the Western Infirmary during 1982-2012. At the end of the study, 67% were seizure-free for at least the past year, a feat accomplished via monotherapy in 83% of cases. The seizure-free rate was 72% in those with generalized epilepsy, significantly better than the 60% figure in those with focal epilepsy. The efficacy rate was 74% with newer AED monotherapy and similar at 77% with monotherapy older drugs. Adverse event rates ranged from a low of 12% with lamotrigine to 56% with topiramate (Topamax), according to the findings published in Epilepsia (2019 Jun;60[6]:1083-90).
Roughly similar outcomes have been reported from Norway in a study of 600 children with epilepsy, median age 7 years, with a median follow-up of 5.8 years that is considerably shorter than that in the Glasgow pediatric study. Overall, 59% of the Norwegian children remained seizure free for at least 1 year, 30% developed drug-resistant epilepsy, and 11% followed an intermediate remitting/relapsing course (Pediatrics. 2018 Jun. doi: 10.1542/peds.2017-4016).
Why the decades of flat pharmacologic outcomes?
The consistently suboptimal seizure-free outcomes obtained over the past 30 years shouldn’t really be surprising, according to Dr. Brodie.
“Although we think we have lots of mechanisms of action and lots of differences between the drugs, they’re arguably all antiseizure drugs and not antiepilepsy drugs. We don’t treat the whale; we treat the spout. We don’t treat what we cannot see; we treat what we can see, which is the seizures, but we’re not influencing the long-term outcome,” the neurologist explained.
The compelling case for early epilepsy surgery
Epilepsy surgery remains underutilized, according to Dr. Brodie and other experts.
The International League Against Epilepsy defines drug-resistant epilepsy as failure to achieve sustained seizure freedom after adequate trials of two tolerated and appropriately chosen and used AED schedules. Dr. Brodie’s work was influential in creating that definition because his data demonstrated the sharply diminishing returns of additional drug trials.
“When do we consider epilepsy surgery? Arguably, the earlier, the better. After two drugs have failed appropriately, I don’t think anybody in this room would argue about that, although people in some of the other rooms might,” he said at the congress.
Influential in his thinking on this score were the impressive results of an early study, the first-ever randomized trial of surgery for epilepsy. In 80 patients with a 21-year history of drug-refractory temporal lobe epilepsy who were randomized to surgery or 1 year of AED therapy, at 1 year of follow-up blinded epileptologists rated 58% of surgically treated patients as free from seizures that impair awareness of self and surroundings, compared with just 8% in the AED group (N Engl J Med. 2001 Aug 2;345[5]:311-8).
“That’s a big outcome, and I’m very keen to ensure that my data continue to drive the push for early surgery,” according to the neurologist.
A Cochrane review of 177 studies totaling more than 16,000 patients concluded that 65% of epilepsy patients had good outcomes following surgery. Prognostic factors associated with better surgical outcomes included complete surgical resection of the epileptogenic focus, the presence of mesial temporal sclerosis, concordance of MRI and EEG findings, and an absence of cortical dysplasia (Cochrane Database Syst Rev. 2019;6:CD010541. doi: 10.1002/14651858.CD010541.pub3).
In addition, a systematic review and meta-analysis by Canadian investigators found that 72% of adults with lesional epilepsy identified by MRI or histopathology were seizure-free after surgery, compared with 36% of those with nonlesional epilepsy. The disparity in outcomes was similar in pediatric epilepsy patients, with seizure freedom after surgery in 74% of those with lesional disease versus 45% with nonlesional epilepsy (Epilepsy Res. 2010 May;89[2-3]:310-8).
Whither are neurostimulatory device therapies headed?
Dr. Brodie was quick to admit that as a pharmacologic researcher, device modalities including vagus nerve stimulation, responsive neurostimulation, and deep brain stimulation are outside his area of expertise. But he’s been following developments in the field with interest.
“These device therapies have shown efficacy in short-term randomized trials, but very few patients attain long-term seizure freedom. I think these are largely palliative techniques. I gave up on these techniques a long time ago because I felt it was a very costly way of reducing seizures by a relatively small margin, and really we need to go a little bit further than that. But I know there’s a lot of work going on at the moment,” he said.
Dr. Brodie reported serving on the scientific advisory boards of more than a half dozen pharmaceutical companies.
BANGKOK – Since founding the Epilepsy Unit at Glasgow’s Western Infirmary 37 years ago, Martin J. Brodie, MD, has seen many changes in the field, including the introduction of more than a dozen new antiepileptic drugs (AEDs) in the past 2 decades.
And based upon this vast clinical experience coupled with his leadership of landmark studies, he has a message for his physician colleagues and their epilepsy patients. And it’s not pretty.
“Has the probability of achieving seizure freedom increased significantly in the last 3 decades? Regrettably, the answer is no,” he declared at the International Epilepsy Congress.
“Over all these years, in terms of seizure freedom there has been no real difference in outcome. There’s really quite a long way to go before we can say that we are doing all that well for people,” he said at the congress sponsored by the International League Against Epilepsy.
In the year 2000, he and his coinvestigators published a prospective, longitudinal, observational cohort study of 470 newly diagnosed patients with epilepsy treated at the Western Infirmary during 1982-1997, all with a minimum of 2 years’ follow-up. Sixty-one percent achieved complete freedom from seizures for at least 1 year on monotherapy, and another 3% did so on polytherapy, for a total rate of 64% (N Engl J Med. 2000 Feb 3;342[5]:314-19).
But these were patients who by and large were treated with older AEDs such as carbamazepine, which has since fallen by the wayside because of toxicities. Scottish neurologists now generally turn to lamotrigine (Lamictal), levetiracetam (Spritam), and other, newer AEDs. So Dr. Brodie and his coworkers recently published a follow-up study, this one featuring 30 years of longitudinal follow-up of 1,795 patients newly treated for epilepsy with AEDs, new and old, during 1982-2012. The investigators demonstrated that the seizure-free survival curves over time were virtually superimposable. In the larger, more recent study, remission was achieved in 55% of patients with AED monotherapy and in another 9% with polytherapy, for a total rate of 64%, identical to the rate in the 2000 study, and as was the case in the earlier study, 36% of patients remained uncontrolled (JAMA Neurol. 2018 Mar 1;75[3]:279-86).
“Overall, the way this population behaves, there’s no difference in efficacy and no difference in tolerability whether you’re using old drugs used properly or new drugs used properly,” said Dr. Brodie, professor of neurology at the University of Glasgow (Scotland).
It’s noteworthy that Sir William R. Gowers, the Londoner who has been called the greatest neurologist of all time, reported a 70% seizure-free rate in 1881, while Dr. Brodie and workers achieved a 64% rate in their 30-year study. “It’s interesting that the numbers are so bad, really, I suppose,” Dr. Brodie commented.
How about outcomes in pediatric epilepsy?
Dr. Brodie and coworkers recently published a 30-year prospective cohort study of 332 adolescent epilepsy patients newly diagnosed and treated at the Western Infirmary during 1982-2012. At the end of the study, 67% were seizure-free for at least the past year, a feat accomplished via monotherapy in 83% of cases. The seizure-free rate was 72% in those with generalized epilepsy, significantly better than the 60% figure in those with focal epilepsy. The efficacy rate was 74% with newer AED monotherapy and similar at 77% with monotherapy older drugs. Adverse event rates ranged from a low of 12% with lamotrigine to 56% with topiramate (Topamax), according to the findings published in Epilepsia (2019 Jun;60[6]:1083-90).
Roughly similar outcomes have been reported from Norway in a study of 600 children with epilepsy, median age 7 years, with a median follow-up of 5.8 years that is considerably shorter than that in the Glasgow pediatric study. Overall, 59% of the Norwegian children remained seizure free for at least 1 year, 30% developed drug-resistant epilepsy, and 11% followed an intermediate remitting/relapsing course (Pediatrics. 2018 Jun. doi: 10.1542/peds.2017-4016).
Why the decades of flat pharmacologic outcomes?
The consistently suboptimal seizure-free outcomes obtained over the past 30 years shouldn’t really be surprising, according to Dr. Brodie.
“Although we think we have lots of mechanisms of action and lots of differences between the drugs, they’re arguably all antiseizure drugs and not antiepilepsy drugs. We don’t treat the whale; we treat the spout. We don’t treat what we cannot see; we treat what we can see, which is the seizures, but we’re not influencing the long-term outcome,” the neurologist explained.
The compelling case for early epilepsy surgery
Epilepsy surgery remains underutilized, according to Dr. Brodie and other experts.
The International League Against Epilepsy defines drug-resistant epilepsy as failure to achieve sustained seizure freedom after adequate trials of two tolerated and appropriately chosen and used AED schedules. Dr. Brodie’s work was influential in creating that definition because his data demonstrated the sharply diminishing returns of additional drug trials.
“When do we consider epilepsy surgery? Arguably, the earlier, the better. After two drugs have failed appropriately, I don’t think anybody in this room would argue about that, although people in some of the other rooms might,” he said at the congress.
Influential in his thinking on this score were the impressive results of an early study, the first-ever randomized trial of surgery for epilepsy. In 80 patients with a 21-year history of drug-refractory temporal lobe epilepsy who were randomized to surgery or 1 year of AED therapy, at 1 year of follow-up blinded epileptologists rated 58% of surgically treated patients as free from seizures that impair awareness of self and surroundings, compared with just 8% in the AED group (N Engl J Med. 2001 Aug 2;345[5]:311-8).
“That’s a big outcome, and I’m very keen to ensure that my data continue to drive the push for early surgery,” according to the neurologist.
A Cochrane review of 177 studies totaling more than 16,000 patients concluded that 65% of epilepsy patients had good outcomes following surgery. Prognostic factors associated with better surgical outcomes included complete surgical resection of the epileptogenic focus, the presence of mesial temporal sclerosis, concordance of MRI and EEG findings, and an absence of cortical dysplasia (Cochrane Database Syst Rev. 2019;6:CD010541. doi: 10.1002/14651858.CD010541.pub3).
In addition, a systematic review and meta-analysis by Canadian investigators found that 72% of adults with lesional epilepsy identified by MRI or histopathology were seizure-free after surgery, compared with 36% of those with nonlesional epilepsy. The disparity in outcomes was similar in pediatric epilepsy patients, with seizure freedom after surgery in 74% of those with lesional disease versus 45% with nonlesional epilepsy (Epilepsy Res. 2010 May;89[2-3]:310-8).
Whither are neurostimulatory device therapies headed?
Dr. Brodie was quick to admit that as a pharmacologic researcher, device modalities including vagus nerve stimulation, responsive neurostimulation, and deep brain stimulation are outside his area of expertise. But he’s been following developments in the field with interest.
“These device therapies have shown efficacy in short-term randomized trials, but very few patients attain long-term seizure freedom. I think these are largely palliative techniques. I gave up on these techniques a long time ago because I felt it was a very costly way of reducing seizures by a relatively small margin, and really we need to go a little bit further than that. But I know there’s a lot of work going on at the moment,” he said.
Dr. Brodie reported serving on the scientific advisory boards of more than a half dozen pharmaceutical companies.
EXPERT ANALYSIS FROM IEC 2019