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Intranasal midazolam as first line for status epilepticus
BANGKOK – Lara Kay, MD, said at the International Epilepsy Congress.
Why? Because status epilepticus is a major medical emergency. It’s associated with substantial morbidity and mortality. And of the various factors that influence outcome in status epilepticus – including age, underlying etiology, and level of consciousness – only one is potentially within physician control: time to treatment, she noted at the congress sponsored by the International League Against Epilepsy.
“Time is brain,” observed Dr. Kay, a neurologist at the epilepsy center at University Hospital Frankfurt.
While intravenous benzodiazepines – for example, lorazepam at 2-4 mg – are widely accepted as the time-honored first-line treatment for status epilepticus, trying to place a line in a patient experiencing this emergency can be a tricky, time-consuming business. Multiple studies have demonstrated that various nonintravenous formulations of benzodiazepines, such as rectal diazepam or buccal or intramuscular midazolam, can be administered much faster and are as effective as intravenous benzodiazepines. But buccal midazolam is quite expensive in Germany, and the ready-to-use intramuscular midazolam applicator that’s available in the United States isn’t marketed in Germany. So several years ago Dr. Kay and her fellow neurologists started having their university hospital pharmacy manufacture intranasal midazolam.
Dr. Kay presented an observational study of 42 consecutive patients with status epilepticus who received intranasal midazolam as first-line treatment. The patients had a mean age of nearly 53 years and 23 were women. The starting dose was 2.5 mg per nostril, moving up to 5 mg per nostril after waiting 5 minutes in initial nonresponders.
Status epilepticus ceased both clinically and by EEG in 24 of the 42 patients, or 57%, in an average of 5 minutes after administration of the intranasal medication at a mean dose of 5.6 mg. Nonresponders received a mean dose of 7.5 mg. There were no significant differences between responders and nonresponders in terms of the proportion presenting with preexisting epilepsy or the epilepsy etiology. However, responders presented at a mean of 54 minutes in status epilepticus, while nonresponders had been in status for 17 minutes.
The 57% response rate with intranasal midazolam is comparable with other investigators’ reported success rates using other benzodiazepines and routes of administration, she noted.
Session cochair Gregory Krauss, MD, commented that he thought the Frankfurt neurologists may have been too cautious in their dosing of intranasal midazolam for status epilepticus.
“Often in the U.S. 5 mg is initially used in each nostril,” according to Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Kay reported having no financial conflicts of interest regarding her study.
SOURCE: Kay L et al. IEC 2019, Abstract P029.
BANGKOK – Lara Kay, MD, said at the International Epilepsy Congress.
Why? Because status epilepticus is a major medical emergency. It’s associated with substantial morbidity and mortality. And of the various factors that influence outcome in status epilepticus – including age, underlying etiology, and level of consciousness – only one is potentially within physician control: time to treatment, she noted at the congress sponsored by the International League Against Epilepsy.
“Time is brain,” observed Dr. Kay, a neurologist at the epilepsy center at University Hospital Frankfurt.
While intravenous benzodiazepines – for example, lorazepam at 2-4 mg – are widely accepted as the time-honored first-line treatment for status epilepticus, trying to place a line in a patient experiencing this emergency can be a tricky, time-consuming business. Multiple studies have demonstrated that various nonintravenous formulations of benzodiazepines, such as rectal diazepam or buccal or intramuscular midazolam, can be administered much faster and are as effective as intravenous benzodiazepines. But buccal midazolam is quite expensive in Germany, and the ready-to-use intramuscular midazolam applicator that’s available in the United States isn’t marketed in Germany. So several years ago Dr. Kay and her fellow neurologists started having their university hospital pharmacy manufacture intranasal midazolam.
Dr. Kay presented an observational study of 42 consecutive patients with status epilepticus who received intranasal midazolam as first-line treatment. The patients had a mean age of nearly 53 years and 23 were women. The starting dose was 2.5 mg per nostril, moving up to 5 mg per nostril after waiting 5 minutes in initial nonresponders.
Status epilepticus ceased both clinically and by EEG in 24 of the 42 patients, or 57%, in an average of 5 minutes after administration of the intranasal medication at a mean dose of 5.6 mg. Nonresponders received a mean dose of 7.5 mg. There were no significant differences between responders and nonresponders in terms of the proportion presenting with preexisting epilepsy or the epilepsy etiology. However, responders presented at a mean of 54 minutes in status epilepticus, while nonresponders had been in status for 17 minutes.
The 57% response rate with intranasal midazolam is comparable with other investigators’ reported success rates using other benzodiazepines and routes of administration, she noted.
Session cochair Gregory Krauss, MD, commented that he thought the Frankfurt neurologists may have been too cautious in their dosing of intranasal midazolam for status epilepticus.
“Often in the U.S. 5 mg is initially used in each nostril,” according to Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Kay reported having no financial conflicts of interest regarding her study.
SOURCE: Kay L et al. IEC 2019, Abstract P029.
BANGKOK – Lara Kay, MD, said at the International Epilepsy Congress.
Why? Because status epilepticus is a major medical emergency. It’s associated with substantial morbidity and mortality. And of the various factors that influence outcome in status epilepticus – including age, underlying etiology, and level of consciousness – only one is potentially within physician control: time to treatment, she noted at the congress sponsored by the International League Against Epilepsy.
“Time is brain,” observed Dr. Kay, a neurologist at the epilepsy center at University Hospital Frankfurt.
While intravenous benzodiazepines – for example, lorazepam at 2-4 mg – are widely accepted as the time-honored first-line treatment for status epilepticus, trying to place a line in a patient experiencing this emergency can be a tricky, time-consuming business. Multiple studies have demonstrated that various nonintravenous formulations of benzodiazepines, such as rectal diazepam or buccal or intramuscular midazolam, can be administered much faster and are as effective as intravenous benzodiazepines. But buccal midazolam is quite expensive in Germany, and the ready-to-use intramuscular midazolam applicator that’s available in the United States isn’t marketed in Germany. So several years ago Dr. Kay and her fellow neurologists started having their university hospital pharmacy manufacture intranasal midazolam.
Dr. Kay presented an observational study of 42 consecutive patients with status epilepticus who received intranasal midazolam as first-line treatment. The patients had a mean age of nearly 53 years and 23 were women. The starting dose was 2.5 mg per nostril, moving up to 5 mg per nostril after waiting 5 minutes in initial nonresponders.
Status epilepticus ceased both clinically and by EEG in 24 of the 42 patients, or 57%, in an average of 5 minutes after administration of the intranasal medication at a mean dose of 5.6 mg. Nonresponders received a mean dose of 7.5 mg. There were no significant differences between responders and nonresponders in terms of the proportion presenting with preexisting epilepsy or the epilepsy etiology. However, responders presented at a mean of 54 minutes in status epilepticus, while nonresponders had been in status for 17 minutes.
The 57% response rate with intranasal midazolam is comparable with other investigators’ reported success rates using other benzodiazepines and routes of administration, she noted.
Session cochair Gregory Krauss, MD, commented that he thought the Frankfurt neurologists may have been too cautious in their dosing of intranasal midazolam for status epilepticus.
“Often in the U.S. 5 mg is initially used in each nostril,” according to Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Kay reported having no financial conflicts of interest regarding her study.
SOURCE: Kay L et al. IEC 2019, Abstract P029.
REPORTING FROM IEC 2019
A practical tool predicts childhood epilepsy diagnosis
BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.
This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.
The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.
Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.
The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.
The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.
The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
Future predictive refinements are under study
Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).
In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).
A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).
Dr. Braun reported having no financial conflicts regarding his presentation.
BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.
This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.
The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.
Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.
The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.
The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.
The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
Future predictive refinements are under study
Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).
In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).
A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).
Dr. Braun reported having no financial conflicts regarding his presentation.
BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.
This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.
The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.
Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.
The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.
The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.
The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
Future predictive refinements are under study
Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).
In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).
A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).
Dr. Braun reported having no financial conflicts regarding his presentation.
REPORTING FROM IEC 2019
‘Pot’ is still hot for Dravet, Lennox-Gastaut
BANGKOK – Interim results of long-term, open-label extension trials of add-on prescription cannabidiol in patients with Dravet syndrome or Lennox-Gastaut syndrome show sustained, clinically meaningful seizure reductions with no new safety concerns, Anup D. Patel, MD, reported at the International Epilepsy Congress.
“Overall, this is a very promising and sustainable result that we were happy to see,” said Dr. Patel, chief of child neurology at Nationwide Children’s Hospital in Columbus, Ohio.
Epidiolex is the brand name for the plant-derived, highly purified cannabidiol (CBD) in an oil-based oral solution at 100 mg/mL. Dr. Patel has been involved in the medication’s development program since the earliest open-label compassionate use study, which was followed by rigorous phase 3, double-blind, placebo-controlled randomized trials, eventually leading to Food and Drug Administration marketing approval for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years of age or older.
“On June 25th, 2018, history was made: for the first time in United States history, a plant-based derivative of marijuana was approved for use as a medication, and it was also the first FDA-approved treatment for Dravet syndrome,” Dr. Patel noted at the congress sponsored by the International League Against Epilepsy.
A total of 96% of the 289 children with Dravet syndrome who completed the 14-week, double-blind, controlled randomized trials enrolled in the open-label, long-term extension study, during which they were on a median of three concurrent antiepileptic drugs along with a mean modal dose of CBD at 22 mg/kg/day. Although the target maintenance dose of CBD was 20 mg/kg/day, as advised in the product labeling, physicians could reduce or increase the dose up to 30 mg/kg/day.
“In the initial compassionate-use study, our site could go up to 50 mg/kg/day,” according to Dr. Patel. “We have plenty of data showing efficacy and continued safety beyond the FDA-recommended dose.”
In the open-label extension study, the median reduction from baseline in monthly seizure frequency assessed in 12-week intervals up to a maximum of week 72 was 44%-57% for convulsive seizures and 49%-67% for total seizures. More than 80% of patients and/or caregivers reported improvement in the patient’s overall condition as assessed on the Subject/Caregiver Global Impression of Change scale.
The pattern of adverse events associated with CBD has been consistent across all of the studies. The most common side effects are diarrhea in about one-third of patients, sleepiness in one-quarter, and decreased appetite in about one-quarter. Seven percent of patients discontinued the long-term extension trial because of adverse events.
Seventy percent of patients remained in the long-term extension study at 1 year.
Twenty-six patients developed liver transaminase levels greater than three times the upper limit of normal, and of note, 23 of the 26 were on concomitant valproic acid. None met criteria for severe drug-induced liver injury, and all recovered either spontaneously or after a reduction in the dose of CBD or valproic acid. But this association between CBD, valproic acid, and increased risk of mild liver injury has been a consistent finding across the clinical trials program.
“This is a very important clinical pearl to take away,” commented Dr. Patel, who is also a pediatric neurologist at Ohio State University.
The interim results of the long-term, open-label extension study of add-on CBD in patients with Lennox-Gastaut syndrome are similar to the Dravet syndrome study. Overall, 99% of the 368 patients with Lennox-Gastaut syndrome who completed the 14-week, double-blind, randomized trials signed up for the open-label extension. During a median follow-up of 61 weeks, the median percent reduction in seizure frequency as assessed in serial 12-week windows was 48%-70% for drop seizures and 48%-63% for total seizures. Twenty-four percent of patients withdrew from the study. Eighty-eight percent of patients or caregivers reported an improvement in overall condition when assessed at weeks 24 and 48. Forty-seven patients developed elevated transaminase levels – typically within the first 2 months on CBD – and 35 of them were on concomitant valproic acid.
More on drug-drug interactions
Elsewhere at IEC 2019, Gilmour Morrison of GW Pharmaceuticals, the Cambridge, England, company that markets Epidiolex, presented the findings of a series of drug-drug interaction studies involving coadministration of their CBD with clobazam (Sympazan and Onfi), valproate, stiripentol (Diacomit), or midazolam (Versed) in adult epilepsy patients and healthy volunteers. The researchers reported a bidirectional drug-drug interaction between Epidiolex and clobazam resulting in increased levels of the active metabolites of both drugs. The mechanism is believed to involve inhibition of cytochrome P450 2C19. However, there were no interactions with midazolam or valproate, and the slight bump in stiripentol levels when given with CBD didn’t reach the level of a clinically meaningful drug-drug interaction, according to the investigators.
On the horizon, Canadian researchers are investigating the possibility that since both the tetrahydrocannabinol (THC) and CBD components of marijuana have been shown to have anticonvulsant effects, adding a bit of THC to CBD will result in even better seizure control than with pure CBD in patients with Dravet syndrome. Investigators at Toronto’s Hospital for Sick Children have conducted a prospective, open-label study of a product containing CBD and THC in a 50:1 ratio as add-on therapy in 20 children with Dravet syndrome. The dose was 2-16 mg/kg/day of CBD and 0.04-0.32 mg/kg/day of THC. The cannabis plant extract used in the study was produced by Tilray, a Canadian pharmaceutical company.
Nineteen of the 20 patients completed the 20-week study. The sole noncompleter died of SUDEP (sudden unexpected death in epilepsy) deemed treatment unrelated. Patients experienced a median 71% reduction in motor seizures, compared with baseline. Sixty-three percent of patients had at least a 50% reduction in seizure frequency. Elevated liver transaminases occurred in patients on concomitant valproic acid, as did platelet abnormalities, which have not been seen in the Epidiolex studies, noted Dr. Patel, who was not involved in the Canadian study (Ann Clin Transl Neurol. 2018 Aug 1;5[9]:1077-88).
Dr. Patel reported serving as a consultant to Greenwich Biosciences, a U.S. offshoot of GW Pharmaceuticals. He receives research grants from that company as well as from the National Institutes of Health and the Pediatric Epilepsy Research Foundation.
BANGKOK – Interim results of long-term, open-label extension trials of add-on prescription cannabidiol in patients with Dravet syndrome or Lennox-Gastaut syndrome show sustained, clinically meaningful seizure reductions with no new safety concerns, Anup D. Patel, MD, reported at the International Epilepsy Congress.
“Overall, this is a very promising and sustainable result that we were happy to see,” said Dr. Patel, chief of child neurology at Nationwide Children’s Hospital in Columbus, Ohio.
Epidiolex is the brand name for the plant-derived, highly purified cannabidiol (CBD) in an oil-based oral solution at 100 mg/mL. Dr. Patel has been involved in the medication’s development program since the earliest open-label compassionate use study, which was followed by rigorous phase 3, double-blind, placebo-controlled randomized trials, eventually leading to Food and Drug Administration marketing approval for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years of age or older.
“On June 25th, 2018, history was made: for the first time in United States history, a plant-based derivative of marijuana was approved for use as a medication, and it was also the first FDA-approved treatment for Dravet syndrome,” Dr. Patel noted at the congress sponsored by the International League Against Epilepsy.
A total of 96% of the 289 children with Dravet syndrome who completed the 14-week, double-blind, controlled randomized trials enrolled in the open-label, long-term extension study, during which they were on a median of three concurrent antiepileptic drugs along with a mean modal dose of CBD at 22 mg/kg/day. Although the target maintenance dose of CBD was 20 mg/kg/day, as advised in the product labeling, physicians could reduce or increase the dose up to 30 mg/kg/day.
“In the initial compassionate-use study, our site could go up to 50 mg/kg/day,” according to Dr. Patel. “We have plenty of data showing efficacy and continued safety beyond the FDA-recommended dose.”
In the open-label extension study, the median reduction from baseline in monthly seizure frequency assessed in 12-week intervals up to a maximum of week 72 was 44%-57% for convulsive seizures and 49%-67% for total seizures. More than 80% of patients and/or caregivers reported improvement in the patient’s overall condition as assessed on the Subject/Caregiver Global Impression of Change scale.
The pattern of adverse events associated with CBD has been consistent across all of the studies. The most common side effects are diarrhea in about one-third of patients, sleepiness in one-quarter, and decreased appetite in about one-quarter. Seven percent of patients discontinued the long-term extension trial because of adverse events.
Seventy percent of patients remained in the long-term extension study at 1 year.
Twenty-six patients developed liver transaminase levels greater than three times the upper limit of normal, and of note, 23 of the 26 were on concomitant valproic acid. None met criteria for severe drug-induced liver injury, and all recovered either spontaneously or after a reduction in the dose of CBD or valproic acid. But this association between CBD, valproic acid, and increased risk of mild liver injury has been a consistent finding across the clinical trials program.
“This is a very important clinical pearl to take away,” commented Dr. Patel, who is also a pediatric neurologist at Ohio State University.
The interim results of the long-term, open-label extension study of add-on CBD in patients with Lennox-Gastaut syndrome are similar to the Dravet syndrome study. Overall, 99% of the 368 patients with Lennox-Gastaut syndrome who completed the 14-week, double-blind, randomized trials signed up for the open-label extension. During a median follow-up of 61 weeks, the median percent reduction in seizure frequency as assessed in serial 12-week windows was 48%-70% for drop seizures and 48%-63% for total seizures. Twenty-four percent of patients withdrew from the study. Eighty-eight percent of patients or caregivers reported an improvement in overall condition when assessed at weeks 24 and 48. Forty-seven patients developed elevated transaminase levels – typically within the first 2 months on CBD – and 35 of them were on concomitant valproic acid.
More on drug-drug interactions
Elsewhere at IEC 2019, Gilmour Morrison of GW Pharmaceuticals, the Cambridge, England, company that markets Epidiolex, presented the findings of a series of drug-drug interaction studies involving coadministration of their CBD with clobazam (Sympazan and Onfi), valproate, stiripentol (Diacomit), or midazolam (Versed) in adult epilepsy patients and healthy volunteers. The researchers reported a bidirectional drug-drug interaction between Epidiolex and clobazam resulting in increased levels of the active metabolites of both drugs. The mechanism is believed to involve inhibition of cytochrome P450 2C19. However, there were no interactions with midazolam or valproate, and the slight bump in stiripentol levels when given with CBD didn’t reach the level of a clinically meaningful drug-drug interaction, according to the investigators.
On the horizon, Canadian researchers are investigating the possibility that since both the tetrahydrocannabinol (THC) and CBD components of marijuana have been shown to have anticonvulsant effects, adding a bit of THC to CBD will result in even better seizure control than with pure CBD in patients with Dravet syndrome. Investigators at Toronto’s Hospital for Sick Children have conducted a prospective, open-label study of a product containing CBD and THC in a 50:1 ratio as add-on therapy in 20 children with Dravet syndrome. The dose was 2-16 mg/kg/day of CBD and 0.04-0.32 mg/kg/day of THC. The cannabis plant extract used in the study was produced by Tilray, a Canadian pharmaceutical company.
Nineteen of the 20 patients completed the 20-week study. The sole noncompleter died of SUDEP (sudden unexpected death in epilepsy) deemed treatment unrelated. Patients experienced a median 71% reduction in motor seizures, compared with baseline. Sixty-three percent of patients had at least a 50% reduction in seizure frequency. Elevated liver transaminases occurred in patients on concomitant valproic acid, as did platelet abnormalities, which have not been seen in the Epidiolex studies, noted Dr. Patel, who was not involved in the Canadian study (Ann Clin Transl Neurol. 2018 Aug 1;5[9]:1077-88).
Dr. Patel reported serving as a consultant to Greenwich Biosciences, a U.S. offshoot of GW Pharmaceuticals. He receives research grants from that company as well as from the National Institutes of Health and the Pediatric Epilepsy Research Foundation.
BANGKOK – Interim results of long-term, open-label extension trials of add-on prescription cannabidiol in patients with Dravet syndrome or Lennox-Gastaut syndrome show sustained, clinically meaningful seizure reductions with no new safety concerns, Anup D. Patel, MD, reported at the International Epilepsy Congress.
“Overall, this is a very promising and sustainable result that we were happy to see,” said Dr. Patel, chief of child neurology at Nationwide Children’s Hospital in Columbus, Ohio.
Epidiolex is the brand name for the plant-derived, highly purified cannabidiol (CBD) in an oil-based oral solution at 100 mg/mL. Dr. Patel has been involved in the medication’s development program since the earliest open-label compassionate use study, which was followed by rigorous phase 3, double-blind, placebo-controlled randomized trials, eventually leading to Food and Drug Administration marketing approval for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years of age or older.
“On June 25th, 2018, history was made: for the first time in United States history, a plant-based derivative of marijuana was approved for use as a medication, and it was also the first FDA-approved treatment for Dravet syndrome,” Dr. Patel noted at the congress sponsored by the International League Against Epilepsy.
A total of 96% of the 289 children with Dravet syndrome who completed the 14-week, double-blind, controlled randomized trials enrolled in the open-label, long-term extension study, during which they were on a median of three concurrent antiepileptic drugs along with a mean modal dose of CBD at 22 mg/kg/day. Although the target maintenance dose of CBD was 20 mg/kg/day, as advised in the product labeling, physicians could reduce or increase the dose up to 30 mg/kg/day.
“In the initial compassionate-use study, our site could go up to 50 mg/kg/day,” according to Dr. Patel. “We have plenty of data showing efficacy and continued safety beyond the FDA-recommended dose.”
In the open-label extension study, the median reduction from baseline in monthly seizure frequency assessed in 12-week intervals up to a maximum of week 72 was 44%-57% for convulsive seizures and 49%-67% for total seizures. More than 80% of patients and/or caregivers reported improvement in the patient’s overall condition as assessed on the Subject/Caregiver Global Impression of Change scale.
The pattern of adverse events associated with CBD has been consistent across all of the studies. The most common side effects are diarrhea in about one-third of patients, sleepiness in one-quarter, and decreased appetite in about one-quarter. Seven percent of patients discontinued the long-term extension trial because of adverse events.
Seventy percent of patients remained in the long-term extension study at 1 year.
Twenty-six patients developed liver transaminase levels greater than three times the upper limit of normal, and of note, 23 of the 26 were on concomitant valproic acid. None met criteria for severe drug-induced liver injury, and all recovered either spontaneously or after a reduction in the dose of CBD or valproic acid. But this association between CBD, valproic acid, and increased risk of mild liver injury has been a consistent finding across the clinical trials program.
“This is a very important clinical pearl to take away,” commented Dr. Patel, who is also a pediatric neurologist at Ohio State University.
The interim results of the long-term, open-label extension study of add-on CBD in patients with Lennox-Gastaut syndrome are similar to the Dravet syndrome study. Overall, 99% of the 368 patients with Lennox-Gastaut syndrome who completed the 14-week, double-blind, randomized trials signed up for the open-label extension. During a median follow-up of 61 weeks, the median percent reduction in seizure frequency as assessed in serial 12-week windows was 48%-70% for drop seizures and 48%-63% for total seizures. Twenty-four percent of patients withdrew from the study. Eighty-eight percent of patients or caregivers reported an improvement in overall condition when assessed at weeks 24 and 48. Forty-seven patients developed elevated transaminase levels – typically within the first 2 months on CBD – and 35 of them were on concomitant valproic acid.
More on drug-drug interactions
Elsewhere at IEC 2019, Gilmour Morrison of GW Pharmaceuticals, the Cambridge, England, company that markets Epidiolex, presented the findings of a series of drug-drug interaction studies involving coadministration of their CBD with clobazam (Sympazan and Onfi), valproate, stiripentol (Diacomit), or midazolam (Versed) in adult epilepsy patients and healthy volunteers. The researchers reported a bidirectional drug-drug interaction between Epidiolex and clobazam resulting in increased levels of the active metabolites of both drugs. The mechanism is believed to involve inhibition of cytochrome P450 2C19. However, there were no interactions with midazolam or valproate, and the slight bump in stiripentol levels when given with CBD didn’t reach the level of a clinically meaningful drug-drug interaction, according to the investigators.
On the horizon, Canadian researchers are investigating the possibility that since both the tetrahydrocannabinol (THC) and CBD components of marijuana have been shown to have anticonvulsant effects, adding a bit of THC to CBD will result in even better seizure control than with pure CBD in patients with Dravet syndrome. Investigators at Toronto’s Hospital for Sick Children have conducted a prospective, open-label study of a product containing CBD and THC in a 50:1 ratio as add-on therapy in 20 children with Dravet syndrome. The dose was 2-16 mg/kg/day of CBD and 0.04-0.32 mg/kg/day of THC. The cannabis plant extract used in the study was produced by Tilray, a Canadian pharmaceutical company.
Nineteen of the 20 patients completed the 20-week study. The sole noncompleter died of SUDEP (sudden unexpected death in epilepsy) deemed treatment unrelated. Patients experienced a median 71% reduction in motor seizures, compared with baseline. Sixty-three percent of patients had at least a 50% reduction in seizure frequency. Elevated liver transaminases occurred in patients on concomitant valproic acid, as did platelet abnormalities, which have not been seen in the Epidiolex studies, noted Dr. Patel, who was not involved in the Canadian study (Ann Clin Transl Neurol. 2018 Aug 1;5[9]:1077-88).
Dr. Patel reported serving as a consultant to Greenwich Biosciences, a U.S. offshoot of GW Pharmaceuticals. He receives research grants from that company as well as from the National Institutes of Health and the Pediatric Epilepsy Research Foundation.
REPORTING FROM IEC 2019
Ketogenic diets are what’s cooking for drug-refractory epilepsy
BANGKOK – For a form of epilepsy treatment that’s been around since the 1920s, ketogenic diet therapy has lately been the focus of a surprising wealth of clinical research and development, Suvasini Sharma, MD, observed at the International Epilepsy Congress.
This high-fat, low-carbohydrate diet is now well established as a valid and effective treatment option for children and adults with drug-refractory epilepsy who aren’t candidates for surgery. That’s about a third of all epilepsy patients. And as the recently overhauled pediatric ketogenic diet therapy (KDT) best practice consensus guidelines emphasize, KDT should be strongly considered after two antiepileptic drugs have failed, and even earlier for several epilepsy syndromes, noted Dr. Sharma, a pediatric neurologist at Lady Hardinge Medical College and Kalawati Saran Children’s Hospital in New Delhi, and a coauthor of the updated guidelines.
“The consensus guidelines recommend that you start thinking about the diet early, without waiting for every drug to fail,” she said at the congress, sponsored by the International League Against Epilepsy.
Among the KDT-related topics she highlighted were the recently revised best practice consensus guidelines; an expanding role for KDT in infants, critical care settings, and in epileptic encephalopathies; mounting evidence that KDT provides additional benefits beyond seizure control; and promising new alternative diet therapies. She also described the challenges of using KDT in a low-resource nation such as India, where most of the 1.3 billion people shop in markets where food isn’t packaged with the nutritional content labels essential to traditional KDTs, and low literacy is common.
KDT best practice guidelines
The latest guidelines, which include the details of standardized KDT protocols as well as a summary of recent translational research into mechanisms of action, replace the previous 10-year-old version. Flexibility is now the watchword. While the classic KDT was started as an inpatient intervention involving several days of fasting followed by multiday gradual reintroduction of calories, that approach is now deemed optional (Epilepsia Open. 2018 May 21;3[2]:175-92).
“By and large, the trend now is going to nonfasting initiation on an outpatient basis, but with more stringent monitoring,” according to Dr. Sharma.
The guidelines note that while the research literature shows that, on average, KDT results in about a 50% chance of at least a 50% reduction in seizure frequency in patients with drug-refractory epilepsy, there are a dozen specific conditions with 70% or greater responder rates: infantile spasms, tuberous sclerosis, epilepsy with myoclonic-atonic seizures, Dravet syndrome, glucose transporter 1 deficiency syndrome (Glut 1DS), pyruvate dehydrogenase deficiency (PDHD), febrile infection-related epilepsy syndrome (FIRES), super-refractory status epilepticus (SRSE), Ohtahara syndrome, complex I mitochondrial disorders, Angelman syndrome, and children with gastrostomy tubes. For Glut1DS and PDHD, KDTs should be considered the treatment of first choice.
Traditionally, KDTs weren’t recommended for children younger than age 2 years. There were concerns that maintaining ketosis and meeting growth requirements were contradictory goals. That’s no longer believed to be so. Indeed, current evidence shows that KDT is highly effective and well tolerated in infants with refractory epilepsy. European guidelines address patient selection, pre-KDT counseling, preferred methods of initiation and KDT discontinuation, and other key issues (Eur J Paediatr Neurol. 2016 Nov;20[6]:798-809).
The guidelines recognize four major, well-studied types of KDT: the classic long-chain triglyceride-centric diet; the medium-chain triglyceride diet; the more user-friendly modified Atkins diet; and low glycemic index therapy. Except in children younger than 2 years old, who should be started on the classic KDT, the consensus panel recommended that the specific KDT selected should be based on the family and child situation and the expertise at the local KDT center. Perceived differences in efficacy between the diets aren’t supported by persuasive evidence.
KDT benefits beyond seizure control
“Most of us who work in the diet scene are aware that patients often report increased alertness, and sometimes improved cognition,” said Dr. Sharma.
That subjective experience is now supported by evidence from a randomized, controlled trial. Dutch investigators who randomized 50 drug-refractory pediatric epilepsy patients to KDT or usual care documented a positive impact of the diet therapy on cognitive activation, mood, and anxious behavior (Epilepsy Behav. 2016 Jul;60:153-7).
More recently, a systematic review showed that while subjective assessments support claims of improved alertness, attention, and global cognition in patients on KDT for refractory epilepsy, structured neuropsychologic testing confirms the enhanced alertness but without significantly improved global cognition. The investigators reported that the improvements were unrelated to decreases in medication, the type of KDT or age at its introduction, or sleep improvement. Rather, the benefits appeared to be due to a combination of seizure reduction and direct effects of KDT on cognition (Epilepsy Behav. 2018 Oct;87:69-77).
There is also encouraging preliminary evidence of a possible protective effect of KDT against sudden unexpected death in epilepsy (SUDEP) in a mouse model (Epilepsia. 2016 Aug;57[8]:e178-82. doi: 10.1111/epi.13444).
The use of KDT in critical care settings
Investigators from the pediatric Status Epilepticus Research Group (pSERG) reported that 10 of 14 patients with convulsive refractory status epilepticus achieved EEG seizure resolution within 7 days after starting KDT. Moreover, 11 patients were able to be weaned off their continuous infusions within 14 days of starting KDT. Treatment-emergent gastroparesis and hypertriglyceridemia occurred in three patients (Epilepsy Res. 2018 Aug;144:1-6).
“It was reasonably well tolerated, but they started it quite late – a median of 13 days after onset of refractory status epilepticus. It should come much earlier on our list of therapies. We shouldn’t be waiting 2 weeks before going to the ketogenic diet, because we can diagnose refractory status epilepticus within 48 hours after arrival in the ICU most of the time,” Dr. Sharma said.
Austrian investigators have pioneered the use of intravenous KDT as a bridge when oral therapy is temporarily impossible because of status epilepticus, surgery, or other reasons. They reported that parental KDT with fat intake of 3.5-4 g/kg per day was safe and effective in their series of 17 young children with epilepsy (Epilepsia Open. 2017 Nov 16;3[1]:30-9).
The future: nonketogenic diet therapies
KDT in its various forms is just too demanding and restrictive for some patients. Nonketotic alternatives are being explored.
Triheptanoin is a synthetic medium-chain triglyceride in the form of an edible, odorless, tasteless oil. Its mechanism of action is by anaplerosis: that is, energy generation via replenishment of the tricarboxylic acid cycle. After demonstration of neuroprotective and anticonvulsant effects in several mouse models, Australian investigators conducted a pilot study of 30- to 100-mL/day of oral triheptanoin as add-on therapy in 12 children with drug-refractory epilepsy. Eight of the 12 took triheptanoin for longer than 12 weeks, and 5 of those 8 experienced a sustained greater than 50% reduction in seizure frequency, including 1 who remained seizure free for 30 weeks. Seven children had diarrhea or other GI side effects (Eur J Paediatr Neurol. 2018 Nov;22[6]:1074-80).
Parisian investigators have developed a nonketotic, palatable combination of amino acids, carbohydrates, and fatty acids with a low ratio of fat to protein-plus-carbohydrates that provided potent protection against seizures in a mouse model. This suggests that the traditional 4:1 ratio sought in KDT isn’t necessary for robust seizure reduction (Sci Rep. 2017 Jul 14;7[1]:5496).
“This is probably going to be the future of nutritional therapy in epilepsy,” Dr. Sharma predicted.
She reported having no financial conflicts regarding her presentation.
BANGKOK – For a form of epilepsy treatment that’s been around since the 1920s, ketogenic diet therapy has lately been the focus of a surprising wealth of clinical research and development, Suvasini Sharma, MD, observed at the International Epilepsy Congress.
This high-fat, low-carbohydrate diet is now well established as a valid and effective treatment option for children and adults with drug-refractory epilepsy who aren’t candidates for surgery. That’s about a third of all epilepsy patients. And as the recently overhauled pediatric ketogenic diet therapy (KDT) best practice consensus guidelines emphasize, KDT should be strongly considered after two antiepileptic drugs have failed, and even earlier for several epilepsy syndromes, noted Dr. Sharma, a pediatric neurologist at Lady Hardinge Medical College and Kalawati Saran Children’s Hospital in New Delhi, and a coauthor of the updated guidelines.
“The consensus guidelines recommend that you start thinking about the diet early, without waiting for every drug to fail,” she said at the congress, sponsored by the International League Against Epilepsy.
Among the KDT-related topics she highlighted were the recently revised best practice consensus guidelines; an expanding role for KDT in infants, critical care settings, and in epileptic encephalopathies; mounting evidence that KDT provides additional benefits beyond seizure control; and promising new alternative diet therapies. She also described the challenges of using KDT in a low-resource nation such as India, where most of the 1.3 billion people shop in markets where food isn’t packaged with the nutritional content labels essential to traditional KDTs, and low literacy is common.
KDT best practice guidelines
The latest guidelines, which include the details of standardized KDT protocols as well as a summary of recent translational research into mechanisms of action, replace the previous 10-year-old version. Flexibility is now the watchword. While the classic KDT was started as an inpatient intervention involving several days of fasting followed by multiday gradual reintroduction of calories, that approach is now deemed optional (Epilepsia Open. 2018 May 21;3[2]:175-92).
“By and large, the trend now is going to nonfasting initiation on an outpatient basis, but with more stringent monitoring,” according to Dr. Sharma.
The guidelines note that while the research literature shows that, on average, KDT results in about a 50% chance of at least a 50% reduction in seizure frequency in patients with drug-refractory epilepsy, there are a dozen specific conditions with 70% or greater responder rates: infantile spasms, tuberous sclerosis, epilepsy with myoclonic-atonic seizures, Dravet syndrome, glucose transporter 1 deficiency syndrome (Glut 1DS), pyruvate dehydrogenase deficiency (PDHD), febrile infection-related epilepsy syndrome (FIRES), super-refractory status epilepticus (SRSE), Ohtahara syndrome, complex I mitochondrial disorders, Angelman syndrome, and children with gastrostomy tubes. For Glut1DS and PDHD, KDTs should be considered the treatment of first choice.
Traditionally, KDTs weren’t recommended for children younger than age 2 years. There were concerns that maintaining ketosis and meeting growth requirements were contradictory goals. That’s no longer believed to be so. Indeed, current evidence shows that KDT is highly effective and well tolerated in infants with refractory epilepsy. European guidelines address patient selection, pre-KDT counseling, preferred methods of initiation and KDT discontinuation, and other key issues (Eur J Paediatr Neurol. 2016 Nov;20[6]:798-809).
The guidelines recognize four major, well-studied types of KDT: the classic long-chain triglyceride-centric diet; the medium-chain triglyceride diet; the more user-friendly modified Atkins diet; and low glycemic index therapy. Except in children younger than 2 years old, who should be started on the classic KDT, the consensus panel recommended that the specific KDT selected should be based on the family and child situation and the expertise at the local KDT center. Perceived differences in efficacy between the diets aren’t supported by persuasive evidence.
KDT benefits beyond seizure control
“Most of us who work in the diet scene are aware that patients often report increased alertness, and sometimes improved cognition,” said Dr. Sharma.
That subjective experience is now supported by evidence from a randomized, controlled trial. Dutch investigators who randomized 50 drug-refractory pediatric epilepsy patients to KDT or usual care documented a positive impact of the diet therapy on cognitive activation, mood, and anxious behavior (Epilepsy Behav. 2016 Jul;60:153-7).
More recently, a systematic review showed that while subjective assessments support claims of improved alertness, attention, and global cognition in patients on KDT for refractory epilepsy, structured neuropsychologic testing confirms the enhanced alertness but without significantly improved global cognition. The investigators reported that the improvements were unrelated to decreases in medication, the type of KDT or age at its introduction, or sleep improvement. Rather, the benefits appeared to be due to a combination of seizure reduction and direct effects of KDT on cognition (Epilepsy Behav. 2018 Oct;87:69-77).
There is also encouraging preliminary evidence of a possible protective effect of KDT against sudden unexpected death in epilepsy (SUDEP) in a mouse model (Epilepsia. 2016 Aug;57[8]:e178-82. doi: 10.1111/epi.13444).
The use of KDT in critical care settings
Investigators from the pediatric Status Epilepticus Research Group (pSERG) reported that 10 of 14 patients with convulsive refractory status epilepticus achieved EEG seizure resolution within 7 days after starting KDT. Moreover, 11 patients were able to be weaned off their continuous infusions within 14 days of starting KDT. Treatment-emergent gastroparesis and hypertriglyceridemia occurred in three patients (Epilepsy Res. 2018 Aug;144:1-6).
“It was reasonably well tolerated, but they started it quite late – a median of 13 days after onset of refractory status epilepticus. It should come much earlier on our list of therapies. We shouldn’t be waiting 2 weeks before going to the ketogenic diet, because we can diagnose refractory status epilepticus within 48 hours after arrival in the ICU most of the time,” Dr. Sharma said.
Austrian investigators have pioneered the use of intravenous KDT as a bridge when oral therapy is temporarily impossible because of status epilepticus, surgery, or other reasons. They reported that parental KDT with fat intake of 3.5-4 g/kg per day was safe and effective in their series of 17 young children with epilepsy (Epilepsia Open. 2017 Nov 16;3[1]:30-9).
The future: nonketogenic diet therapies
KDT in its various forms is just too demanding and restrictive for some patients. Nonketotic alternatives are being explored.
Triheptanoin is a synthetic medium-chain triglyceride in the form of an edible, odorless, tasteless oil. Its mechanism of action is by anaplerosis: that is, energy generation via replenishment of the tricarboxylic acid cycle. After demonstration of neuroprotective and anticonvulsant effects in several mouse models, Australian investigators conducted a pilot study of 30- to 100-mL/day of oral triheptanoin as add-on therapy in 12 children with drug-refractory epilepsy. Eight of the 12 took triheptanoin for longer than 12 weeks, and 5 of those 8 experienced a sustained greater than 50% reduction in seizure frequency, including 1 who remained seizure free for 30 weeks. Seven children had diarrhea or other GI side effects (Eur J Paediatr Neurol. 2018 Nov;22[6]:1074-80).
Parisian investigators have developed a nonketotic, palatable combination of amino acids, carbohydrates, and fatty acids with a low ratio of fat to protein-plus-carbohydrates that provided potent protection against seizures in a mouse model. This suggests that the traditional 4:1 ratio sought in KDT isn’t necessary for robust seizure reduction (Sci Rep. 2017 Jul 14;7[1]:5496).
“This is probably going to be the future of nutritional therapy in epilepsy,” Dr. Sharma predicted.
She reported having no financial conflicts regarding her presentation.
BANGKOK – For a form of epilepsy treatment that’s been around since the 1920s, ketogenic diet therapy has lately been the focus of a surprising wealth of clinical research and development, Suvasini Sharma, MD, observed at the International Epilepsy Congress.
This high-fat, low-carbohydrate diet is now well established as a valid and effective treatment option for children and adults with drug-refractory epilepsy who aren’t candidates for surgery. That’s about a third of all epilepsy patients. And as the recently overhauled pediatric ketogenic diet therapy (KDT) best practice consensus guidelines emphasize, KDT should be strongly considered after two antiepileptic drugs have failed, and even earlier for several epilepsy syndromes, noted Dr. Sharma, a pediatric neurologist at Lady Hardinge Medical College and Kalawati Saran Children’s Hospital in New Delhi, and a coauthor of the updated guidelines.
“The consensus guidelines recommend that you start thinking about the diet early, without waiting for every drug to fail,” she said at the congress, sponsored by the International League Against Epilepsy.
Among the KDT-related topics she highlighted were the recently revised best practice consensus guidelines; an expanding role for KDT in infants, critical care settings, and in epileptic encephalopathies; mounting evidence that KDT provides additional benefits beyond seizure control; and promising new alternative diet therapies. She also described the challenges of using KDT in a low-resource nation such as India, where most of the 1.3 billion people shop in markets where food isn’t packaged with the nutritional content labels essential to traditional KDTs, and low literacy is common.
KDT best practice guidelines
The latest guidelines, which include the details of standardized KDT protocols as well as a summary of recent translational research into mechanisms of action, replace the previous 10-year-old version. Flexibility is now the watchword. While the classic KDT was started as an inpatient intervention involving several days of fasting followed by multiday gradual reintroduction of calories, that approach is now deemed optional (Epilepsia Open. 2018 May 21;3[2]:175-92).
“By and large, the trend now is going to nonfasting initiation on an outpatient basis, but with more stringent monitoring,” according to Dr. Sharma.
The guidelines note that while the research literature shows that, on average, KDT results in about a 50% chance of at least a 50% reduction in seizure frequency in patients with drug-refractory epilepsy, there are a dozen specific conditions with 70% or greater responder rates: infantile spasms, tuberous sclerosis, epilepsy with myoclonic-atonic seizures, Dravet syndrome, glucose transporter 1 deficiency syndrome (Glut 1DS), pyruvate dehydrogenase deficiency (PDHD), febrile infection-related epilepsy syndrome (FIRES), super-refractory status epilepticus (SRSE), Ohtahara syndrome, complex I mitochondrial disorders, Angelman syndrome, and children with gastrostomy tubes. For Glut1DS and PDHD, KDTs should be considered the treatment of first choice.
Traditionally, KDTs weren’t recommended for children younger than age 2 years. There were concerns that maintaining ketosis and meeting growth requirements were contradictory goals. That’s no longer believed to be so. Indeed, current evidence shows that KDT is highly effective and well tolerated in infants with refractory epilepsy. European guidelines address patient selection, pre-KDT counseling, preferred methods of initiation and KDT discontinuation, and other key issues (Eur J Paediatr Neurol. 2016 Nov;20[6]:798-809).
The guidelines recognize four major, well-studied types of KDT: the classic long-chain triglyceride-centric diet; the medium-chain triglyceride diet; the more user-friendly modified Atkins diet; and low glycemic index therapy. Except in children younger than 2 years old, who should be started on the classic KDT, the consensus panel recommended that the specific KDT selected should be based on the family and child situation and the expertise at the local KDT center. Perceived differences in efficacy between the diets aren’t supported by persuasive evidence.
KDT benefits beyond seizure control
“Most of us who work in the diet scene are aware that patients often report increased alertness, and sometimes improved cognition,” said Dr. Sharma.
That subjective experience is now supported by evidence from a randomized, controlled trial. Dutch investigators who randomized 50 drug-refractory pediatric epilepsy patients to KDT or usual care documented a positive impact of the diet therapy on cognitive activation, mood, and anxious behavior (Epilepsy Behav. 2016 Jul;60:153-7).
More recently, a systematic review showed that while subjective assessments support claims of improved alertness, attention, and global cognition in patients on KDT for refractory epilepsy, structured neuropsychologic testing confirms the enhanced alertness but without significantly improved global cognition. The investigators reported that the improvements were unrelated to decreases in medication, the type of KDT or age at its introduction, or sleep improvement. Rather, the benefits appeared to be due to a combination of seizure reduction and direct effects of KDT on cognition (Epilepsy Behav. 2018 Oct;87:69-77).
There is also encouraging preliminary evidence of a possible protective effect of KDT against sudden unexpected death in epilepsy (SUDEP) in a mouse model (Epilepsia. 2016 Aug;57[8]:e178-82. doi: 10.1111/epi.13444).
The use of KDT in critical care settings
Investigators from the pediatric Status Epilepticus Research Group (pSERG) reported that 10 of 14 patients with convulsive refractory status epilepticus achieved EEG seizure resolution within 7 days after starting KDT. Moreover, 11 patients were able to be weaned off their continuous infusions within 14 days of starting KDT. Treatment-emergent gastroparesis and hypertriglyceridemia occurred in three patients (Epilepsy Res. 2018 Aug;144:1-6).
“It was reasonably well tolerated, but they started it quite late – a median of 13 days after onset of refractory status epilepticus. It should come much earlier on our list of therapies. We shouldn’t be waiting 2 weeks before going to the ketogenic diet, because we can diagnose refractory status epilepticus within 48 hours after arrival in the ICU most of the time,” Dr. Sharma said.
Austrian investigators have pioneered the use of intravenous KDT as a bridge when oral therapy is temporarily impossible because of status epilepticus, surgery, or other reasons. They reported that parental KDT with fat intake of 3.5-4 g/kg per day was safe and effective in their series of 17 young children with epilepsy (Epilepsia Open. 2017 Nov 16;3[1]:30-9).
The future: nonketogenic diet therapies
KDT in its various forms is just too demanding and restrictive for some patients. Nonketotic alternatives are being explored.
Triheptanoin is a synthetic medium-chain triglyceride in the form of an edible, odorless, tasteless oil. Its mechanism of action is by anaplerosis: that is, energy generation via replenishment of the tricarboxylic acid cycle. After demonstration of neuroprotective and anticonvulsant effects in several mouse models, Australian investigators conducted a pilot study of 30- to 100-mL/day of oral triheptanoin as add-on therapy in 12 children with drug-refractory epilepsy. Eight of the 12 took triheptanoin for longer than 12 weeks, and 5 of those 8 experienced a sustained greater than 50% reduction in seizure frequency, including 1 who remained seizure free for 30 weeks. Seven children had diarrhea or other GI side effects (Eur J Paediatr Neurol. 2018 Nov;22[6]:1074-80).
Parisian investigators have developed a nonketotic, palatable combination of amino acids, carbohydrates, and fatty acids with a low ratio of fat to protein-plus-carbohydrates that provided potent protection against seizures in a mouse model. This suggests that the traditional 4:1 ratio sought in KDT isn’t necessary for robust seizure reduction (Sci Rep. 2017 Jul 14;7[1]:5496).
“This is probably going to be the future of nutritional therapy in epilepsy,” Dr. Sharma predicted.
She reported having no financial conflicts regarding her presentation.
REPORTING FROM IEC 2019
ECT breaks super-refractory status epilepticus
BANGKOK –
“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.
Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.
A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).
And realistically, these small case series are as good as the supporting evidence is likely to get.
“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.
Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.
The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm3. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.
ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.
Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.
At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.
Dr. Nguyen’s presentation met with undisguised audience skepticism.
“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.
Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.
“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.
Another audience member said the treatment strategy smacks of homeopathy.
“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.
“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.
“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.
Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.
Dr. Nguyen reported having no financial conflicts.
SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.
BANGKOK –
“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.
Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.
A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).
And realistically, these small case series are as good as the supporting evidence is likely to get.
“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.
Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.
The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm3. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.
ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.
Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.
At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.
Dr. Nguyen’s presentation met with undisguised audience skepticism.
“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.
Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.
“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.
Another audience member said the treatment strategy smacks of homeopathy.
“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.
“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.
“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.
Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.
Dr. Nguyen reported having no financial conflicts.
SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.
BANGKOK –
“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.
Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.
A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).
And realistically, these small case series are as good as the supporting evidence is likely to get.
“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.
Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.
The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm3. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.
ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.
Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.
At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.
Dr. Nguyen’s presentation met with undisguised audience skepticism.
“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.
Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.
“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.
Another audience member said the treatment strategy smacks of homeopathy.
“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.
“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.
“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.
Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.
Dr. Nguyen reported having no financial conflicts.
SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.
REPORTING FROM IEC 2019
Mortality is high in pediatric superrefractory status epilepticus
BANGKOK – presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.
“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.
The study included 15 consecutive patients aged between 1 month and 17 years treated for superrefractory status epilepticus (SRSE) during 2011-2017 at the Chinese University of Hong Kong, where Dr. Yau practices. Seven children died during their index hospital admission, with a median time to death of 8 days. Two more died within several years post discharge.
Morbidity was substantial: At follow-up 1 year after the index episode of SRSE, two patients had a Glasgow Outcome Scale (GOS) score of 3, indicative of severe disability; three patients had moderate disability, with a GOS of 4; and two patients were in a vegetative state, with a GOS of 2, both of whom subsequently died of aspiration pneumonia. Only 1 of the 15 patients had a good recovery. Through 8 years of follow-up, all six survivors had epilepsy. Common nonneurologic deficits included a predisposition to a variety of infections.
By way of background, Dr. Yau noted that convulsive status epilepticus is the most common neurologic emergency in children, with an incidence of about 20 episodes per 100,000. Of affected children, 10%-40% develop refractory status, with reported mortality rates of 16%-43%. SRSE is a term reserved for persistent or recurrent seizures 24 hours or more after onset of general anesthesia for management of refractory status.
The impetus for Dr. Yau’s study was the dearth of data on SRSE in children. The literature consists of a few case series totaling well under 100 patients.
The Hong Kong case series included 15 patients with SRSE who had a median age of 7.9 years, only 1 of whom had preexisting epilepsy, a case of epileptic encephalopathy with severe developmental delay. Of the 15, 12 were boys. The patients were placed on a median of four antiepileptic drugs. Those who survived to discharge spent a median of 17.8 days under general anesthesia and 42.5 days in the pediatric ICU.
The SRSE etiologies included febrile infection–related epilepsy syndrome in two cases, four serious infections, four cases of autoimmune etiology, two cases of epileptic encephalopathy, one patient with hypoxia caused by severe croup, and two of unknown origin despite intensive work-up.
The four in-hospital deaths caused by acute cerebral edema occurred a median 6.5 days after admission. There were also two deaths because of uncontrolled sepsis and one because of intraventricular bleeding secondary to thrombotic thrombocytopenic purpura thought to have occurred as a complication of interactions between the numerous prescribed medications. All six children with an infectious or unknown etiology died in hospital, whereas none of those with an autoimmune etiology, epileptic encephalopathy, or hypoxia did. Duration of anesthesia did not predict mortality.
Other investigators have reported that younger age is associated with higher mortality, but that was not true in the Hong Kong experience. Neither of the two children aged less than 3 years died during their index hospitalization. All 7 deaths occurred in the 13 children age 3 years or older.
When asked whether she thought SRSE or the underlying disorder was the bigger contributor to mortality, Dr. Yau replied that she believes the prolonged refractory seizures may have worsened cerebral edema in some patients and thereby have been the cause of death.
She reported having no financial conflicts regarding her study.
BANGKOK – presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.
“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.
The study included 15 consecutive patients aged between 1 month and 17 years treated for superrefractory status epilepticus (SRSE) during 2011-2017 at the Chinese University of Hong Kong, where Dr. Yau practices. Seven children died during their index hospital admission, with a median time to death of 8 days. Two more died within several years post discharge.
Morbidity was substantial: At follow-up 1 year after the index episode of SRSE, two patients had a Glasgow Outcome Scale (GOS) score of 3, indicative of severe disability; three patients had moderate disability, with a GOS of 4; and two patients were in a vegetative state, with a GOS of 2, both of whom subsequently died of aspiration pneumonia. Only 1 of the 15 patients had a good recovery. Through 8 years of follow-up, all six survivors had epilepsy. Common nonneurologic deficits included a predisposition to a variety of infections.
By way of background, Dr. Yau noted that convulsive status epilepticus is the most common neurologic emergency in children, with an incidence of about 20 episodes per 100,000. Of affected children, 10%-40% develop refractory status, with reported mortality rates of 16%-43%. SRSE is a term reserved for persistent or recurrent seizures 24 hours or more after onset of general anesthesia for management of refractory status.
The impetus for Dr. Yau’s study was the dearth of data on SRSE in children. The literature consists of a few case series totaling well under 100 patients.
The Hong Kong case series included 15 patients with SRSE who had a median age of 7.9 years, only 1 of whom had preexisting epilepsy, a case of epileptic encephalopathy with severe developmental delay. Of the 15, 12 were boys. The patients were placed on a median of four antiepileptic drugs. Those who survived to discharge spent a median of 17.8 days under general anesthesia and 42.5 days in the pediatric ICU.
The SRSE etiologies included febrile infection–related epilepsy syndrome in two cases, four serious infections, four cases of autoimmune etiology, two cases of epileptic encephalopathy, one patient with hypoxia caused by severe croup, and two of unknown origin despite intensive work-up.
The four in-hospital deaths caused by acute cerebral edema occurred a median 6.5 days after admission. There were also two deaths because of uncontrolled sepsis and one because of intraventricular bleeding secondary to thrombotic thrombocytopenic purpura thought to have occurred as a complication of interactions between the numerous prescribed medications. All six children with an infectious or unknown etiology died in hospital, whereas none of those with an autoimmune etiology, epileptic encephalopathy, or hypoxia did. Duration of anesthesia did not predict mortality.
Other investigators have reported that younger age is associated with higher mortality, but that was not true in the Hong Kong experience. Neither of the two children aged less than 3 years died during their index hospitalization. All 7 deaths occurred in the 13 children age 3 years or older.
When asked whether she thought SRSE or the underlying disorder was the bigger contributor to mortality, Dr. Yau replied that she believes the prolonged refractory seizures may have worsened cerebral edema in some patients and thereby have been the cause of death.
She reported having no financial conflicts regarding her study.
BANGKOK – presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.
“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.
The study included 15 consecutive patients aged between 1 month and 17 years treated for superrefractory status epilepticus (SRSE) during 2011-2017 at the Chinese University of Hong Kong, where Dr. Yau practices. Seven children died during their index hospital admission, with a median time to death of 8 days. Two more died within several years post discharge.
Morbidity was substantial: At follow-up 1 year after the index episode of SRSE, two patients had a Glasgow Outcome Scale (GOS) score of 3, indicative of severe disability; three patients had moderate disability, with a GOS of 4; and two patients were in a vegetative state, with a GOS of 2, both of whom subsequently died of aspiration pneumonia. Only 1 of the 15 patients had a good recovery. Through 8 years of follow-up, all six survivors had epilepsy. Common nonneurologic deficits included a predisposition to a variety of infections.
By way of background, Dr. Yau noted that convulsive status epilepticus is the most common neurologic emergency in children, with an incidence of about 20 episodes per 100,000. Of affected children, 10%-40% develop refractory status, with reported mortality rates of 16%-43%. SRSE is a term reserved for persistent or recurrent seizures 24 hours or more after onset of general anesthesia for management of refractory status.
The impetus for Dr. Yau’s study was the dearth of data on SRSE in children. The literature consists of a few case series totaling well under 100 patients.
The Hong Kong case series included 15 patients with SRSE who had a median age of 7.9 years, only 1 of whom had preexisting epilepsy, a case of epileptic encephalopathy with severe developmental delay. Of the 15, 12 were boys. The patients were placed on a median of four antiepileptic drugs. Those who survived to discharge spent a median of 17.8 days under general anesthesia and 42.5 days in the pediatric ICU.
The SRSE etiologies included febrile infection–related epilepsy syndrome in two cases, four serious infections, four cases of autoimmune etiology, two cases of epileptic encephalopathy, one patient with hypoxia caused by severe croup, and two of unknown origin despite intensive work-up.
The four in-hospital deaths caused by acute cerebral edema occurred a median 6.5 days after admission. There were also two deaths because of uncontrolled sepsis and one because of intraventricular bleeding secondary to thrombotic thrombocytopenic purpura thought to have occurred as a complication of interactions between the numerous prescribed medications. All six children with an infectious or unknown etiology died in hospital, whereas none of those with an autoimmune etiology, epileptic encephalopathy, or hypoxia did. Duration of anesthesia did not predict mortality.
Other investigators have reported that younger age is associated with higher mortality, but that was not true in the Hong Kong experience. Neither of the two children aged less than 3 years died during their index hospitalization. All 7 deaths occurred in the 13 children age 3 years or older.
When asked whether she thought SRSE or the underlying disorder was the bigger contributor to mortality, Dr. Yau replied that she believes the prolonged refractory seizures may have worsened cerebral edema in some patients and thereby have been the cause of death.
She reported having no financial conflicts regarding her study.
REPORTING FROM IEC 2019
Neonatal epileptic syndromes are surprisingly common
BANGKOK – Katherine B. Howell, MD, reported at the International Epilepsy Congress.
“This is an important finding. It’s a considerably larger number than might have been expected and likely has two contributing factors. Neonatal seizures were previously not considered epilepsy, so many previous studies excluded neonates and the conditions were underrecognized. And our large number of ictal EEGs allowed identification of ictal activation, which is a feature of EIMFS [epilepsy of infancy with migrating focal seizures]. Without those ictal recordings, the diagnosis of EIMFS may not have been made,” according to Dr. Howell, a neurologist at the Royal Children’s Hospital and University of Melbourne.
She presented a population-based study of all infants born with severe epilepsies of infancy (SEI) during a 2-year period in the Australian state of Victoria, which is considered an ideal environment for epidemiologic studies because government-funded health care is available to all. SEI was defined as seizures beginning before age 18 months, occurring at a rate of at least one per day for 1 week or weekly for 1 month, refractory to adequate trials of at least two antiepileptic drugs, and accompanied by an epileptiform EEG abnormality. Her focus was on the electroclinical phenotypes of the affected children because of the high clinical utility of this information.
“Assigning an epileptic syndrome is highly useful for clinician-to-clinician communication of an infant’s phenotype. It guides investigation of etiology and possibly selection of optimal therapy, such as steroids in West syndrome. And it can inform prognosis,” Dr. Howell said at the congress sponsored by the International League Against Epilepsy.
She and her coinvestigators analyzed the detailed records of all 114 infants with SEI born during the study period. The incidence was 1 in 2,000 live births.
“Among infants with epilepsy, this patient group with SEI is most critical to better understand. Effective treatment is often not available, the seizure and developmental outcomes are frequently devastating, and the health burden massive,” the neurologist observed.
The full spectrum of SEI
With the help of ictal EEGs, home seizure recordings, MRI scans, and genomic testing, the investigators were able to classify more than 85% of the infants. About 64% had a prototypic syndrome at onset, such as West syndrome, which accounted for 33% of all SEI, or Dravet syndrome, which was diagnosed in 3%.
The prevalence of the prototypic neonatal and early infantile epileptic syndromes was notably higher than previously reported by others: EIMFS accounted for 9% of total SEI, early infantile epileptic encephalopathy (EIEE) for 7%, and early myoclonic encephalopathy (EME) for 2%. This translated to an incidence of 1 in 28,000 live births for EIEE, 1 in 111,000 for EME, and 1 in 22,500 for EIMFS.
“While neither EIEE nor EIMFS are common, these incidences are actually not that much lower than the reported incidence of Dravet syndrome,” the neurologist pointed out.
About 36% of SEI didn’t fit into any of the prototypic syndromes. However, more than half of this subgroup, or 19% of total SEI, were prototypic syndrome like, a designation Dr. Howell and her coworkers used for cases that possessed most but not all of the well-recognized features of a particular prototypic syndrome; for example, West syndrome–like seizures but without hypsarrhythmia. Whether these prototypic syndrome-like SEI have etiologies and outcomes similar to or distinct from the prototypic syndromes remains a topic for further study.
SEI etiologies
A total of 14 patients had SEI because of an acquired syndrome attributed to brain injury, 31 were because of brain malformation, 21 involved single gene disorders, 9 were of chromosomal etiology, and 7 had a metabolic cause.
The key finding with regard to etiology was the glaring difference between children with West syndrome, its variants, or unifocal epilepsies as compared with the rest of the SEI patients. Those with West syndrome, a West syndrome–like designation, or unifocal epilepsies most commonly had a structural etiology for their SEI. Indeed, of the 52 children with West syndrome or a variant, 10 had an acquired brain injury as their etiology and 17 had a brain malformation. And of the 12 patients with unifocal SEI, 1 had a brain injury and 9 had brain malformations.
In contrast, children with neonatal or early infantile epileptic syndromes had predominantly genetic rather than structural etiologies. Of the 20 children with EIEE, EIMFS, or EME, none had brain injury as the etiology, only 1 had a brain malformation, but 9 had a single gene or chromosomal etiology.
Outcomes
“The outcome data highlight the extreme severity of SEI and the imperative for novel treatments: 16% mortality overall, so one in six was deceased by age 2 years. The infants who died after the neonatal period all had profound delays, and almost all had ongoing seizures until their death. Most survivors also had developmental delay, with severity ranging from mild to moderate in 49% to severe/profound in 41%. Just 10 of 114 children had normal development,” Dr. Howell reported.
However, there was a notable difference in outcomes between the various syndromes, and this information is highly relevant prognostically. Of the 20 children with neonatal and early infantile epileptic syndromes, 11 died and the other 9 had profound developmental delay. In contrast, the outlook was far better for children with West syndrome, West syndrome–like variants, or focal epilepsies: Among 64 affected patients, there were just 2 deaths, normal development in 9 patients, mild to moderate developmental delay in 34, and severe/profound delay in 19.
Dr. Howell reported having no financial conflicts regarding this study, which was supported by governmental research grants.
SOURCE: Howell KB et al. IEC 2019, Abstract P053.
BANGKOK – Katherine B. Howell, MD, reported at the International Epilepsy Congress.
“This is an important finding. It’s a considerably larger number than might have been expected and likely has two contributing factors. Neonatal seizures were previously not considered epilepsy, so many previous studies excluded neonates and the conditions were underrecognized. And our large number of ictal EEGs allowed identification of ictal activation, which is a feature of EIMFS [epilepsy of infancy with migrating focal seizures]. Without those ictal recordings, the diagnosis of EIMFS may not have been made,” according to Dr. Howell, a neurologist at the Royal Children’s Hospital and University of Melbourne.
She presented a population-based study of all infants born with severe epilepsies of infancy (SEI) during a 2-year period in the Australian state of Victoria, which is considered an ideal environment for epidemiologic studies because government-funded health care is available to all. SEI was defined as seizures beginning before age 18 months, occurring at a rate of at least one per day for 1 week or weekly for 1 month, refractory to adequate trials of at least two antiepileptic drugs, and accompanied by an epileptiform EEG abnormality. Her focus was on the electroclinical phenotypes of the affected children because of the high clinical utility of this information.
“Assigning an epileptic syndrome is highly useful for clinician-to-clinician communication of an infant’s phenotype. It guides investigation of etiology and possibly selection of optimal therapy, such as steroids in West syndrome. And it can inform prognosis,” Dr. Howell said at the congress sponsored by the International League Against Epilepsy.
She and her coinvestigators analyzed the detailed records of all 114 infants with SEI born during the study period. The incidence was 1 in 2,000 live births.
“Among infants with epilepsy, this patient group with SEI is most critical to better understand. Effective treatment is often not available, the seizure and developmental outcomes are frequently devastating, and the health burden massive,” the neurologist observed.
The full spectrum of SEI
With the help of ictal EEGs, home seizure recordings, MRI scans, and genomic testing, the investigators were able to classify more than 85% of the infants. About 64% had a prototypic syndrome at onset, such as West syndrome, which accounted for 33% of all SEI, or Dravet syndrome, which was diagnosed in 3%.
The prevalence of the prototypic neonatal and early infantile epileptic syndromes was notably higher than previously reported by others: EIMFS accounted for 9% of total SEI, early infantile epileptic encephalopathy (EIEE) for 7%, and early myoclonic encephalopathy (EME) for 2%. This translated to an incidence of 1 in 28,000 live births for EIEE, 1 in 111,000 for EME, and 1 in 22,500 for EIMFS.
“While neither EIEE nor EIMFS are common, these incidences are actually not that much lower than the reported incidence of Dravet syndrome,” the neurologist pointed out.
About 36% of SEI didn’t fit into any of the prototypic syndromes. However, more than half of this subgroup, or 19% of total SEI, were prototypic syndrome like, a designation Dr. Howell and her coworkers used for cases that possessed most but not all of the well-recognized features of a particular prototypic syndrome; for example, West syndrome–like seizures but without hypsarrhythmia. Whether these prototypic syndrome-like SEI have etiologies and outcomes similar to or distinct from the prototypic syndromes remains a topic for further study.
SEI etiologies
A total of 14 patients had SEI because of an acquired syndrome attributed to brain injury, 31 were because of brain malformation, 21 involved single gene disorders, 9 were of chromosomal etiology, and 7 had a metabolic cause.
The key finding with regard to etiology was the glaring difference between children with West syndrome, its variants, or unifocal epilepsies as compared with the rest of the SEI patients. Those with West syndrome, a West syndrome–like designation, or unifocal epilepsies most commonly had a structural etiology for their SEI. Indeed, of the 52 children with West syndrome or a variant, 10 had an acquired brain injury as their etiology and 17 had a brain malformation. And of the 12 patients with unifocal SEI, 1 had a brain injury and 9 had brain malformations.
In contrast, children with neonatal or early infantile epileptic syndromes had predominantly genetic rather than structural etiologies. Of the 20 children with EIEE, EIMFS, or EME, none had brain injury as the etiology, only 1 had a brain malformation, but 9 had a single gene or chromosomal etiology.
Outcomes
“The outcome data highlight the extreme severity of SEI and the imperative for novel treatments: 16% mortality overall, so one in six was deceased by age 2 years. The infants who died after the neonatal period all had profound delays, and almost all had ongoing seizures until their death. Most survivors also had developmental delay, with severity ranging from mild to moderate in 49% to severe/profound in 41%. Just 10 of 114 children had normal development,” Dr. Howell reported.
However, there was a notable difference in outcomes between the various syndromes, and this information is highly relevant prognostically. Of the 20 children with neonatal and early infantile epileptic syndromes, 11 died and the other 9 had profound developmental delay. In contrast, the outlook was far better for children with West syndrome, West syndrome–like variants, or focal epilepsies: Among 64 affected patients, there were just 2 deaths, normal development in 9 patients, mild to moderate developmental delay in 34, and severe/profound delay in 19.
Dr. Howell reported having no financial conflicts regarding this study, which was supported by governmental research grants.
SOURCE: Howell KB et al. IEC 2019, Abstract P053.
BANGKOK – Katherine B. Howell, MD, reported at the International Epilepsy Congress.
“This is an important finding. It’s a considerably larger number than might have been expected and likely has two contributing factors. Neonatal seizures were previously not considered epilepsy, so many previous studies excluded neonates and the conditions were underrecognized. And our large number of ictal EEGs allowed identification of ictal activation, which is a feature of EIMFS [epilepsy of infancy with migrating focal seizures]. Without those ictal recordings, the diagnosis of EIMFS may not have been made,” according to Dr. Howell, a neurologist at the Royal Children’s Hospital and University of Melbourne.
She presented a population-based study of all infants born with severe epilepsies of infancy (SEI) during a 2-year period in the Australian state of Victoria, which is considered an ideal environment for epidemiologic studies because government-funded health care is available to all. SEI was defined as seizures beginning before age 18 months, occurring at a rate of at least one per day for 1 week or weekly for 1 month, refractory to adequate trials of at least two antiepileptic drugs, and accompanied by an epileptiform EEG abnormality. Her focus was on the electroclinical phenotypes of the affected children because of the high clinical utility of this information.
“Assigning an epileptic syndrome is highly useful for clinician-to-clinician communication of an infant’s phenotype. It guides investigation of etiology and possibly selection of optimal therapy, such as steroids in West syndrome. And it can inform prognosis,” Dr. Howell said at the congress sponsored by the International League Against Epilepsy.
She and her coinvestigators analyzed the detailed records of all 114 infants with SEI born during the study period. The incidence was 1 in 2,000 live births.
“Among infants with epilepsy, this patient group with SEI is most critical to better understand. Effective treatment is often not available, the seizure and developmental outcomes are frequently devastating, and the health burden massive,” the neurologist observed.
The full spectrum of SEI
With the help of ictal EEGs, home seizure recordings, MRI scans, and genomic testing, the investigators were able to classify more than 85% of the infants. About 64% had a prototypic syndrome at onset, such as West syndrome, which accounted for 33% of all SEI, or Dravet syndrome, which was diagnosed in 3%.
The prevalence of the prototypic neonatal and early infantile epileptic syndromes was notably higher than previously reported by others: EIMFS accounted for 9% of total SEI, early infantile epileptic encephalopathy (EIEE) for 7%, and early myoclonic encephalopathy (EME) for 2%. This translated to an incidence of 1 in 28,000 live births for EIEE, 1 in 111,000 for EME, and 1 in 22,500 for EIMFS.
“While neither EIEE nor EIMFS are common, these incidences are actually not that much lower than the reported incidence of Dravet syndrome,” the neurologist pointed out.
About 36% of SEI didn’t fit into any of the prototypic syndromes. However, more than half of this subgroup, or 19% of total SEI, were prototypic syndrome like, a designation Dr. Howell and her coworkers used for cases that possessed most but not all of the well-recognized features of a particular prototypic syndrome; for example, West syndrome–like seizures but without hypsarrhythmia. Whether these prototypic syndrome-like SEI have etiologies and outcomes similar to or distinct from the prototypic syndromes remains a topic for further study.
SEI etiologies
A total of 14 patients had SEI because of an acquired syndrome attributed to brain injury, 31 were because of brain malformation, 21 involved single gene disorders, 9 were of chromosomal etiology, and 7 had a metabolic cause.
The key finding with regard to etiology was the glaring difference between children with West syndrome, its variants, or unifocal epilepsies as compared with the rest of the SEI patients. Those with West syndrome, a West syndrome–like designation, or unifocal epilepsies most commonly had a structural etiology for their SEI. Indeed, of the 52 children with West syndrome or a variant, 10 had an acquired brain injury as their etiology and 17 had a brain malformation. And of the 12 patients with unifocal SEI, 1 had a brain injury and 9 had brain malformations.
In contrast, children with neonatal or early infantile epileptic syndromes had predominantly genetic rather than structural etiologies. Of the 20 children with EIEE, EIMFS, or EME, none had brain injury as the etiology, only 1 had a brain malformation, but 9 had a single gene or chromosomal etiology.
Outcomes
“The outcome data highlight the extreme severity of SEI and the imperative for novel treatments: 16% mortality overall, so one in six was deceased by age 2 years. The infants who died after the neonatal period all had profound delays, and almost all had ongoing seizures until their death. Most survivors also had developmental delay, with severity ranging from mild to moderate in 49% to severe/profound in 41%. Just 10 of 114 children had normal development,” Dr. Howell reported.
However, there was a notable difference in outcomes between the various syndromes, and this information is highly relevant prognostically. Of the 20 children with neonatal and early infantile epileptic syndromes, 11 died and the other 9 had profound developmental delay. In contrast, the outlook was far better for children with West syndrome, West syndrome–like variants, or focal epilepsies: Among 64 affected patients, there were just 2 deaths, normal development in 9 patients, mild to moderate developmental delay in 34, and severe/profound delay in 19.
Dr. Howell reported having no financial conflicts regarding this study, which was supported by governmental research grants.
SOURCE: Howell KB et al. IEC 2019, Abstract P053.
REPORTING FROM IEC 2019
Epilepsy surgery outcome prediction seeks to gain ground
BANGKOK –
She and her colleagues have created and validated an online risk prediction tool that clinicians can use to predict a patient’s individualized likelihood of complete freedom from seizures 2 and 5 years after undergoing resective brain surgery for drug-resistant epilepsy. The risk predictor, known as the Epilepsy Surgery Nomogram, uses a handful of simple clinical characteristics – patient gender, pathologic cause of the seizures, the proposed type of epilepsy surgery, the presence or absence of generalized tonic-clonic seizures, epilepsy duration, and preoperative seizure frequency – and spits out the patient’s predicted seizure outcome, she explained at the congress, sponsored by the International League Against Epilepsy.
“The point here is that every patient is an individual. And to give people predictions based on 500- or 600-patient Kaplan-Meier-derived curves that just provide the average outcome for the whole cohort isn’t really going to give them what they need as far as their individualized chance of becoming seizure free,” said Dr. Jehi, a neurologist at the Cleveland Clinic.
Similarly, reliance solely upon clinical judgment is a minefield. Multiple biases prevent physicians from making objective medical predictions, she continued.
“We think of the process of medical decision-making and outcome prediction as being a process that is logical and rational, where the accumulation of knowledge improves the decisions that we make, and where past experience improves judgment, and where collective decisions are more reliable. This is what intuitively we all think. That’s why we think we are invincible as physicians. And to that I say, really? There is a wealth of literature that actually disproves each one of these points,” Dr. Jehi declared.
Outcomes of brain surgery for drug-resistant epilepsy have remained static for more than half a century: Ten years after surgery, roughly half of treated patients remain completely seizure free. The inability of clinicians to use advanced statistics to inform potential surgical candidates about their individualized chance of becoming seizure free has probably contributed to underutilization of epilepsy surgery, she added.
The Epilepsy Surgery Nomogram was developed through detailed analysis of the records of 846 patients who underwent epilepsy surgery at the Cleveland Clinic. The resultant nomogram was then validated in a cohort of 604 patients who had resective surgery at the Mayo Clinic and epilepsy surgery centers in Brazil, Italy, and France. In the development cohort, the rate of complete freedom from seizures was 57% at 2 years and 40% at 5 years. In the validation study, the nomogram had a concordance statistic of 0.60 for complete freedom from seizures, which is considered better than chance, but well below the 0.80 threshold defined as strong concordance (Lancet Neurol. 2015 Mar;14[3]:283-90).
However, in an era when personalized medicine has become a catch phrase, the Epilepsy Surgery Nomogram has captured the attention of officials at the National Institutes of Health. Indeed, Dr. Jehi and her coworkers have received a $3.4 million, 5-year grant from the NIH to improve their risk prediction model by incorporating additional variables, including EEG data, MRI findings, family history, and genetic information. The enhanced risk calculator also will include a predictor of the likelihood that an individual will experience clinically meaningful improvement in quality of life in response to epilepsy surgery, since that’s an important outcome even in the absence of 100% freedom from seizures.
Recently, Dr. Jehi and coworkers have developed and then externally validated nomograms to predict the individualized risk of clinically relevant postoperative naming decline after temporal lobe epilepsy surgery in adults. A model based upon five variables – side of surgery, sex, education, age at epilepsy onset, and age at epilepsy surgery – performed very well, with a concordance statistic of 0.81. Moreover, a second nomogram predicting moderate to severe postoperative naming decline on the basis of just three variables – side of surgery, age at epilepsy onset, and preoperative score on the Boston Naming Test – had a concordance statistic of 0.84 (Neurology. 2018 Dec 4;91[23]:e2144-e2152. doi: 10.1212/WNL.0000000000006629).
“Our future hopefully is one where there will always be room for gut feelings and intuition because we definitely need them. We want to honor them. But hopefully it is one where algorithms can help our guesses be more educated and where the science of algorithms and predictive modeling can help inform our outcome predictions and decision-making process,” she said.
The original Epilepsy Surgery Nomogram project was funded by the Cleveland Clinic Epilepsy Center. The postoperative naming decline nomograms project was funded by the NIH.
BANGKOK –
She and her colleagues have created and validated an online risk prediction tool that clinicians can use to predict a patient’s individualized likelihood of complete freedom from seizures 2 and 5 years after undergoing resective brain surgery for drug-resistant epilepsy. The risk predictor, known as the Epilepsy Surgery Nomogram, uses a handful of simple clinical characteristics – patient gender, pathologic cause of the seizures, the proposed type of epilepsy surgery, the presence or absence of generalized tonic-clonic seizures, epilepsy duration, and preoperative seizure frequency – and spits out the patient’s predicted seizure outcome, she explained at the congress, sponsored by the International League Against Epilepsy.
“The point here is that every patient is an individual. And to give people predictions based on 500- or 600-patient Kaplan-Meier-derived curves that just provide the average outcome for the whole cohort isn’t really going to give them what they need as far as their individualized chance of becoming seizure free,” said Dr. Jehi, a neurologist at the Cleveland Clinic.
Similarly, reliance solely upon clinical judgment is a minefield. Multiple biases prevent physicians from making objective medical predictions, she continued.
“We think of the process of medical decision-making and outcome prediction as being a process that is logical and rational, where the accumulation of knowledge improves the decisions that we make, and where past experience improves judgment, and where collective decisions are more reliable. This is what intuitively we all think. That’s why we think we are invincible as physicians. And to that I say, really? There is a wealth of literature that actually disproves each one of these points,” Dr. Jehi declared.
Outcomes of brain surgery for drug-resistant epilepsy have remained static for more than half a century: Ten years after surgery, roughly half of treated patients remain completely seizure free. The inability of clinicians to use advanced statistics to inform potential surgical candidates about their individualized chance of becoming seizure free has probably contributed to underutilization of epilepsy surgery, she added.
The Epilepsy Surgery Nomogram was developed through detailed analysis of the records of 846 patients who underwent epilepsy surgery at the Cleveland Clinic. The resultant nomogram was then validated in a cohort of 604 patients who had resective surgery at the Mayo Clinic and epilepsy surgery centers in Brazil, Italy, and France. In the development cohort, the rate of complete freedom from seizures was 57% at 2 years and 40% at 5 years. In the validation study, the nomogram had a concordance statistic of 0.60 for complete freedom from seizures, which is considered better than chance, but well below the 0.80 threshold defined as strong concordance (Lancet Neurol. 2015 Mar;14[3]:283-90).
However, in an era when personalized medicine has become a catch phrase, the Epilepsy Surgery Nomogram has captured the attention of officials at the National Institutes of Health. Indeed, Dr. Jehi and her coworkers have received a $3.4 million, 5-year grant from the NIH to improve their risk prediction model by incorporating additional variables, including EEG data, MRI findings, family history, and genetic information. The enhanced risk calculator also will include a predictor of the likelihood that an individual will experience clinically meaningful improvement in quality of life in response to epilepsy surgery, since that’s an important outcome even in the absence of 100% freedom from seizures.
Recently, Dr. Jehi and coworkers have developed and then externally validated nomograms to predict the individualized risk of clinically relevant postoperative naming decline after temporal lobe epilepsy surgery in adults. A model based upon five variables – side of surgery, sex, education, age at epilepsy onset, and age at epilepsy surgery – performed very well, with a concordance statistic of 0.81. Moreover, a second nomogram predicting moderate to severe postoperative naming decline on the basis of just three variables – side of surgery, age at epilepsy onset, and preoperative score on the Boston Naming Test – had a concordance statistic of 0.84 (Neurology. 2018 Dec 4;91[23]:e2144-e2152. doi: 10.1212/WNL.0000000000006629).
“Our future hopefully is one where there will always be room for gut feelings and intuition because we definitely need them. We want to honor them. But hopefully it is one where algorithms can help our guesses be more educated and where the science of algorithms and predictive modeling can help inform our outcome predictions and decision-making process,” she said.
The original Epilepsy Surgery Nomogram project was funded by the Cleveland Clinic Epilepsy Center. The postoperative naming decline nomograms project was funded by the NIH.
BANGKOK –
She and her colleagues have created and validated an online risk prediction tool that clinicians can use to predict a patient’s individualized likelihood of complete freedom from seizures 2 and 5 years after undergoing resective brain surgery for drug-resistant epilepsy. The risk predictor, known as the Epilepsy Surgery Nomogram, uses a handful of simple clinical characteristics – patient gender, pathologic cause of the seizures, the proposed type of epilepsy surgery, the presence or absence of generalized tonic-clonic seizures, epilepsy duration, and preoperative seizure frequency – and spits out the patient’s predicted seizure outcome, she explained at the congress, sponsored by the International League Against Epilepsy.
“The point here is that every patient is an individual. And to give people predictions based on 500- or 600-patient Kaplan-Meier-derived curves that just provide the average outcome for the whole cohort isn’t really going to give them what they need as far as their individualized chance of becoming seizure free,” said Dr. Jehi, a neurologist at the Cleveland Clinic.
Similarly, reliance solely upon clinical judgment is a minefield. Multiple biases prevent physicians from making objective medical predictions, she continued.
“We think of the process of medical decision-making and outcome prediction as being a process that is logical and rational, where the accumulation of knowledge improves the decisions that we make, and where past experience improves judgment, and where collective decisions are more reliable. This is what intuitively we all think. That’s why we think we are invincible as physicians. And to that I say, really? There is a wealth of literature that actually disproves each one of these points,” Dr. Jehi declared.
Outcomes of brain surgery for drug-resistant epilepsy have remained static for more than half a century: Ten years after surgery, roughly half of treated patients remain completely seizure free. The inability of clinicians to use advanced statistics to inform potential surgical candidates about their individualized chance of becoming seizure free has probably contributed to underutilization of epilepsy surgery, she added.
The Epilepsy Surgery Nomogram was developed through detailed analysis of the records of 846 patients who underwent epilepsy surgery at the Cleveland Clinic. The resultant nomogram was then validated in a cohort of 604 patients who had resective surgery at the Mayo Clinic and epilepsy surgery centers in Brazil, Italy, and France. In the development cohort, the rate of complete freedom from seizures was 57% at 2 years and 40% at 5 years. In the validation study, the nomogram had a concordance statistic of 0.60 for complete freedom from seizures, which is considered better than chance, but well below the 0.80 threshold defined as strong concordance (Lancet Neurol. 2015 Mar;14[3]:283-90).
However, in an era when personalized medicine has become a catch phrase, the Epilepsy Surgery Nomogram has captured the attention of officials at the National Institutes of Health. Indeed, Dr. Jehi and her coworkers have received a $3.4 million, 5-year grant from the NIH to improve their risk prediction model by incorporating additional variables, including EEG data, MRI findings, family history, and genetic information. The enhanced risk calculator also will include a predictor of the likelihood that an individual will experience clinically meaningful improvement in quality of life in response to epilepsy surgery, since that’s an important outcome even in the absence of 100% freedom from seizures.
Recently, Dr. Jehi and coworkers have developed and then externally validated nomograms to predict the individualized risk of clinically relevant postoperative naming decline after temporal lobe epilepsy surgery in adults. A model based upon five variables – side of surgery, sex, education, age at epilepsy onset, and age at epilepsy surgery – performed very well, with a concordance statistic of 0.81. Moreover, a second nomogram predicting moderate to severe postoperative naming decline on the basis of just three variables – side of surgery, age at epilepsy onset, and preoperative score on the Boston Naming Test – had a concordance statistic of 0.84 (Neurology. 2018 Dec 4;91[23]:e2144-e2152. doi: 10.1212/WNL.0000000000006629).
“Our future hopefully is one where there will always be room for gut feelings and intuition because we definitely need them. We want to honor them. But hopefully it is one where algorithms can help our guesses be more educated and where the science of algorithms and predictive modeling can help inform our outcome predictions and decision-making process,” she said.
The original Epilepsy Surgery Nomogram project was funded by the Cleveland Clinic Epilepsy Center. The postoperative naming decline nomograms project was funded by the NIH.
REPORTING FROM IEC 2019
Antiepileptic drug outcomes have remained flat for 3 decades
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
Liberalized low–glycemic-index diet effective for seizure reduction
BANGKOK – in a randomized, double-blind, 24-week, noninferiority study.
The low–glycemic-index diet (LGID) was introduced as a kinder, gentler, variant of the classic ketogenic diet for seizure frequency reduction. The ketogenic diet’s efficacy for this purpose is well established, but compliance is a problem and discontinuation rates are high. Yet even though the LGID was designed to be less onerous than the ketogenic diet, many children and parents also find the 7-days-a-week LGID to be excessively burdensome. This was the impetus for pitting the daily LGID against an intermittent version – 5 days on, 2 days off – in a randomized trial, Prateek K. Panda, MD, explained at the International Epilepsy Congress.
The hypothesis of this noninferiority trial was that adherence to the liberalized LGID would be similar to or better than that with the daily LGID regimen, with resultant similar reductions in seizure frequency. And further, that patients on the intermittent LGID would feel better because it would help improve depleted glycogen stores important for daily activity and that the liberalized diet would also be rated more favorably by caregivers, Dr. Panda said at the congress sponsored by the International League Against Epilepsy.
The 24-week, single-center trial included 122 children ages 1-15 years with drug-resistant epilepsy. At baseline they averaged 99 seizures per week by parental diary despite being on a median of four antiepileptic drugs. A total of 88% of participants had some form of structural epilepsy; the rest had a probable or confirmed genetic cause for their seizure disorder, according to Dr. Panda of the All-India Institute of Medical Sciences in New Delhi.
The standard daily LGID was comprised of 10% carbohydrate, 30% protein, and 60% fat, with only low–glycemic-index foods permitted. The cohort randomized to the liberalized diet ate that way on weekdays; however, on Saturdays and Sundays their diet was 20% carbohydrate, 30% protein, and 50% fat, with both medium- and low–glycemic-index foods allowed.
The primary outcome was the mean reduction in seizures per week by caregiver records at 24 weeks. The reduction from baseline was 54% in the strict LGID group and not significantly different at 49% in the intermittent LGID patients. Overall, 54% of patients in the strict LGID arm experienced a greater than 50% reduction in weekly seizure frequency, as did 50% on the liberalized diet, a nonsignificant difference.
There were five study dropouts in the strict LGID group and three in the liberalized LGID cohort. The two groups showed similar improvements over baseline in measures of social function, behavior, and cognition. Parents of children in the liberalized LGID group rated that diet as significantly less difficult to administer than those randomized to the strict LGID therapy.
Mean hemoglobin A1c improved in the strict LGID patients from 5.7% at baseline to 5.1% at both 12 and 24 weeks. The intermittent LGID group went from 5.6% to 5.0% and then to 5.2%. There was no correlation between HbA1c and reduction in seizure frequency. In contrast, serum beta-hydroxybutyrate levels showed a moderate correlation with seizure frequency, a novel finding which if confirmed might render beta-hydroxybutyrate useful as a biomarker, according to Dr. Panda.
Adverse events – mostly dyslipidemia and GI complaints such as vomiting or constipation – occurred in 25% of the strict LGID group and 13% with the intermittent LGID. All adverse events were mild.
Dr. Panda reported having no financial conflicts regarding the study, sponsored by the All-India Institute of Medical Sciences.
SOURCE: Panda PK et al. IEC 2019, Abstract P056.
BANGKOK – in a randomized, double-blind, 24-week, noninferiority study.
The low–glycemic-index diet (LGID) was introduced as a kinder, gentler, variant of the classic ketogenic diet for seizure frequency reduction. The ketogenic diet’s efficacy for this purpose is well established, but compliance is a problem and discontinuation rates are high. Yet even though the LGID was designed to be less onerous than the ketogenic diet, many children and parents also find the 7-days-a-week LGID to be excessively burdensome. This was the impetus for pitting the daily LGID against an intermittent version – 5 days on, 2 days off – in a randomized trial, Prateek K. Panda, MD, explained at the International Epilepsy Congress.
The hypothesis of this noninferiority trial was that adherence to the liberalized LGID would be similar to or better than that with the daily LGID regimen, with resultant similar reductions in seizure frequency. And further, that patients on the intermittent LGID would feel better because it would help improve depleted glycogen stores important for daily activity and that the liberalized diet would also be rated more favorably by caregivers, Dr. Panda said at the congress sponsored by the International League Against Epilepsy.
The 24-week, single-center trial included 122 children ages 1-15 years with drug-resistant epilepsy. At baseline they averaged 99 seizures per week by parental diary despite being on a median of four antiepileptic drugs. A total of 88% of participants had some form of structural epilepsy; the rest had a probable or confirmed genetic cause for their seizure disorder, according to Dr. Panda of the All-India Institute of Medical Sciences in New Delhi.
The standard daily LGID was comprised of 10% carbohydrate, 30% protein, and 60% fat, with only low–glycemic-index foods permitted. The cohort randomized to the liberalized diet ate that way on weekdays; however, on Saturdays and Sundays their diet was 20% carbohydrate, 30% protein, and 50% fat, with both medium- and low–glycemic-index foods allowed.
The primary outcome was the mean reduction in seizures per week by caregiver records at 24 weeks. The reduction from baseline was 54% in the strict LGID group and not significantly different at 49% in the intermittent LGID patients. Overall, 54% of patients in the strict LGID arm experienced a greater than 50% reduction in weekly seizure frequency, as did 50% on the liberalized diet, a nonsignificant difference.
There were five study dropouts in the strict LGID group and three in the liberalized LGID cohort. The two groups showed similar improvements over baseline in measures of social function, behavior, and cognition. Parents of children in the liberalized LGID group rated that diet as significantly less difficult to administer than those randomized to the strict LGID therapy.
Mean hemoglobin A1c improved in the strict LGID patients from 5.7% at baseline to 5.1% at both 12 and 24 weeks. The intermittent LGID group went from 5.6% to 5.0% and then to 5.2%. There was no correlation between HbA1c and reduction in seizure frequency. In contrast, serum beta-hydroxybutyrate levels showed a moderate correlation with seizure frequency, a novel finding which if confirmed might render beta-hydroxybutyrate useful as a biomarker, according to Dr. Panda.
Adverse events – mostly dyslipidemia and GI complaints such as vomiting or constipation – occurred in 25% of the strict LGID group and 13% with the intermittent LGID. All adverse events were mild.
Dr. Panda reported having no financial conflicts regarding the study, sponsored by the All-India Institute of Medical Sciences.
SOURCE: Panda PK et al. IEC 2019, Abstract P056.
BANGKOK – in a randomized, double-blind, 24-week, noninferiority study.
The low–glycemic-index diet (LGID) was introduced as a kinder, gentler, variant of the classic ketogenic diet for seizure frequency reduction. The ketogenic diet’s efficacy for this purpose is well established, but compliance is a problem and discontinuation rates are high. Yet even though the LGID was designed to be less onerous than the ketogenic diet, many children and parents also find the 7-days-a-week LGID to be excessively burdensome. This was the impetus for pitting the daily LGID against an intermittent version – 5 days on, 2 days off – in a randomized trial, Prateek K. Panda, MD, explained at the International Epilepsy Congress.
The hypothesis of this noninferiority trial was that adherence to the liberalized LGID would be similar to or better than that with the daily LGID regimen, with resultant similar reductions in seizure frequency. And further, that patients on the intermittent LGID would feel better because it would help improve depleted glycogen stores important for daily activity and that the liberalized diet would also be rated more favorably by caregivers, Dr. Panda said at the congress sponsored by the International League Against Epilepsy.
The 24-week, single-center trial included 122 children ages 1-15 years with drug-resistant epilepsy. At baseline they averaged 99 seizures per week by parental diary despite being on a median of four antiepileptic drugs. A total of 88% of participants had some form of structural epilepsy; the rest had a probable or confirmed genetic cause for their seizure disorder, according to Dr. Panda of the All-India Institute of Medical Sciences in New Delhi.
The standard daily LGID was comprised of 10% carbohydrate, 30% protein, and 60% fat, with only low–glycemic-index foods permitted. The cohort randomized to the liberalized diet ate that way on weekdays; however, on Saturdays and Sundays their diet was 20% carbohydrate, 30% protein, and 50% fat, with both medium- and low–glycemic-index foods allowed.
The primary outcome was the mean reduction in seizures per week by caregiver records at 24 weeks. The reduction from baseline was 54% in the strict LGID group and not significantly different at 49% in the intermittent LGID patients. Overall, 54% of patients in the strict LGID arm experienced a greater than 50% reduction in weekly seizure frequency, as did 50% on the liberalized diet, a nonsignificant difference.
There were five study dropouts in the strict LGID group and three in the liberalized LGID cohort. The two groups showed similar improvements over baseline in measures of social function, behavior, and cognition. Parents of children in the liberalized LGID group rated that diet as significantly less difficult to administer than those randomized to the strict LGID therapy.
Mean hemoglobin A1c improved in the strict LGID patients from 5.7% at baseline to 5.1% at both 12 and 24 weeks. The intermittent LGID group went from 5.6% to 5.0% and then to 5.2%. There was no correlation between HbA1c and reduction in seizure frequency. In contrast, serum beta-hydroxybutyrate levels showed a moderate correlation with seizure frequency, a novel finding which if confirmed might render beta-hydroxybutyrate useful as a biomarker, according to Dr. Panda.
Adverse events – mostly dyslipidemia and GI complaints such as vomiting or constipation – occurred in 25% of the strict LGID group and 13% with the intermittent LGID. All adverse events were mild.
Dr. Panda reported having no financial conflicts regarding the study, sponsored by the All-India Institute of Medical Sciences.
SOURCE: Panda PK et al. IEC 2019, Abstract P056.
REPORTING FROM IEC 2019