User login
Epilepsy
High infantile spasm risk should contraindicate sodium channel blocker antiepileptics
BALTIMORE – “This is scary and warrants caution,” said senior investigator and pediatric neurologist Shaun Hussain, MD, a pediatric neurologist at Mattel Children’s Hospital at UCLA. Because of the findings, “we are avoiding the use of voltage-gated sodium channel blockade in any child at risk for infantile spasms. More broadly, we are avoiding [them] in any infant if there is a good alternative medication, of which there are many in most cases.”
There have been a few previous case reports linking voltage-gated sodium channel blockers (SCBs) – which include oxcarbazepine, carbamazepine, lacosamide, and phenytoin – to infantile spasms, but they are still commonly used for infant seizures. There was some disagreement at UCLA whether there really was a link, so Dr. Hussain and his team took a look at the university’s experience. They matched 50 children with nonsyndromic epilepsy who subsequently developed video-EEG confirmed infantile spasms (cases) to 50 children who also had nonsyndromic epilepsy but did not develop spasms, based on follow-up duration and age and date of epilepsy onset.
The team then looked to see what drugs they had been on; it turned out that cases and controls were about equally as likely to have been treated with any specific antiepileptic, including SCBs. Infantile spasms were substantially more likely with SCB exposure in children with spasm risk factors, which also include focal cortical dysplasia, Aicardi syndrome, and other problems (HR 7.0; 95%; CI 2.5-19.8; P less than .001). Spasms were also more likely among even low-risk children treated with SCBs, although the trend was not statistically significant.
In the end, “we wonder how many cases of infantile spasms could [have been] prevented entirely if we had avoided sodium channel blockade,” Dr. Hussain said at the annual meeting of the American Epilepsy Society.
With so many other seizure options available – levetiracetam, topiramate, and phenobarbital, to name just a few – maybe it would be best “to stay away from” SCBs entirely in “infants with any form of epilepsy,” said lead investigator Jaeden Heesch, an undergraduate researcher who worked with Dr. Hussain.
It is unclear why SCBs increase infantile spasm risk; maybe nonselective voltage-gated sodium channel blockade interferes with proper neuron function in susceptible children, similar to the effects of sodium voltage-gated channel alpha subunit 1 mutations in Dravet syndrome, Dr. Hussain said. Perhaps the findings will inspire drug development. “If nonselective sodium channel blockade is bad, perhaps selective modulation of voltage-gated sodium currents [could be] beneficial or protective,” he said.
The age of epilepsy onset in the study was around 2 months. Children who went on to develop infantile spasms had an average of almost two seizures per day, versus fewer than one among controls, and were on an average of two, versus about 1.5 antiepileptics. The differences were not statistically significant.
The study looked at SCB exposure overall, but it’s possible that infantile spasm risk differs among the various class members.
The work was funded by the Elsie and Isaac Fogelman Endowment, the Hughes Family Foundation, and the UCLA Children’s Discovery and Innovation Institute. The investigators didn’t have any relevant disclosures.
SOURCE: Heesch J et al. AES 2019. Abstract 2.234.
BALTIMORE – “This is scary and warrants caution,” said senior investigator and pediatric neurologist Shaun Hussain, MD, a pediatric neurologist at Mattel Children’s Hospital at UCLA. Because of the findings, “we are avoiding the use of voltage-gated sodium channel blockade in any child at risk for infantile spasms. More broadly, we are avoiding [them] in any infant if there is a good alternative medication, of which there are many in most cases.”
There have been a few previous case reports linking voltage-gated sodium channel blockers (SCBs) – which include oxcarbazepine, carbamazepine, lacosamide, and phenytoin – to infantile spasms, but they are still commonly used for infant seizures. There was some disagreement at UCLA whether there really was a link, so Dr. Hussain and his team took a look at the university’s experience. They matched 50 children with nonsyndromic epilepsy who subsequently developed video-EEG confirmed infantile spasms (cases) to 50 children who also had nonsyndromic epilepsy but did not develop spasms, based on follow-up duration and age and date of epilepsy onset.
The team then looked to see what drugs they had been on; it turned out that cases and controls were about equally as likely to have been treated with any specific antiepileptic, including SCBs. Infantile spasms were substantially more likely with SCB exposure in children with spasm risk factors, which also include focal cortical dysplasia, Aicardi syndrome, and other problems (HR 7.0; 95%; CI 2.5-19.8; P less than .001). Spasms were also more likely among even low-risk children treated with SCBs, although the trend was not statistically significant.
In the end, “we wonder how many cases of infantile spasms could [have been] prevented entirely if we had avoided sodium channel blockade,” Dr. Hussain said at the annual meeting of the American Epilepsy Society.
With so many other seizure options available – levetiracetam, topiramate, and phenobarbital, to name just a few – maybe it would be best “to stay away from” SCBs entirely in “infants with any form of epilepsy,” said lead investigator Jaeden Heesch, an undergraduate researcher who worked with Dr. Hussain.
It is unclear why SCBs increase infantile spasm risk; maybe nonselective voltage-gated sodium channel blockade interferes with proper neuron function in susceptible children, similar to the effects of sodium voltage-gated channel alpha subunit 1 mutations in Dravet syndrome, Dr. Hussain said. Perhaps the findings will inspire drug development. “If nonselective sodium channel blockade is bad, perhaps selective modulation of voltage-gated sodium currents [could be] beneficial or protective,” he said.
The age of epilepsy onset in the study was around 2 months. Children who went on to develop infantile spasms had an average of almost two seizures per day, versus fewer than one among controls, and were on an average of two, versus about 1.5 antiepileptics. The differences were not statistically significant.
The study looked at SCB exposure overall, but it’s possible that infantile spasm risk differs among the various class members.
The work was funded by the Elsie and Isaac Fogelman Endowment, the Hughes Family Foundation, and the UCLA Children’s Discovery and Innovation Institute. The investigators didn’t have any relevant disclosures.
SOURCE: Heesch J et al. AES 2019. Abstract 2.234.
BALTIMORE – “This is scary and warrants caution,” said senior investigator and pediatric neurologist Shaun Hussain, MD, a pediatric neurologist at Mattel Children’s Hospital at UCLA. Because of the findings, “we are avoiding the use of voltage-gated sodium channel blockade in any child at risk for infantile spasms. More broadly, we are avoiding [them] in any infant if there is a good alternative medication, of which there are many in most cases.”
There have been a few previous case reports linking voltage-gated sodium channel blockers (SCBs) – which include oxcarbazepine, carbamazepine, lacosamide, and phenytoin – to infantile spasms, but they are still commonly used for infant seizures. There was some disagreement at UCLA whether there really was a link, so Dr. Hussain and his team took a look at the university’s experience. They matched 50 children with nonsyndromic epilepsy who subsequently developed video-EEG confirmed infantile spasms (cases) to 50 children who also had nonsyndromic epilepsy but did not develop spasms, based on follow-up duration and age and date of epilepsy onset.
The team then looked to see what drugs they had been on; it turned out that cases and controls were about equally as likely to have been treated with any specific antiepileptic, including SCBs. Infantile spasms were substantially more likely with SCB exposure in children with spasm risk factors, which also include focal cortical dysplasia, Aicardi syndrome, and other problems (HR 7.0; 95%; CI 2.5-19.8; P less than .001). Spasms were also more likely among even low-risk children treated with SCBs, although the trend was not statistically significant.
In the end, “we wonder how many cases of infantile spasms could [have been] prevented entirely if we had avoided sodium channel blockade,” Dr. Hussain said at the annual meeting of the American Epilepsy Society.
With so many other seizure options available – levetiracetam, topiramate, and phenobarbital, to name just a few – maybe it would be best “to stay away from” SCBs entirely in “infants with any form of epilepsy,” said lead investigator Jaeden Heesch, an undergraduate researcher who worked with Dr. Hussain.
It is unclear why SCBs increase infantile spasm risk; maybe nonselective voltage-gated sodium channel blockade interferes with proper neuron function in susceptible children, similar to the effects of sodium voltage-gated channel alpha subunit 1 mutations in Dravet syndrome, Dr. Hussain said. Perhaps the findings will inspire drug development. “If nonselective sodium channel blockade is bad, perhaps selective modulation of voltage-gated sodium currents [could be] beneficial or protective,” he said.
The age of epilepsy onset in the study was around 2 months. Children who went on to develop infantile spasms had an average of almost two seizures per day, versus fewer than one among controls, and were on an average of two, versus about 1.5 antiepileptics. The differences were not statistically significant.
The study looked at SCB exposure overall, but it’s possible that infantile spasm risk differs among the various class members.
The work was funded by the Elsie and Isaac Fogelman Endowment, the Hughes Family Foundation, and the UCLA Children’s Discovery and Innovation Institute. The investigators didn’t have any relevant disclosures.
SOURCE: Heesch J et al. AES 2019. Abstract 2.234.
REPORTING FROM AES 2019
Study delineates spectrum of Dravet syndrome phenotypes
BALTIMORE – , researchers said at the annual meeting of the American Epilepsy Society. About half of patients have an afebrile seizure as their first seizure, and it is common for patients to present with seizures before age 5 months. Patients also may have seizure onset after age 18 months, said Wenhui Li, a researcher affiliated with Children’s Hospital of Fudan University in Shanghai and University of Melbourne, and colleagues.
“Subtle differences in Dravet syndrome phenotypes lead to delayed diagnosis,” the researchers said. “Understanding key features within the phenotypic spectrum will assist clinicians in evaluating whether a child has Dravet syndrome, facilitating early diagnosis for precision therapies.”
Typically, Dravet syndrome is thought to begin with prolonged febrile hemiclonic or generalized tonic-clonic seizures at about age 6 months in normally developing infants. Multiple seizure types occur during subsequent years, including focal impaired awareness, bilateral tonic-clonic, absence, and myoclonic seizures.
Patients often do not receive a diagnosis of Dravet syndrome until they are older than 3 years, after “developmental plateau or regression occurs in the second year,” the investigators said. “Earlier diagnosis is critical for optimal management.”
To outline the range of phenotypes, researchers analyzed the clinical histories of 188 patients with Dravet syndrome and pathogenic SCN1A variants. They excluded from their analysis patients with SCN1A-positive genetic epilepsy with febrile seizures plus (GEFS+).
In all, 53% of the patients were female, and 2% had developmental delay prior to the onset of seizures. Age at seizure onset ranged from 1.5 months to 21 months (median, 5.75 months). Three patients had seizure onset after age 12 months, the authors noted.
In cases where the first seizure type could be classified, 52% had generalized tonic-clonic seizures at onset, 37% had hemiclonic seizures, 4% myoclonic seizures, 4% focal impaired awareness seizures, and 0.5% absence seizures. In addition, 1% had hemiclonic and myoclonic seizures, and 2% had tonic-clonic and myoclonic seizures.
Fifty-four percent of patients were febrile during their first seizure, and 46% were afebrile.
Status epilepticus as the first seizure occurred in about 44% of cases, while 35% of patients had a first seizure duration of 5 minutes or less.
The researchers had no disclosures.
SOURCE: Li W et al. AES 2019. Abstract 2.116.
BALTIMORE – , researchers said at the annual meeting of the American Epilepsy Society. About half of patients have an afebrile seizure as their first seizure, and it is common for patients to present with seizures before age 5 months. Patients also may have seizure onset after age 18 months, said Wenhui Li, a researcher affiliated with Children’s Hospital of Fudan University in Shanghai and University of Melbourne, and colleagues.
“Subtle differences in Dravet syndrome phenotypes lead to delayed diagnosis,” the researchers said. “Understanding key features within the phenotypic spectrum will assist clinicians in evaluating whether a child has Dravet syndrome, facilitating early diagnosis for precision therapies.”
Typically, Dravet syndrome is thought to begin with prolonged febrile hemiclonic or generalized tonic-clonic seizures at about age 6 months in normally developing infants. Multiple seizure types occur during subsequent years, including focal impaired awareness, bilateral tonic-clonic, absence, and myoclonic seizures.
Patients often do not receive a diagnosis of Dravet syndrome until they are older than 3 years, after “developmental plateau or regression occurs in the second year,” the investigators said. “Earlier diagnosis is critical for optimal management.”
To outline the range of phenotypes, researchers analyzed the clinical histories of 188 patients with Dravet syndrome and pathogenic SCN1A variants. They excluded from their analysis patients with SCN1A-positive genetic epilepsy with febrile seizures plus (GEFS+).
In all, 53% of the patients were female, and 2% had developmental delay prior to the onset of seizures. Age at seizure onset ranged from 1.5 months to 21 months (median, 5.75 months). Three patients had seizure onset after age 12 months, the authors noted.
In cases where the first seizure type could be classified, 52% had generalized tonic-clonic seizures at onset, 37% had hemiclonic seizures, 4% myoclonic seizures, 4% focal impaired awareness seizures, and 0.5% absence seizures. In addition, 1% had hemiclonic and myoclonic seizures, and 2% had tonic-clonic and myoclonic seizures.
Fifty-four percent of patients were febrile during their first seizure, and 46% were afebrile.
Status epilepticus as the first seizure occurred in about 44% of cases, while 35% of patients had a first seizure duration of 5 minutes or less.
The researchers had no disclosures.
SOURCE: Li W et al. AES 2019. Abstract 2.116.
BALTIMORE – , researchers said at the annual meeting of the American Epilepsy Society. About half of patients have an afebrile seizure as their first seizure, and it is common for patients to present with seizures before age 5 months. Patients also may have seizure onset after age 18 months, said Wenhui Li, a researcher affiliated with Children’s Hospital of Fudan University in Shanghai and University of Melbourne, and colleagues.
“Subtle differences in Dravet syndrome phenotypes lead to delayed diagnosis,” the researchers said. “Understanding key features within the phenotypic spectrum will assist clinicians in evaluating whether a child has Dravet syndrome, facilitating early diagnosis for precision therapies.”
Typically, Dravet syndrome is thought to begin with prolonged febrile hemiclonic or generalized tonic-clonic seizures at about age 6 months in normally developing infants. Multiple seizure types occur during subsequent years, including focal impaired awareness, bilateral tonic-clonic, absence, and myoclonic seizures.
Patients often do not receive a diagnosis of Dravet syndrome until they are older than 3 years, after “developmental plateau or regression occurs in the second year,” the investigators said. “Earlier diagnosis is critical for optimal management.”
To outline the range of phenotypes, researchers analyzed the clinical histories of 188 patients with Dravet syndrome and pathogenic SCN1A variants. They excluded from their analysis patients with SCN1A-positive genetic epilepsy with febrile seizures plus (GEFS+).
In all, 53% of the patients were female, and 2% had developmental delay prior to the onset of seizures. Age at seizure onset ranged from 1.5 months to 21 months (median, 5.75 months). Three patients had seizure onset after age 12 months, the authors noted.
In cases where the first seizure type could be classified, 52% had generalized tonic-clonic seizures at onset, 37% had hemiclonic seizures, 4% myoclonic seizures, 4% focal impaired awareness seizures, and 0.5% absence seizures. In addition, 1% had hemiclonic and myoclonic seizures, and 2% had tonic-clonic and myoclonic seizures.
Fifty-four percent of patients were febrile during their first seizure, and 46% were afebrile.
Status epilepticus as the first seizure occurred in about 44% of cases, while 35% of patients had a first seizure duration of 5 minutes or less.
The researchers had no disclosures.
SOURCE: Li W et al. AES 2019. Abstract 2.116.
REPORTING FROM AES 2019
Reduction in convulsive seizure frequency is associated with improved executive function in Dravet syndrome
BALTIMORE – according to data presented at the annual meeting of the American Epilepsy Society. Large reductions in convulsive seizure frequency for prolonged periods may improve everyday deficits in executive function in these patients, according to the investigators.
Dravet syndrome often entails cognitive impairment, including deficits in executive function. The frequency and severity of convulsive seizures are believed to worsen cognitive impairment over time, but few researchers have conducted long-term studies to test this hypothesis. Adjunctive fenfluramine significantly reduced the frequency of convulsive seizures and improved executive function after 14 weeks in a phase 3 study of patients with Dravet syndrome.
An open-label extension of a phase 3 study
In an open-label extension of this study, Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco, Benioff Children’s Hospital, and colleagues analyzed the relationship between changes in convulsive seizure frequency and executive function. The investigators also examined the effect of reducing convulsive seizure frequency by comparing patients with profound reductions (greater than 75%) versus patients with minimal reductions (less than 25%).
Patients aged 2-18 years entered the open-label study and received adjunctive fenfluramine for 1 year. At the beginning of the open-label phase, the dose was titrated to effect. The dose ranged from 0.2 mg/kg per day to 0.7 mg/kg per day and was administered as 2.5 mg/mL of fenfluramine. The maximum dose was 17 mg with stiripentol or 26 mg without.
The investigators calculated the percent difference in convulsive seizure frequency per 28 days from baseline to the end of the open-label study. They evaluated executive function using the Behavior Rating Inventory of Executive Function (BRIEF), which caregivers completed at baseline and year 1 for patients aged 5-18 years. Scores on the BRIEF were updated to the newer version: BRIEF2. Dr. Sullivan and colleagues calculated Spearman’s rho correlation coefficients to evaluate the association between BRIEF2 Behavior Regulation Index, Emotion Regulation Index, Cognitive Regulation Index, and Global Executive Composite scores. Lower scores on the BRIEF2 indexes and composite indicate better executive functioning. In addition, the researchers compared clinically meaningful change in BRIEF2 indexes and composite scores from baseline to year 1 between patients with minimal and profound reductions in convulsive seizure frequency using Fisher’s exact test. They defined a clinically meaningful change as an improvement in the Reliable Change Index of greater than 95%.
Profound reduction in seizure frequency was common
At the time of analysis, 53 patients had completed at least 1 year of open-label fenfluramine and had baseline and year 1 BRIEF2 data. Patients’ median age was 10 years, and 57% of patients were male. The median reduction from prerandomization baseline in convulsive seizure frequency was 71%. The reduction ranged from 99.7% to 55.0%.
Twenty-four (45%) patients had a reduction in convulsive seizure frequency of greater than 75%, and 11 (21%) had a reduction of less than 25%. Change in convulsive seizure frequency correlated significantly with Emotion Regulation Index and Global Executive Composite. Change in seizure frequency tended to correlate with Cognitive Regulation Index, but the result was not statistically significant. Change in convulsive seizure frequency was not significantly associated with Behavior Regulation Index. A significantly higher percentage of patients in the profound responder group had significant, clinically meaningful improvements on Emotion Regulation Index and Global Executive Composite, compared with minimal responders.
Zogenix, the company that is developing fenfluramine as a treatment for Dravet syndrome, funded the study. Several investigators are employees of Zogenix.
SOURCE: Bishop KI et al. AES 2019, Abstract 2.438.
BALTIMORE – according to data presented at the annual meeting of the American Epilepsy Society. Large reductions in convulsive seizure frequency for prolonged periods may improve everyday deficits in executive function in these patients, according to the investigators.
Dravet syndrome often entails cognitive impairment, including deficits in executive function. The frequency and severity of convulsive seizures are believed to worsen cognitive impairment over time, but few researchers have conducted long-term studies to test this hypothesis. Adjunctive fenfluramine significantly reduced the frequency of convulsive seizures and improved executive function after 14 weeks in a phase 3 study of patients with Dravet syndrome.
An open-label extension of a phase 3 study
In an open-label extension of this study, Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco, Benioff Children’s Hospital, and colleagues analyzed the relationship between changes in convulsive seizure frequency and executive function. The investigators also examined the effect of reducing convulsive seizure frequency by comparing patients with profound reductions (greater than 75%) versus patients with minimal reductions (less than 25%).
Patients aged 2-18 years entered the open-label study and received adjunctive fenfluramine for 1 year. At the beginning of the open-label phase, the dose was titrated to effect. The dose ranged from 0.2 mg/kg per day to 0.7 mg/kg per day and was administered as 2.5 mg/mL of fenfluramine. The maximum dose was 17 mg with stiripentol or 26 mg without.
The investigators calculated the percent difference in convulsive seizure frequency per 28 days from baseline to the end of the open-label study. They evaluated executive function using the Behavior Rating Inventory of Executive Function (BRIEF), which caregivers completed at baseline and year 1 for patients aged 5-18 years. Scores on the BRIEF were updated to the newer version: BRIEF2. Dr. Sullivan and colleagues calculated Spearman’s rho correlation coefficients to evaluate the association between BRIEF2 Behavior Regulation Index, Emotion Regulation Index, Cognitive Regulation Index, and Global Executive Composite scores. Lower scores on the BRIEF2 indexes and composite indicate better executive functioning. In addition, the researchers compared clinically meaningful change in BRIEF2 indexes and composite scores from baseline to year 1 between patients with minimal and profound reductions in convulsive seizure frequency using Fisher’s exact test. They defined a clinically meaningful change as an improvement in the Reliable Change Index of greater than 95%.
Profound reduction in seizure frequency was common
At the time of analysis, 53 patients had completed at least 1 year of open-label fenfluramine and had baseline and year 1 BRIEF2 data. Patients’ median age was 10 years, and 57% of patients were male. The median reduction from prerandomization baseline in convulsive seizure frequency was 71%. The reduction ranged from 99.7% to 55.0%.
Twenty-four (45%) patients had a reduction in convulsive seizure frequency of greater than 75%, and 11 (21%) had a reduction of less than 25%. Change in convulsive seizure frequency correlated significantly with Emotion Regulation Index and Global Executive Composite. Change in seizure frequency tended to correlate with Cognitive Regulation Index, but the result was not statistically significant. Change in convulsive seizure frequency was not significantly associated with Behavior Regulation Index. A significantly higher percentage of patients in the profound responder group had significant, clinically meaningful improvements on Emotion Regulation Index and Global Executive Composite, compared with minimal responders.
Zogenix, the company that is developing fenfluramine as a treatment for Dravet syndrome, funded the study. Several investigators are employees of Zogenix.
SOURCE: Bishop KI et al. AES 2019, Abstract 2.438.
BALTIMORE – according to data presented at the annual meeting of the American Epilepsy Society. Large reductions in convulsive seizure frequency for prolonged periods may improve everyday deficits in executive function in these patients, according to the investigators.
Dravet syndrome often entails cognitive impairment, including deficits in executive function. The frequency and severity of convulsive seizures are believed to worsen cognitive impairment over time, but few researchers have conducted long-term studies to test this hypothesis. Adjunctive fenfluramine significantly reduced the frequency of convulsive seizures and improved executive function after 14 weeks in a phase 3 study of patients with Dravet syndrome.
An open-label extension of a phase 3 study
In an open-label extension of this study, Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco, Benioff Children’s Hospital, and colleagues analyzed the relationship between changes in convulsive seizure frequency and executive function. The investigators also examined the effect of reducing convulsive seizure frequency by comparing patients with profound reductions (greater than 75%) versus patients with minimal reductions (less than 25%).
Patients aged 2-18 years entered the open-label study and received adjunctive fenfluramine for 1 year. At the beginning of the open-label phase, the dose was titrated to effect. The dose ranged from 0.2 mg/kg per day to 0.7 mg/kg per day and was administered as 2.5 mg/mL of fenfluramine. The maximum dose was 17 mg with stiripentol or 26 mg without.
The investigators calculated the percent difference in convulsive seizure frequency per 28 days from baseline to the end of the open-label study. They evaluated executive function using the Behavior Rating Inventory of Executive Function (BRIEF), which caregivers completed at baseline and year 1 for patients aged 5-18 years. Scores on the BRIEF were updated to the newer version: BRIEF2. Dr. Sullivan and colleagues calculated Spearman’s rho correlation coefficients to evaluate the association between BRIEF2 Behavior Regulation Index, Emotion Regulation Index, Cognitive Regulation Index, and Global Executive Composite scores. Lower scores on the BRIEF2 indexes and composite indicate better executive functioning. In addition, the researchers compared clinically meaningful change in BRIEF2 indexes and composite scores from baseline to year 1 between patients with minimal and profound reductions in convulsive seizure frequency using Fisher’s exact test. They defined a clinically meaningful change as an improvement in the Reliable Change Index of greater than 95%.
Profound reduction in seizure frequency was common
At the time of analysis, 53 patients had completed at least 1 year of open-label fenfluramine and had baseline and year 1 BRIEF2 data. Patients’ median age was 10 years, and 57% of patients were male. The median reduction from prerandomization baseline in convulsive seizure frequency was 71%. The reduction ranged from 99.7% to 55.0%.
Twenty-four (45%) patients had a reduction in convulsive seizure frequency of greater than 75%, and 11 (21%) had a reduction of less than 25%. Change in convulsive seizure frequency correlated significantly with Emotion Regulation Index and Global Executive Composite. Change in seizure frequency tended to correlate with Cognitive Regulation Index, but the result was not statistically significant. Change in convulsive seizure frequency was not significantly associated with Behavior Regulation Index. A significantly higher percentage of patients in the profound responder group had significant, clinically meaningful improvements on Emotion Regulation Index and Global Executive Composite, compared with minimal responders.
Zogenix, the company that is developing fenfluramine as a treatment for Dravet syndrome, funded the study. Several investigators are employees of Zogenix.
SOURCE: Bishop KI et al. AES 2019, Abstract 2.438.
REPORTING FROM AES 2019
Scalp EEG predicts temporal lobe resection success
BALTIMORE – In a review of 43 temporal lobe epilepsy patients at Yale University in New Haven, Conn., anteromedial temporal resection (AMTR) failed in every case in which initial ictal rhythm on scalp EEG spread beyond the medial temporal lobe to other brain regions within 10 seconds.
Among the 33 patients who had no spread on preoperative scalp EEG or who spread in 10 or more seconds, 31 (94%) had a good outcome, meaning they were seizure free or had only auras after AMTR. The findings could mean that scalp EEG can predict surgery outcome.
AMTR works in the majority of patients with refractory temporal lobe epilepsy, but about 10-20% continue to have seizures. Senior investigator Pue Farooque, DO, from Yale University wanted to find a way to identify patients likely to fail surgery beforehand to help counsel patients on what to expect and also to know when other treatment options might be a better bet.
“If you see seizures are spreading quickly to another area, like the frontal lobe or the temporal neocortex, you could implant RNS [responsive neurostimulation]” instead of doing an ATMR, “and that might improve your outcomes,” she said at the American Epilepsy Society’s annual meeting.
The findings are essentially the same as when the group used intracranial EEG to detect fast spread in a previous report, but scalp EEG is noninvasive and allows for easy preoperative assessment (JAMA Neurol. 2019 Apr 1;76[4]:462-9).
The team also found in their new study that diffuse hypometabolism in the entire temporal lobe on quantitative PET also predicted poor ATMR outcomes (P less than .001), but Dr. Farooque said more work is needed to quantify the finding. The investigators also plan to assess the predictive value of resting functional MRI.
The take home, she said, is that “we can do better” with epilepsy surgery, and “there are noninvasive markers we can use to help guide us.”
It’s unclear why more rapid seizure spread would predict AMTR failure. In the earlier study with intracranial EEG, the investigators said “the results are best explained by attributing epileptogenic potential to sites of early seizure spread that were not included in resection. This mechanism of failure implies that a distributed epileptogenic network rather than a single epileptogenic focus may underlie surgically refractory epilepsy.”
Patients in the new report had epilepsy for a mean of 24.4 years, and 25 (58%) were women; 30 cases (69%) were lesional, and follow-up was at least a year. The contralateral or lateralized seizure spread ranged from 1 to 63 seconds, with a mean of 18.5 seconds. Among patients who failed AMTR, seizure spread occurred at a mean of 7.1 seconds.
Electrographic pattern at onset and location of interictal epileptiform discharges did not predict outcome
There was no industry funding, and Dr. Farooque didn’t have any relevant disclosures.
SOURCE: Chiari J et al. AES 2019, Abstract 1.36.
BALTIMORE – In a review of 43 temporal lobe epilepsy patients at Yale University in New Haven, Conn., anteromedial temporal resection (AMTR) failed in every case in which initial ictal rhythm on scalp EEG spread beyond the medial temporal lobe to other brain regions within 10 seconds.
Among the 33 patients who had no spread on preoperative scalp EEG or who spread in 10 or more seconds, 31 (94%) had a good outcome, meaning they were seizure free or had only auras after AMTR. The findings could mean that scalp EEG can predict surgery outcome.
AMTR works in the majority of patients with refractory temporal lobe epilepsy, but about 10-20% continue to have seizures. Senior investigator Pue Farooque, DO, from Yale University wanted to find a way to identify patients likely to fail surgery beforehand to help counsel patients on what to expect and also to know when other treatment options might be a better bet.
“If you see seizures are spreading quickly to another area, like the frontal lobe or the temporal neocortex, you could implant RNS [responsive neurostimulation]” instead of doing an ATMR, “and that might improve your outcomes,” she said at the American Epilepsy Society’s annual meeting.
The findings are essentially the same as when the group used intracranial EEG to detect fast spread in a previous report, but scalp EEG is noninvasive and allows for easy preoperative assessment (JAMA Neurol. 2019 Apr 1;76[4]:462-9).
The team also found in their new study that diffuse hypometabolism in the entire temporal lobe on quantitative PET also predicted poor ATMR outcomes (P less than .001), but Dr. Farooque said more work is needed to quantify the finding. The investigators also plan to assess the predictive value of resting functional MRI.
The take home, she said, is that “we can do better” with epilepsy surgery, and “there are noninvasive markers we can use to help guide us.”
It’s unclear why more rapid seizure spread would predict AMTR failure. In the earlier study with intracranial EEG, the investigators said “the results are best explained by attributing epileptogenic potential to sites of early seizure spread that were not included in resection. This mechanism of failure implies that a distributed epileptogenic network rather than a single epileptogenic focus may underlie surgically refractory epilepsy.”
Patients in the new report had epilepsy for a mean of 24.4 years, and 25 (58%) were women; 30 cases (69%) were lesional, and follow-up was at least a year. The contralateral or lateralized seizure spread ranged from 1 to 63 seconds, with a mean of 18.5 seconds. Among patients who failed AMTR, seizure spread occurred at a mean of 7.1 seconds.
Electrographic pattern at onset and location of interictal epileptiform discharges did not predict outcome
There was no industry funding, and Dr. Farooque didn’t have any relevant disclosures.
SOURCE: Chiari J et al. AES 2019, Abstract 1.36.
BALTIMORE – In a review of 43 temporal lobe epilepsy patients at Yale University in New Haven, Conn., anteromedial temporal resection (AMTR) failed in every case in which initial ictal rhythm on scalp EEG spread beyond the medial temporal lobe to other brain regions within 10 seconds.
Among the 33 patients who had no spread on preoperative scalp EEG or who spread in 10 or more seconds, 31 (94%) had a good outcome, meaning they were seizure free or had only auras after AMTR. The findings could mean that scalp EEG can predict surgery outcome.
AMTR works in the majority of patients with refractory temporal lobe epilepsy, but about 10-20% continue to have seizures. Senior investigator Pue Farooque, DO, from Yale University wanted to find a way to identify patients likely to fail surgery beforehand to help counsel patients on what to expect and also to know when other treatment options might be a better bet.
“If you see seizures are spreading quickly to another area, like the frontal lobe or the temporal neocortex, you could implant RNS [responsive neurostimulation]” instead of doing an ATMR, “and that might improve your outcomes,” she said at the American Epilepsy Society’s annual meeting.
The findings are essentially the same as when the group used intracranial EEG to detect fast spread in a previous report, but scalp EEG is noninvasive and allows for easy preoperative assessment (JAMA Neurol. 2019 Apr 1;76[4]:462-9).
The team also found in their new study that diffuse hypometabolism in the entire temporal lobe on quantitative PET also predicted poor ATMR outcomes (P less than .001), but Dr. Farooque said more work is needed to quantify the finding. The investigators also plan to assess the predictive value of resting functional MRI.
The take home, she said, is that “we can do better” with epilepsy surgery, and “there are noninvasive markers we can use to help guide us.”
It’s unclear why more rapid seizure spread would predict AMTR failure. In the earlier study with intracranial EEG, the investigators said “the results are best explained by attributing epileptogenic potential to sites of early seizure spread that were not included in resection. This mechanism of failure implies that a distributed epileptogenic network rather than a single epileptogenic focus may underlie surgically refractory epilepsy.”
Patients in the new report had epilepsy for a mean of 24.4 years, and 25 (58%) were women; 30 cases (69%) were lesional, and follow-up was at least a year. The contralateral or lateralized seizure spread ranged from 1 to 63 seconds, with a mean of 18.5 seconds. Among patients who failed AMTR, seizure spread occurred at a mean of 7.1 seconds.
Electrographic pattern at onset and location of interictal epileptiform discharges did not predict outcome
There was no industry funding, and Dr. Farooque didn’t have any relevant disclosures.
SOURCE: Chiari J et al. AES 2019, Abstract 1.36.
REPORTING FROM AES 2019
Outcomes of epilepsy surgery at 1 year may be better among older patients
BALTIMORE – Older patients may have better outcomes at 1 year after resective surgery for epilepsy than the general population does, according to research presented at the annual meeting of the American Epilepsy Society. A tendency toward greater prevalence of lesional epilepsy and temporal lobe epilepsy (TLE) in the older patients in the study population could explain this difference in outcomes. Although surgery might entail greater risks in older patients, the decision to operate should be based on the patient’s inherent risk, and not on his or her age, said Juan S. Bottan, MD, neurosurgery resident at Hospital Pedro De Elizalde in Buenos Aires, and colleagues.
Epilepsy surgery as a treatment for elderly patients is controversial. These patients generally are not considered to be surgical candidates because of concerns about long disease duration and increased surgical risk. Recent literature, however, suggests that elderly patients can benefit from surgery. Lang et al. found that epilepsy surgery success rates can be higher in selected older patients than in younger patients, although older patients may be at greater risk for postoperative hygroma and memory deficits.
Dr. Bottan and colleagues sought to analyze the role of resective surgery in patients older than age 60 years by evaluating surgical outcomes and safety. The investigators retrospectively analyzed 595 patients who underwent resective epilepsy surgery at Western University in London, Ontario, during 1999-2019. Eligible participants had drug-resistant epilepsy that had failed the best medical management. The researchers identified 31 patients aged 60 years or older and randomly selected 60 patients aged 59 years or younger as a control group. Dr. Bottan and colleagues analyzed the population’s characteristics, presurgical evaluations, postoperative outcome, and complications.
The investigators found no significant differences between groups in terms of hemisphere dominance, side of surgery, the ratio of patients with lesional epilepsy to patients with nonlesional epilepsy, and incidence of TLE over extratemporal epilepsy.
Nevertheless, extratemporal epilepsy was more frequent in older patients. Age and duration of epilepsy were significantly greater in older patients, and invasive recording was significantly more common in younger patients.
The most common pathology results in older patients were mesial temporal sclerosis (39%), gliosis (19%), and other (19%). Among younger patients, the most common pathology results were mesial temporal sclerosis (25%), gliosis (25%), and focal cortical dysplasia (15%).
The rates of Engel Class I outcome at 6 months, 1 year, and 2 years were 92.9%, 88.5%, and 94.7% among older patients and 75%, 63.5%, and 75.8% among younger patients, respectively. The difference between groups in Engel Class I outcome at 1 year was statistically significant. Patients with TLE had a better seizure outcome, regardless of age group, but the rate of good outcome was higher among older patients. The rate of complications was higher among older patients, but the difference was not statistically significant.
The study was not supported by external funding, and the investigators had no disclosures.
SOURCE: Bottan JS et al. AES 2019, Abstract 1.343.
BALTIMORE – Older patients may have better outcomes at 1 year after resective surgery for epilepsy than the general population does, according to research presented at the annual meeting of the American Epilepsy Society. A tendency toward greater prevalence of lesional epilepsy and temporal lobe epilepsy (TLE) in the older patients in the study population could explain this difference in outcomes. Although surgery might entail greater risks in older patients, the decision to operate should be based on the patient’s inherent risk, and not on his or her age, said Juan S. Bottan, MD, neurosurgery resident at Hospital Pedro De Elizalde in Buenos Aires, and colleagues.
Epilepsy surgery as a treatment for elderly patients is controversial. These patients generally are not considered to be surgical candidates because of concerns about long disease duration and increased surgical risk. Recent literature, however, suggests that elderly patients can benefit from surgery. Lang et al. found that epilepsy surgery success rates can be higher in selected older patients than in younger patients, although older patients may be at greater risk for postoperative hygroma and memory deficits.
Dr. Bottan and colleagues sought to analyze the role of resective surgery in patients older than age 60 years by evaluating surgical outcomes and safety. The investigators retrospectively analyzed 595 patients who underwent resective epilepsy surgery at Western University in London, Ontario, during 1999-2019. Eligible participants had drug-resistant epilepsy that had failed the best medical management. The researchers identified 31 patients aged 60 years or older and randomly selected 60 patients aged 59 years or younger as a control group. Dr. Bottan and colleagues analyzed the population’s characteristics, presurgical evaluations, postoperative outcome, and complications.
The investigators found no significant differences between groups in terms of hemisphere dominance, side of surgery, the ratio of patients with lesional epilepsy to patients with nonlesional epilepsy, and incidence of TLE over extratemporal epilepsy.
Nevertheless, extratemporal epilepsy was more frequent in older patients. Age and duration of epilepsy were significantly greater in older patients, and invasive recording was significantly more common in younger patients.
The most common pathology results in older patients were mesial temporal sclerosis (39%), gliosis (19%), and other (19%). Among younger patients, the most common pathology results were mesial temporal sclerosis (25%), gliosis (25%), and focal cortical dysplasia (15%).
The rates of Engel Class I outcome at 6 months, 1 year, and 2 years were 92.9%, 88.5%, and 94.7% among older patients and 75%, 63.5%, and 75.8% among younger patients, respectively. The difference between groups in Engel Class I outcome at 1 year was statistically significant. Patients with TLE had a better seizure outcome, regardless of age group, but the rate of good outcome was higher among older patients. The rate of complications was higher among older patients, but the difference was not statistically significant.
The study was not supported by external funding, and the investigators had no disclosures.
SOURCE: Bottan JS et al. AES 2019, Abstract 1.343.
BALTIMORE – Older patients may have better outcomes at 1 year after resective surgery for epilepsy than the general population does, according to research presented at the annual meeting of the American Epilepsy Society. A tendency toward greater prevalence of lesional epilepsy and temporal lobe epilepsy (TLE) in the older patients in the study population could explain this difference in outcomes. Although surgery might entail greater risks in older patients, the decision to operate should be based on the patient’s inherent risk, and not on his or her age, said Juan S. Bottan, MD, neurosurgery resident at Hospital Pedro De Elizalde in Buenos Aires, and colleagues.
Epilepsy surgery as a treatment for elderly patients is controversial. These patients generally are not considered to be surgical candidates because of concerns about long disease duration and increased surgical risk. Recent literature, however, suggests that elderly patients can benefit from surgery. Lang et al. found that epilepsy surgery success rates can be higher in selected older patients than in younger patients, although older patients may be at greater risk for postoperative hygroma and memory deficits.
Dr. Bottan and colleagues sought to analyze the role of resective surgery in patients older than age 60 years by evaluating surgical outcomes and safety. The investigators retrospectively analyzed 595 patients who underwent resective epilepsy surgery at Western University in London, Ontario, during 1999-2019. Eligible participants had drug-resistant epilepsy that had failed the best medical management. The researchers identified 31 patients aged 60 years or older and randomly selected 60 patients aged 59 years or younger as a control group. Dr. Bottan and colleagues analyzed the population’s characteristics, presurgical evaluations, postoperative outcome, and complications.
The investigators found no significant differences between groups in terms of hemisphere dominance, side of surgery, the ratio of patients with lesional epilepsy to patients with nonlesional epilepsy, and incidence of TLE over extratemporal epilepsy.
Nevertheless, extratemporal epilepsy was more frequent in older patients. Age and duration of epilepsy were significantly greater in older patients, and invasive recording was significantly more common in younger patients.
The most common pathology results in older patients were mesial temporal sclerosis (39%), gliosis (19%), and other (19%). Among younger patients, the most common pathology results were mesial temporal sclerosis (25%), gliosis (25%), and focal cortical dysplasia (15%).
The rates of Engel Class I outcome at 6 months, 1 year, and 2 years were 92.9%, 88.5%, and 94.7% among older patients and 75%, 63.5%, and 75.8% among younger patients, respectively. The difference between groups in Engel Class I outcome at 1 year was statistically significant. Patients with TLE had a better seizure outcome, regardless of age group, but the rate of good outcome was higher among older patients. The rate of complications was higher among older patients, but the difference was not statistically significant.
The study was not supported by external funding, and the investigators had no disclosures.
SOURCE: Bottan JS et al. AES 2019, Abstract 1.343.
REPORTING FROM AES 2019
Researchers mine free-text diary entries for seizure cluster insights
BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.
To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.
“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.
Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.
An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.
“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.
Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:
- Massive ongoing cluster with about 20% apneic events.
- My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
- Started feeling like I was having an aura and pulled over.
- Thought about suicide for the first time in a while.
Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.
UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.
SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.
BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.
To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.
“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.
Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.
An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.
“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.
Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:
- Massive ongoing cluster with about 20% apneic events.
- My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
- Started feeling like I was having an aura and pulled over.
- Thought about suicide for the first time in a while.
Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.
UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.
SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.
BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.
To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.
“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.
Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.
An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.
“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.
Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:
- Massive ongoing cluster with about 20% apneic events.
- My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
- Started feeling like I was having an aura and pulled over.
- Thought about suicide for the first time in a while.
Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.
UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.
SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.
REPORTING FROM AES 2019
Skip CTs for breakthrough seizures in chronic epilepsy
BALTIMORE – Head CTs for breakthrough seizures in chronic epilepsy are useful for known structural triggers such as brain tumors, but they don’t change management for most patients, according to a review from the SUNY Upstate Medical University, Syracuse, N.Y., emergency department.
“Nonselective use of ED neuroimaging in patients with no new neurological findings” and no known structural problem, is “very low yield, and increases the use of hospital resources and radiation exposure without impacting the immediate care,” concluded investigators led by Shahram Izadyar, MD, an epileptologist and associate professor of neurology at the university.
In short, CTs for breakthrough seizures – routine in many EDs – usually are a waste of time and money. Absent a known structural cause, “there really isn’t a reason to do imaging,” he said at the American Epilepsy Society annual meeting.
Dr. Izadyar wanted to look into the issue after noticing how common CTs were among his breakthrough patients. He and his team reviewed 90 adults with an established diagnosis of epilepsy and on at least one antiepileptic who presented to the university ED for breakthrough seizures during 2017-2018; 39 (43.3%) had head CTs, 51 (56.7%) did not.
CT changed management in three of the four patients (4.4%) who had a known brain tumor, leading, for instance, to steroids for increased tumor edema. The rest of the patients had nonfocal exams, and imaging had no impact on management.
There was no rhyme or reason why some people got CTs and others didn’t; it seemed to be dependent on the provider. Defensive medicine probably had something to do with it, as well as saving time by ordering a CT instead of doing a neurologic exam, Dr. Izadyar said.
People aren’t going to stop doing defensive medicine, but even a small reduction in unnecessary CTs would “be a positive change.” There’s the cost issue, but also the radiation exposure, which is considerable when people end up in the ED every few months for breakthrough seizures, he said.
There were no differences between the CT and no-CT groups in the suspected causes of breakthroughs (P = .93). About half the cases were probably because of noncompliance, about a quarter from sleep deprivation, and the rest from a change in seizure medication or some other issue.
Dr. Izadyar said the next step is taking the findings to his ED colleagues, and perhaps calculating how much money the university would save by skipping CTs in chronic epilepsy patients with no known structural problem.
There were slightly more men than women in the study, and the mean age was 38 years.
There was no industry funding, and the investigators didn’t have any relevant disclosures.
SOURCE: Ali S et al. AES 2019. Abstract 1.213.
BALTIMORE – Head CTs for breakthrough seizures in chronic epilepsy are useful for known structural triggers such as brain tumors, but they don’t change management for most patients, according to a review from the SUNY Upstate Medical University, Syracuse, N.Y., emergency department.
“Nonselective use of ED neuroimaging in patients with no new neurological findings” and no known structural problem, is “very low yield, and increases the use of hospital resources and radiation exposure without impacting the immediate care,” concluded investigators led by Shahram Izadyar, MD, an epileptologist and associate professor of neurology at the university.
In short, CTs for breakthrough seizures – routine in many EDs – usually are a waste of time and money. Absent a known structural cause, “there really isn’t a reason to do imaging,” he said at the American Epilepsy Society annual meeting.
Dr. Izadyar wanted to look into the issue after noticing how common CTs were among his breakthrough patients. He and his team reviewed 90 adults with an established diagnosis of epilepsy and on at least one antiepileptic who presented to the university ED for breakthrough seizures during 2017-2018; 39 (43.3%) had head CTs, 51 (56.7%) did not.
CT changed management in three of the four patients (4.4%) who had a known brain tumor, leading, for instance, to steroids for increased tumor edema. The rest of the patients had nonfocal exams, and imaging had no impact on management.
There was no rhyme or reason why some people got CTs and others didn’t; it seemed to be dependent on the provider. Defensive medicine probably had something to do with it, as well as saving time by ordering a CT instead of doing a neurologic exam, Dr. Izadyar said.
People aren’t going to stop doing defensive medicine, but even a small reduction in unnecessary CTs would “be a positive change.” There’s the cost issue, but also the radiation exposure, which is considerable when people end up in the ED every few months for breakthrough seizures, he said.
There were no differences between the CT and no-CT groups in the suspected causes of breakthroughs (P = .93). About half the cases were probably because of noncompliance, about a quarter from sleep deprivation, and the rest from a change in seizure medication or some other issue.
Dr. Izadyar said the next step is taking the findings to his ED colleagues, and perhaps calculating how much money the university would save by skipping CTs in chronic epilepsy patients with no known structural problem.
There were slightly more men than women in the study, and the mean age was 38 years.
There was no industry funding, and the investigators didn’t have any relevant disclosures.
SOURCE: Ali S et al. AES 2019. Abstract 1.213.
BALTIMORE – Head CTs for breakthrough seizures in chronic epilepsy are useful for known structural triggers such as brain tumors, but they don’t change management for most patients, according to a review from the SUNY Upstate Medical University, Syracuse, N.Y., emergency department.
“Nonselective use of ED neuroimaging in patients with no new neurological findings” and no known structural problem, is “very low yield, and increases the use of hospital resources and radiation exposure without impacting the immediate care,” concluded investigators led by Shahram Izadyar, MD, an epileptologist and associate professor of neurology at the university.
In short, CTs for breakthrough seizures – routine in many EDs – usually are a waste of time and money. Absent a known structural cause, “there really isn’t a reason to do imaging,” he said at the American Epilepsy Society annual meeting.
Dr. Izadyar wanted to look into the issue after noticing how common CTs were among his breakthrough patients. He and his team reviewed 90 adults with an established diagnosis of epilepsy and on at least one antiepileptic who presented to the university ED for breakthrough seizures during 2017-2018; 39 (43.3%) had head CTs, 51 (56.7%) did not.
CT changed management in three of the four patients (4.4%) who had a known brain tumor, leading, for instance, to steroids for increased tumor edema. The rest of the patients had nonfocal exams, and imaging had no impact on management.
There was no rhyme or reason why some people got CTs and others didn’t; it seemed to be dependent on the provider. Defensive medicine probably had something to do with it, as well as saving time by ordering a CT instead of doing a neurologic exam, Dr. Izadyar said.
People aren’t going to stop doing defensive medicine, but even a small reduction in unnecessary CTs would “be a positive change.” There’s the cost issue, but also the radiation exposure, which is considerable when people end up in the ED every few months for breakthrough seizures, he said.
There were no differences between the CT and no-CT groups in the suspected causes of breakthroughs (P = .93). About half the cases were probably because of noncompliance, about a quarter from sleep deprivation, and the rest from a change in seizure medication or some other issue.
Dr. Izadyar said the next step is taking the findings to his ED colleagues, and perhaps calculating how much money the university would save by skipping CTs in chronic epilepsy patients with no known structural problem.
There were slightly more men than women in the study, and the mean age was 38 years.
There was no industry funding, and the investigators didn’t have any relevant disclosures.
SOURCE: Ali S et al. AES 2019. Abstract 1.213.
REPORTING FROM AES 2019
Trial finds three drugs equally effective for established status epilepticus
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
FROM NEJM
Key clinical point: Among children and adults with benzodiazepine-refractory status epilepticus, fosphenytoin, valproate, and levetiracetam each stop seizures by 60 minutes in approximately half of patients.
Major finding: Absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
Study details: The Established Status Epilepticus Treatment Trial (ESETT) was a blinded, comparative-effectiveness trial that enrolled 384 patients at 57 hospital EDs in the United States.
Disclosures: The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Source: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
‘Remarkable’ seizure-free rates seen with adjunctive cenobamate
In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
FROM LANCET NEUROLOGY
Celiac disease may underlie seizures
CHARLOTTE, N.C. – , according to a retrospective chart review presented at the annual meeting of the Child Neurology Society. Associations between celiac disease and seizures may have implications for screening and treatment, said study author Shanna Swartwood, MD, a fellow in the department of pediatric neurology at University of Utah in Salt Lake City.
“Screening for [celiac disease] early in patients with epilepsy, specifically with temporal EEG findings and intractable epilepsy, is warranted given the improvement of seizure burden that may result from exclusion of gluten from the diet,” said Dr. Swartwood and colleagues.
About 10% of patients with celiac disease have clinical neurologic manifestations, such as seizures. To characterize features of epilepsy in a pediatric population with celiac disease and to examine the effect of a gluten-free diet on seizure burden, Dr. Swartwood and colleagues reviewed patients treated at Primary Children’s Hospital in Salt Lake City since 2002. They identified patients with ICD-10 codes for seizures or epilepsy and celiac disease and reviewed 187 charts in all.
In all, 40 patients with seizures had biopsy-proven celiac disease, and 22 had a diagnosis of celiac disease based on the presence of antibodies. Among those with biopsy-proven celiac disease, 43% had intractable seizures. Among those with antibody-positive celiac disease, 31% had intractable seizures.
Among patients with intractable epilepsy, seizure onset preceded the diagnosis of celiac disease by an average of 5 years. For patients with nonintractable epilepsy, the first seizure occurred 1 year before the celiac disease diagnosis on average, but some patients received a celiac disease diagnosis first.
Focal seizures with secondary generalization and generalized tonic clonic seizures were the most common seizure types in this cohort. Epileptiform activity most often was seen in the temporal lobe. While other studies in patients with celiac disease have found occipital epileptiform activity to be the most common, only one patient in this cohort had activity in that location, Dr. Swartwood noted.
Patients with intractable seizures who adhered to a gluten-free diet “had a fairly robust response in terms of seizure improvement,” she said. Seizure improvement, including a decrease in seizure frequency or a decrease in antiepileptic medication dosage, occurred in seven of nine patients in the biopsy-proven group and in two of three patients in the antibody-positive group who adhered to a gluten-free diet and had intractable seizures. One patient was able to stop antiepileptic medication, and one patient had a complete resolution of seizure activity.
The researchers plan to further study the relationship between celiac disease and epilepsy, including whether various HLA subtypes of celiac disease correlate with seizures, said coinvestigator Cristina Trandafir, MD, PhD, assistant professor of pediatric neurology at University of Utah.
The chart review included relatively few patients with limited data. Nevertheless, the results suggest that there may be “substantial lag time” from first seizure to celiac disease diagnosis and that “earlier diagnosis and earlier placement on a gluten-free diet may be beneficial,” Dr. Swartwood said. Celiac disease may be asymptomatic, and screening for celiac disease with a blood test may make sense for patients with intractable seizures, she said.
The researchers had no relevant disclosures.
CHARLOTTE, N.C. – , according to a retrospective chart review presented at the annual meeting of the Child Neurology Society. Associations between celiac disease and seizures may have implications for screening and treatment, said study author Shanna Swartwood, MD, a fellow in the department of pediatric neurology at University of Utah in Salt Lake City.
“Screening for [celiac disease] early in patients with epilepsy, specifically with temporal EEG findings and intractable epilepsy, is warranted given the improvement of seizure burden that may result from exclusion of gluten from the diet,” said Dr. Swartwood and colleagues.
About 10% of patients with celiac disease have clinical neurologic manifestations, such as seizures. To characterize features of epilepsy in a pediatric population with celiac disease and to examine the effect of a gluten-free diet on seizure burden, Dr. Swartwood and colleagues reviewed patients treated at Primary Children’s Hospital in Salt Lake City since 2002. They identified patients with ICD-10 codes for seizures or epilepsy and celiac disease and reviewed 187 charts in all.
In all, 40 patients with seizures had biopsy-proven celiac disease, and 22 had a diagnosis of celiac disease based on the presence of antibodies. Among those with biopsy-proven celiac disease, 43% had intractable seizures. Among those with antibody-positive celiac disease, 31% had intractable seizures.
Among patients with intractable epilepsy, seizure onset preceded the diagnosis of celiac disease by an average of 5 years. For patients with nonintractable epilepsy, the first seizure occurred 1 year before the celiac disease diagnosis on average, but some patients received a celiac disease diagnosis first.
Focal seizures with secondary generalization and generalized tonic clonic seizures were the most common seizure types in this cohort. Epileptiform activity most often was seen in the temporal lobe. While other studies in patients with celiac disease have found occipital epileptiform activity to be the most common, only one patient in this cohort had activity in that location, Dr. Swartwood noted.
Patients with intractable seizures who adhered to a gluten-free diet “had a fairly robust response in terms of seizure improvement,” she said. Seizure improvement, including a decrease in seizure frequency or a decrease in antiepileptic medication dosage, occurred in seven of nine patients in the biopsy-proven group and in two of three patients in the antibody-positive group who adhered to a gluten-free diet and had intractable seizures. One patient was able to stop antiepileptic medication, and one patient had a complete resolution of seizure activity.
The researchers plan to further study the relationship between celiac disease and epilepsy, including whether various HLA subtypes of celiac disease correlate with seizures, said coinvestigator Cristina Trandafir, MD, PhD, assistant professor of pediatric neurology at University of Utah.
The chart review included relatively few patients with limited data. Nevertheless, the results suggest that there may be “substantial lag time” from first seizure to celiac disease diagnosis and that “earlier diagnosis and earlier placement on a gluten-free diet may be beneficial,” Dr. Swartwood said. Celiac disease may be asymptomatic, and screening for celiac disease with a blood test may make sense for patients with intractable seizures, she said.
The researchers had no relevant disclosures.
CHARLOTTE, N.C. – , according to a retrospective chart review presented at the annual meeting of the Child Neurology Society. Associations between celiac disease and seizures may have implications for screening and treatment, said study author Shanna Swartwood, MD, a fellow in the department of pediatric neurology at University of Utah in Salt Lake City.
“Screening for [celiac disease] early in patients with epilepsy, specifically with temporal EEG findings and intractable epilepsy, is warranted given the improvement of seizure burden that may result from exclusion of gluten from the diet,” said Dr. Swartwood and colleagues.
About 10% of patients with celiac disease have clinical neurologic manifestations, such as seizures. To characterize features of epilepsy in a pediatric population with celiac disease and to examine the effect of a gluten-free diet on seizure burden, Dr. Swartwood and colleagues reviewed patients treated at Primary Children’s Hospital in Salt Lake City since 2002. They identified patients with ICD-10 codes for seizures or epilepsy and celiac disease and reviewed 187 charts in all.
In all, 40 patients with seizures had biopsy-proven celiac disease, and 22 had a diagnosis of celiac disease based on the presence of antibodies. Among those with biopsy-proven celiac disease, 43% had intractable seizures. Among those with antibody-positive celiac disease, 31% had intractable seizures.
Among patients with intractable epilepsy, seizure onset preceded the diagnosis of celiac disease by an average of 5 years. For patients with nonintractable epilepsy, the first seizure occurred 1 year before the celiac disease diagnosis on average, but some patients received a celiac disease diagnosis first.
Focal seizures with secondary generalization and generalized tonic clonic seizures were the most common seizure types in this cohort. Epileptiform activity most often was seen in the temporal lobe. While other studies in patients with celiac disease have found occipital epileptiform activity to be the most common, only one patient in this cohort had activity in that location, Dr. Swartwood noted.
Patients with intractable seizures who adhered to a gluten-free diet “had a fairly robust response in terms of seizure improvement,” she said. Seizure improvement, including a decrease in seizure frequency or a decrease in antiepileptic medication dosage, occurred in seven of nine patients in the biopsy-proven group and in two of three patients in the antibody-positive group who adhered to a gluten-free diet and had intractable seizures. One patient was able to stop antiepileptic medication, and one patient had a complete resolution of seizure activity.
The researchers plan to further study the relationship between celiac disease and epilepsy, including whether various HLA subtypes of celiac disease correlate with seizures, said coinvestigator Cristina Trandafir, MD, PhD, assistant professor of pediatric neurology at University of Utah.
The chart review included relatively few patients with limited data. Nevertheless, the results suggest that there may be “substantial lag time” from first seizure to celiac disease diagnosis and that “earlier diagnosis and earlier placement on a gluten-free diet may be beneficial,” Dr. Swartwood said. Celiac disease may be asymptomatic, and screening for celiac disease with a blood test may make sense for patients with intractable seizures, she said.
The researchers had no relevant disclosures.
REPORTING FROM CNS 2019