User login
How does CBD compare and interact with other AEDs?
according to a review published in Developmental Medicine & Child Neurology. “Careful down-titration of benzodiazepines is essential to minimize sedation with adjunctive CBD,” the authors said.
Although CBD’s antiepileptic mechanisms “are not fully elucidated, it is clear that administration of CBD as adjunct therapy decreases seizure frequency in patients with Dravet syndrome and Lennox-Gastaut syndrome,” wrote Shayma Ali, a doctoral student in the department of pediatrics and child health at the University of Otago in Wellington, New Zealand, and her colleagues. “Contrary to public expectation of miraculous results, CBD has a similar antiepileptic and side effect profile to other AEDs. Nevertheless, as individual children with these developmental and epileptic encephalopathies are often refractory to available AEDs, the addition of another potentially effective therapeutic medicine will be warmly welcomed by families and physicians.”
The FDA approved Epidiolex, a pharmaceutical-grade oral solution that is 98% CBD, in June of 2018. In September of 2018, the Drug Enforcement Administration classified it as a Schedule V controlled substance. Patients’ use of nonpharmaceutical grade CBD products, including those combined with tetrahydrocannabinol (THC), “raises concerns about the use of products with THC on the developing brain,” the review authors said.
Randomized trials
Three randomized, controlled, double-blind trials in patients with Dravet syndrome and Lennox-Gastaut syndrome found that CBD, compared with placebo, results in greater median seizure reductions (38%-41% vs. 13%-19%) and responder rates (i.e., the proportion of patients with 50% reductions in convulsive or drop seizures; 39%-46% vs. 14%-27%).
Common adverse effects include somnolence, diarrhea, decreased appetite, fatigue, lethargy, pyrexia, and vomiting. Hepatic transaminases became elevated in some patients, and this result occurred more often in patients taking valproate.
No phase 2 or phase 3 trials have assessed the efficacy of CBD without coadministration of other AEDs, and CBD’s efficacy may relate to its impact on the pharmacokinetics of coadministered AEDs. “The most important clinical interaction is between CBD and clobazam, as [the dose of] clobazam often needs to be lowered because of excessive sedation,” wrote Ms. Ali and her colleagues. CBD inhibits CYP2C19 and CYP3A4 – enzymes that are involved in clobazam metabolism – which results in high plasma concentrations of clobazam’s active metabolite, norclobazam. Plasma levels of topiramate, rufinamide, zonisamide, and eslicarbazepine also may increase when these drugs are taken with CBD.
Challenges and opportunities
Of the hundreds of compounds in the marijuana plant, CBD “has the most evidence of antiepileptic efficacy and does not have the psychoactive effects” of THC, the authors said. Little evidence supports the combination of THC and CBD for the treatment of epilepsy. In addition, research indicates that THC can have a proconvulsive effect in animal models and harm the development of the human brain.
Investigators are evaluating alternative routes of CBD delivery to avoid first-pass metabolism, such as oromucosal sprays, transdermal gels, eye drops, intranasal sprays, and rectal suppositories. “Alternative methods of administration ... deserve consideration, particularly for the developmental and epileptic encephalopathies population, as administration of oral medication can be challenging,” they said.
SOURCE: Ali S et al. Dev Med Child Neurol. 2018. doi: 10.1111/dmcn.14087.
according to a review published in Developmental Medicine & Child Neurology. “Careful down-titration of benzodiazepines is essential to minimize sedation with adjunctive CBD,” the authors said.
Although CBD’s antiepileptic mechanisms “are not fully elucidated, it is clear that administration of CBD as adjunct therapy decreases seizure frequency in patients with Dravet syndrome and Lennox-Gastaut syndrome,” wrote Shayma Ali, a doctoral student in the department of pediatrics and child health at the University of Otago in Wellington, New Zealand, and her colleagues. “Contrary to public expectation of miraculous results, CBD has a similar antiepileptic and side effect profile to other AEDs. Nevertheless, as individual children with these developmental and epileptic encephalopathies are often refractory to available AEDs, the addition of another potentially effective therapeutic medicine will be warmly welcomed by families and physicians.”
The FDA approved Epidiolex, a pharmaceutical-grade oral solution that is 98% CBD, in June of 2018. In September of 2018, the Drug Enforcement Administration classified it as a Schedule V controlled substance. Patients’ use of nonpharmaceutical grade CBD products, including those combined with tetrahydrocannabinol (THC), “raises concerns about the use of products with THC on the developing brain,” the review authors said.
Randomized trials
Three randomized, controlled, double-blind trials in patients with Dravet syndrome and Lennox-Gastaut syndrome found that CBD, compared with placebo, results in greater median seizure reductions (38%-41% vs. 13%-19%) and responder rates (i.e., the proportion of patients with 50% reductions in convulsive or drop seizures; 39%-46% vs. 14%-27%).
Common adverse effects include somnolence, diarrhea, decreased appetite, fatigue, lethargy, pyrexia, and vomiting. Hepatic transaminases became elevated in some patients, and this result occurred more often in patients taking valproate.
No phase 2 or phase 3 trials have assessed the efficacy of CBD without coadministration of other AEDs, and CBD’s efficacy may relate to its impact on the pharmacokinetics of coadministered AEDs. “The most important clinical interaction is between CBD and clobazam, as [the dose of] clobazam often needs to be lowered because of excessive sedation,” wrote Ms. Ali and her colleagues. CBD inhibits CYP2C19 and CYP3A4 – enzymes that are involved in clobazam metabolism – which results in high plasma concentrations of clobazam’s active metabolite, norclobazam. Plasma levels of topiramate, rufinamide, zonisamide, and eslicarbazepine also may increase when these drugs are taken with CBD.
Challenges and opportunities
Of the hundreds of compounds in the marijuana plant, CBD “has the most evidence of antiepileptic efficacy and does not have the psychoactive effects” of THC, the authors said. Little evidence supports the combination of THC and CBD for the treatment of epilepsy. In addition, research indicates that THC can have a proconvulsive effect in animal models and harm the development of the human brain.
Investigators are evaluating alternative routes of CBD delivery to avoid first-pass metabolism, such as oromucosal sprays, transdermal gels, eye drops, intranasal sprays, and rectal suppositories. “Alternative methods of administration ... deserve consideration, particularly for the developmental and epileptic encephalopathies population, as administration of oral medication can be challenging,” they said.
SOURCE: Ali S et al. Dev Med Child Neurol. 2018. doi: 10.1111/dmcn.14087.
according to a review published in Developmental Medicine & Child Neurology. “Careful down-titration of benzodiazepines is essential to minimize sedation with adjunctive CBD,” the authors said.
Although CBD’s antiepileptic mechanisms “are not fully elucidated, it is clear that administration of CBD as adjunct therapy decreases seizure frequency in patients with Dravet syndrome and Lennox-Gastaut syndrome,” wrote Shayma Ali, a doctoral student in the department of pediatrics and child health at the University of Otago in Wellington, New Zealand, and her colleagues. “Contrary to public expectation of miraculous results, CBD has a similar antiepileptic and side effect profile to other AEDs. Nevertheless, as individual children with these developmental and epileptic encephalopathies are often refractory to available AEDs, the addition of another potentially effective therapeutic medicine will be warmly welcomed by families and physicians.”
The FDA approved Epidiolex, a pharmaceutical-grade oral solution that is 98% CBD, in June of 2018. In September of 2018, the Drug Enforcement Administration classified it as a Schedule V controlled substance. Patients’ use of nonpharmaceutical grade CBD products, including those combined with tetrahydrocannabinol (THC), “raises concerns about the use of products with THC on the developing brain,” the review authors said.
Randomized trials
Three randomized, controlled, double-blind trials in patients with Dravet syndrome and Lennox-Gastaut syndrome found that CBD, compared with placebo, results in greater median seizure reductions (38%-41% vs. 13%-19%) and responder rates (i.e., the proportion of patients with 50% reductions in convulsive or drop seizures; 39%-46% vs. 14%-27%).
Common adverse effects include somnolence, diarrhea, decreased appetite, fatigue, lethargy, pyrexia, and vomiting. Hepatic transaminases became elevated in some patients, and this result occurred more often in patients taking valproate.
No phase 2 or phase 3 trials have assessed the efficacy of CBD without coadministration of other AEDs, and CBD’s efficacy may relate to its impact on the pharmacokinetics of coadministered AEDs. “The most important clinical interaction is between CBD and clobazam, as [the dose of] clobazam often needs to be lowered because of excessive sedation,” wrote Ms. Ali and her colleagues. CBD inhibits CYP2C19 and CYP3A4 – enzymes that are involved in clobazam metabolism – which results in high plasma concentrations of clobazam’s active metabolite, norclobazam. Plasma levels of topiramate, rufinamide, zonisamide, and eslicarbazepine also may increase when these drugs are taken with CBD.
Challenges and opportunities
Of the hundreds of compounds in the marijuana plant, CBD “has the most evidence of antiepileptic efficacy and does not have the psychoactive effects” of THC, the authors said. Little evidence supports the combination of THC and CBD for the treatment of epilepsy. In addition, research indicates that THC can have a proconvulsive effect in animal models and harm the development of the human brain.
Investigators are evaluating alternative routes of CBD delivery to avoid first-pass metabolism, such as oromucosal sprays, transdermal gels, eye drops, intranasal sprays, and rectal suppositories. “Alternative methods of administration ... deserve consideration, particularly for the developmental and epileptic encephalopathies population, as administration of oral medication can be challenging,” they said.
SOURCE: Ali S et al. Dev Med Child Neurol. 2018. doi: 10.1111/dmcn.14087.
FROM DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY
Key clinical point: Cannabidiol’s efficacy is similar to that of other antiepileptic drugs.
Major finding: Cannabidiol inhibits CYP2C19 and CYP3A4, which are involved in clobazam metabolism.
Study details: An invited review.
Disclosures: No disclosures were reported.
Source: Ali S et al. Dev Med Child Neurol. 2018. doi: 10.1111/dmcn.14087.
How often is AED treatment delayed for patients with epilepsy?
NEW ORLEANS – , according to an Australian study presented at the annual meeting of the American Epilepsy Society. Most untreated patients begin an AED after experiencing subsequent seizures, however.
“The decision to start or withhold treatment reflects the complex interplay between factors perceived to influence the predicted risk of seizure recurrence, which remain imprecise, and personal factors,” said lead study author Zhibin Chen, PhD, a biostatistician at the University of Melbourne and colleagues.
Many patients with epilepsy in resource-poor countries may not receive AED therapy for socioeconomic reasons, but little is known about untreated epilepsy in high-income countries. To assess the extent of and reasons for patients not receiving AEDs when treatment is accessible and affordable, Dr. Chen and colleagues prospectively recruited adult patients who attended the first-seizure clinics of publicly funded hospitals in Western Australia between May 1, 1999, and May 31, 2016. The patients had new-onset seizures and were referred by primary care or emergency department physicians. The health care system provided universal coverage for patients’ hospital admissions, outpatient visits, investigations, and treatment.
The researchers identified patients with newly diagnosed epilepsy and reviewed medical records to determine the proportion of untreated patients and the reasons for not starting treatment at each follow-up visit. The investigators compared the sociodemographic factors, neuroimaging, and EEG findings of treated and untreated patients.
In all, 1,317 people attended the clinics during the study period, and 610 patients (61% male; median age, 40) received a diagnosis of epilepsy and met 2014 International League Against Epilepsy (ILAE) diagnostic criteria for epilepsy. Patients were followed for a median of 5.7 years.
Of the 610 patients with epilepsy, 31% did not start AED treatment at the time of diagnosis – 16.4% because the neurologist did not recommend treatment and 14.6% because the patient declined treatment despite a neurologist’s recommendation to start therapy.
Patients’ reasons for not starting treatment included doubts about the need for treatment or about the epilepsy diagnosis, as well as concerns about medication side effects. Neurologists’ reasons for not beginning treatment included a patient having only one seizure and awaiting further results. The presence of seizure-precipitating factors (e.g., flashing lights, sleep deprivation, stress, or alcohol use) was another reason that patients and neurologists commonly cited for not initiating treatment.
Among the 189 initially untreated patients, 62.4% started treatment after a median delay of 95 days, “mainly after further seizures,” the investigators said. Patients with epilepsy who were older, from lower socioeconomic areas, had experienced more seizures, or had epileptogenic lesions on neuroimaging were more likely to initiate AED treatment at diagnosis.
“The percentage of people who were not initially prescribed AEDs was much higher than expected and suggests that untreated epilepsy exists not just in resource-poor, but also in wealthy countries,” said Dr. Chen.
More research is needed to assess the long-term outcomes of patient with seizure-precipitating factors who initiate AEDs immediately, compared with those who try avoidance of precipitating factors alone, said Dr. Chen.
This study was supported by a grant from UCB Pharma.
SOURCE: Chen Z et al. AES 2018, Abstract 3.421.
NEW ORLEANS – , according to an Australian study presented at the annual meeting of the American Epilepsy Society. Most untreated patients begin an AED after experiencing subsequent seizures, however.
“The decision to start or withhold treatment reflects the complex interplay between factors perceived to influence the predicted risk of seizure recurrence, which remain imprecise, and personal factors,” said lead study author Zhibin Chen, PhD, a biostatistician at the University of Melbourne and colleagues.
Many patients with epilepsy in resource-poor countries may not receive AED therapy for socioeconomic reasons, but little is known about untreated epilepsy in high-income countries. To assess the extent of and reasons for patients not receiving AEDs when treatment is accessible and affordable, Dr. Chen and colleagues prospectively recruited adult patients who attended the first-seizure clinics of publicly funded hospitals in Western Australia between May 1, 1999, and May 31, 2016. The patients had new-onset seizures and were referred by primary care or emergency department physicians. The health care system provided universal coverage for patients’ hospital admissions, outpatient visits, investigations, and treatment.
The researchers identified patients with newly diagnosed epilepsy and reviewed medical records to determine the proportion of untreated patients and the reasons for not starting treatment at each follow-up visit. The investigators compared the sociodemographic factors, neuroimaging, and EEG findings of treated and untreated patients.
In all, 1,317 people attended the clinics during the study period, and 610 patients (61% male; median age, 40) received a diagnosis of epilepsy and met 2014 International League Against Epilepsy (ILAE) diagnostic criteria for epilepsy. Patients were followed for a median of 5.7 years.
Of the 610 patients with epilepsy, 31% did not start AED treatment at the time of diagnosis – 16.4% because the neurologist did not recommend treatment and 14.6% because the patient declined treatment despite a neurologist’s recommendation to start therapy.
Patients’ reasons for not starting treatment included doubts about the need for treatment or about the epilepsy diagnosis, as well as concerns about medication side effects. Neurologists’ reasons for not beginning treatment included a patient having only one seizure and awaiting further results. The presence of seizure-precipitating factors (e.g., flashing lights, sleep deprivation, stress, or alcohol use) was another reason that patients and neurologists commonly cited for not initiating treatment.
Among the 189 initially untreated patients, 62.4% started treatment after a median delay of 95 days, “mainly after further seizures,” the investigators said. Patients with epilepsy who were older, from lower socioeconomic areas, had experienced more seizures, or had epileptogenic lesions on neuroimaging were more likely to initiate AED treatment at diagnosis.
“The percentage of people who were not initially prescribed AEDs was much higher than expected and suggests that untreated epilepsy exists not just in resource-poor, but also in wealthy countries,” said Dr. Chen.
More research is needed to assess the long-term outcomes of patient with seizure-precipitating factors who initiate AEDs immediately, compared with those who try avoidance of precipitating factors alone, said Dr. Chen.
This study was supported by a grant from UCB Pharma.
SOURCE: Chen Z et al. AES 2018, Abstract 3.421.
NEW ORLEANS – , according to an Australian study presented at the annual meeting of the American Epilepsy Society. Most untreated patients begin an AED after experiencing subsequent seizures, however.
“The decision to start or withhold treatment reflects the complex interplay between factors perceived to influence the predicted risk of seizure recurrence, which remain imprecise, and personal factors,” said lead study author Zhibin Chen, PhD, a biostatistician at the University of Melbourne and colleagues.
Many patients with epilepsy in resource-poor countries may not receive AED therapy for socioeconomic reasons, but little is known about untreated epilepsy in high-income countries. To assess the extent of and reasons for patients not receiving AEDs when treatment is accessible and affordable, Dr. Chen and colleagues prospectively recruited adult patients who attended the first-seizure clinics of publicly funded hospitals in Western Australia between May 1, 1999, and May 31, 2016. The patients had new-onset seizures and were referred by primary care or emergency department physicians. The health care system provided universal coverage for patients’ hospital admissions, outpatient visits, investigations, and treatment.
The researchers identified patients with newly diagnosed epilepsy and reviewed medical records to determine the proportion of untreated patients and the reasons for not starting treatment at each follow-up visit. The investigators compared the sociodemographic factors, neuroimaging, and EEG findings of treated and untreated patients.
In all, 1,317 people attended the clinics during the study period, and 610 patients (61% male; median age, 40) received a diagnosis of epilepsy and met 2014 International League Against Epilepsy (ILAE) diagnostic criteria for epilepsy. Patients were followed for a median of 5.7 years.
Of the 610 patients with epilepsy, 31% did not start AED treatment at the time of diagnosis – 16.4% because the neurologist did not recommend treatment and 14.6% because the patient declined treatment despite a neurologist’s recommendation to start therapy.
Patients’ reasons for not starting treatment included doubts about the need for treatment or about the epilepsy diagnosis, as well as concerns about medication side effects. Neurologists’ reasons for not beginning treatment included a patient having only one seizure and awaiting further results. The presence of seizure-precipitating factors (e.g., flashing lights, sleep deprivation, stress, or alcohol use) was another reason that patients and neurologists commonly cited for not initiating treatment.
Among the 189 initially untreated patients, 62.4% started treatment after a median delay of 95 days, “mainly after further seizures,” the investigators said. Patients with epilepsy who were older, from lower socioeconomic areas, had experienced more seizures, or had epileptogenic lesions on neuroimaging were more likely to initiate AED treatment at diagnosis.
“The percentage of people who were not initially prescribed AEDs was much higher than expected and suggests that untreated epilepsy exists not just in resource-poor, but also in wealthy countries,” said Dr. Chen.
More research is needed to assess the long-term outcomes of patient with seizure-precipitating factors who initiate AEDs immediately, compared with those who try avoidance of precipitating factors alone, said Dr. Chen.
This study was supported by a grant from UCB Pharma.
SOURCE: Chen Z et al. AES 2018, Abstract 3.421.
REPORTING FROM AES 2018
Key clinical point: Delayed initiation of antiepileptic drug treatment may be more common than thought.
Major finding: More than 30% of patients with epilepsy do not initiate treatment at diagnosis.
Study details: Review of 610 patients with newly diagnosed epilepsy who were seen at clinics in Western Australia.
Disclosures: The study was supported by a grant from UCB Pharma.
Source: Chen Z et al. AES 2018, Abstract 3.421.
Bioequivalents lamotrigine, levetiracetam control new-onset focal seizures equally well
NEW ORLEANS – Bioequivalent generic formulations of levetiracetam and lamotrigine reduced seizures by a similar extent over 2 years in a retrospective study of patients with newly diagnosed focal epilepsy.
Each drug had a specific adverse event profile, with lamotrigine associated with rash and levetiracetam with mood disorders, Sirichai Chayasirisobhon, MD, said at the annual meeting of the American Epilepsy Society. This finding can play into the initial therapeutic decision, said Dr. Chayasirisobhon of Kaiser Permanente Southern California. “If someone comes in with depression or mood disorder, I will start on lamotrigine, not levetiracetam. And we can decrease the chance of rash with a very slow titration, as we did here, starting with just 5 mg/kg and working up over 6 months.”
Although the drugs have a somewhat similar teratogenic profile, Dr. Chayasirisobhon added that he favors lamotrigine for women of childbearing years. “It’s a little bit better choice for them I think.”
His retrospective analysis followed 442 patients from first seizure and medical therapy for 2 years. The generic medications came from Kaiser Permanente’s central pharmacy. They were single-source, with a proven 95% bioequivalence. The main outcome was the percentage of patients who became seizure free and remained so. Any seizure, whether febrile, breakthroughs, or from titration, was considered a failure. These patients were dropped from the study. Any patient who developed a drug-related rash was dropped from the study and started on another medication.
More women than men took lamotrigine (113 vs. 75), whereas more men took levetiracetam (148 vs. 106). Those taking lamotrigine were younger than were those taking levetiracetam (30 vs. 40 years).
At the end of 2 years, there was no statistically significant difference in the primary outcome of being free from seizures (66.5% with lamotrigine vs. 72.4% with levetiracetam). In the lamotrigine group, 33.5% were eliminated from the study, 24% because they had a seizure, and the rest due to an adverse event. In the levetiracetam group, 27.6% were eliminated, 13% because they had a seizure and the rest because of an adverse event.
Adverse events in the lamotrigine group included rash (12), dizziness (3), lethargy (1), and mood changes (2). Among the levetiracetam group, adverse events included dizziness (3), lethargy (7), mood changes (20), slowed thinking (4), depression (2) and headache (1).
“Rash was the main event we saw in this group, and this was even when we did a very slow titration of 5 mg/kg per week,” Dr. Chayasirisobhon said. “Any sign of rash or itching at all, we told them to stop immediately and call us. Fortunately, we had no cases of Steven-Johnson syndrome and all our cases of rash were transient. But in the levetiracetam group, the mood changes are the major thing. Some of the patients became very agitated and aggressive. Whenever we see a patient for the first time, we always ask about mood changes, and we instruct the family to call and report any changes in mood immediately.”
Aside from reproductive age, however, Dr. Chayasirisobhon generally prefers to start new patients on levetiracetam. Its safety profile is remarkable, he said, recounting a case report he published in 2010 (Acta Neurol Taiwan. 2010;19:292-5).
The paper describes a male patient who decided to commit suicide after an argument with his wife. He took his levetiracetam and walked to his father’s grave, swallowing pills the entire time. When he arrived at the grave, he had taken around 65 grams of the medication. “The amazing thing was, he’s still walking, just a little unsteady. Then he decided he’s not ready to die,” Dr. Chayasirisobhon said. “He was able to call 911, so he’s still talking fine. When they checked his level it was so high, but he remained unimpaired except for the unsteady gait and some nystagmus.”
The study did not receive outside funding. Dr. Chayasirisobhon had no financial disclosures.
NEW ORLEANS – Bioequivalent generic formulations of levetiracetam and lamotrigine reduced seizures by a similar extent over 2 years in a retrospective study of patients with newly diagnosed focal epilepsy.
Each drug had a specific adverse event profile, with lamotrigine associated with rash and levetiracetam with mood disorders, Sirichai Chayasirisobhon, MD, said at the annual meeting of the American Epilepsy Society. This finding can play into the initial therapeutic decision, said Dr. Chayasirisobhon of Kaiser Permanente Southern California. “If someone comes in with depression or mood disorder, I will start on lamotrigine, not levetiracetam. And we can decrease the chance of rash with a very slow titration, as we did here, starting with just 5 mg/kg and working up over 6 months.”
Although the drugs have a somewhat similar teratogenic profile, Dr. Chayasirisobhon added that he favors lamotrigine for women of childbearing years. “It’s a little bit better choice for them I think.”
His retrospective analysis followed 442 patients from first seizure and medical therapy for 2 years. The generic medications came from Kaiser Permanente’s central pharmacy. They were single-source, with a proven 95% bioequivalence. The main outcome was the percentage of patients who became seizure free and remained so. Any seizure, whether febrile, breakthroughs, or from titration, was considered a failure. These patients were dropped from the study. Any patient who developed a drug-related rash was dropped from the study and started on another medication.
More women than men took lamotrigine (113 vs. 75), whereas more men took levetiracetam (148 vs. 106). Those taking lamotrigine were younger than were those taking levetiracetam (30 vs. 40 years).
At the end of 2 years, there was no statistically significant difference in the primary outcome of being free from seizures (66.5% with lamotrigine vs. 72.4% with levetiracetam). In the lamotrigine group, 33.5% were eliminated from the study, 24% because they had a seizure, and the rest due to an adverse event. In the levetiracetam group, 27.6% were eliminated, 13% because they had a seizure and the rest because of an adverse event.
Adverse events in the lamotrigine group included rash (12), dizziness (3), lethargy (1), and mood changes (2). Among the levetiracetam group, adverse events included dizziness (3), lethargy (7), mood changes (20), slowed thinking (4), depression (2) and headache (1).
“Rash was the main event we saw in this group, and this was even when we did a very slow titration of 5 mg/kg per week,” Dr. Chayasirisobhon said. “Any sign of rash or itching at all, we told them to stop immediately and call us. Fortunately, we had no cases of Steven-Johnson syndrome and all our cases of rash were transient. But in the levetiracetam group, the mood changes are the major thing. Some of the patients became very agitated and aggressive. Whenever we see a patient for the first time, we always ask about mood changes, and we instruct the family to call and report any changes in mood immediately.”
Aside from reproductive age, however, Dr. Chayasirisobhon generally prefers to start new patients on levetiracetam. Its safety profile is remarkable, he said, recounting a case report he published in 2010 (Acta Neurol Taiwan. 2010;19:292-5).
The paper describes a male patient who decided to commit suicide after an argument with his wife. He took his levetiracetam and walked to his father’s grave, swallowing pills the entire time. When he arrived at the grave, he had taken around 65 grams of the medication. “The amazing thing was, he’s still walking, just a little unsteady. Then he decided he’s not ready to die,” Dr. Chayasirisobhon said. “He was able to call 911, so he’s still talking fine. When they checked his level it was so high, but he remained unimpaired except for the unsteady gait and some nystagmus.”
The study did not receive outside funding. Dr. Chayasirisobhon had no financial disclosures.
NEW ORLEANS – Bioequivalent generic formulations of levetiracetam and lamotrigine reduced seizures by a similar extent over 2 years in a retrospective study of patients with newly diagnosed focal epilepsy.
Each drug had a specific adverse event profile, with lamotrigine associated with rash and levetiracetam with mood disorders, Sirichai Chayasirisobhon, MD, said at the annual meeting of the American Epilepsy Society. This finding can play into the initial therapeutic decision, said Dr. Chayasirisobhon of Kaiser Permanente Southern California. “If someone comes in with depression or mood disorder, I will start on lamotrigine, not levetiracetam. And we can decrease the chance of rash with a very slow titration, as we did here, starting with just 5 mg/kg and working up over 6 months.”
Although the drugs have a somewhat similar teratogenic profile, Dr. Chayasirisobhon added that he favors lamotrigine for women of childbearing years. “It’s a little bit better choice for them I think.”
His retrospective analysis followed 442 patients from first seizure and medical therapy for 2 years. The generic medications came from Kaiser Permanente’s central pharmacy. They were single-source, with a proven 95% bioequivalence. The main outcome was the percentage of patients who became seizure free and remained so. Any seizure, whether febrile, breakthroughs, or from titration, was considered a failure. These patients were dropped from the study. Any patient who developed a drug-related rash was dropped from the study and started on another medication.
More women than men took lamotrigine (113 vs. 75), whereas more men took levetiracetam (148 vs. 106). Those taking lamotrigine were younger than were those taking levetiracetam (30 vs. 40 years).
At the end of 2 years, there was no statistically significant difference in the primary outcome of being free from seizures (66.5% with lamotrigine vs. 72.4% with levetiracetam). In the lamotrigine group, 33.5% were eliminated from the study, 24% because they had a seizure, and the rest due to an adverse event. In the levetiracetam group, 27.6% were eliminated, 13% because they had a seizure and the rest because of an adverse event.
Adverse events in the lamotrigine group included rash (12), dizziness (3), lethargy (1), and mood changes (2). Among the levetiracetam group, adverse events included dizziness (3), lethargy (7), mood changes (20), slowed thinking (4), depression (2) and headache (1).
“Rash was the main event we saw in this group, and this was even when we did a very slow titration of 5 mg/kg per week,” Dr. Chayasirisobhon said. “Any sign of rash or itching at all, we told them to stop immediately and call us. Fortunately, we had no cases of Steven-Johnson syndrome and all our cases of rash were transient. But in the levetiracetam group, the mood changes are the major thing. Some of the patients became very agitated and aggressive. Whenever we see a patient for the first time, we always ask about mood changes, and we instruct the family to call and report any changes in mood immediately.”
Aside from reproductive age, however, Dr. Chayasirisobhon generally prefers to start new patients on levetiracetam. Its safety profile is remarkable, he said, recounting a case report he published in 2010 (Acta Neurol Taiwan. 2010;19:292-5).
The paper describes a male patient who decided to commit suicide after an argument with his wife. He took his levetiracetam and walked to his father’s grave, swallowing pills the entire time. When he arrived at the grave, he had taken around 65 grams of the medication. “The amazing thing was, he’s still walking, just a little unsteady. Then he decided he’s not ready to die,” Dr. Chayasirisobhon said. “He was able to call 911, so he’s still talking fine. When they checked his level it was so high, but he remained unimpaired except for the unsteady gait and some nystagmus.”
The study did not receive outside funding. Dr. Chayasirisobhon had no financial disclosures.
REPORTING FROM AES 2018
Key clinical point:
Major finding: At 2 years, 66.5% of the lamotrigine group and 72.4% of the levetiracetam group were seizure free.
Study details: The retrospective study comprised 442 patients.
Disclosures: The study did not receive outside funding. Dr. Chayasirisobhon had no financial disclosures.
Source: Chayasirisobhon S et al. AES 2018, Abstract 2.147.
‘Error neuron’ EEG findings could open up future clinical applications
, and this activity can be tracked through a scalp EEG pattern called error-related negativity, according to findings from experiments carried out during intracranial EEG recordings of candidates for surgical treatment of epilepsy.
“Our results suggest that coordinated neural activity can serve as a substrate for information routing that enables the performance-monitoring system to communicate the need for behavioral control to other brain regions, including those that maintain flexible goal information, such as the lateral prefrontal cortex and the frontal polar cortex,” first author Zhongzheng Fu, a PhD student at the California Institute of Technology in Pasadena, Calif., and Cedars-Sinai Medical Center, Los Angeles, and his colleagues reported in Neuron.
The findings offer insights that could lead to treatments for conditions in which the important executive function task of error self-monitoring is unbalanced, such as obsessive-compulsive disorder and schizophrenia, the authors noted in a press release.
“We discovered that the activity of error neurons correlates with the size of the ERN [error-related negativity],” Mr. Fu said. “This identifies the brain area that causes the ERN and helps explain what it signifies. This new insight might allow doctors to use the ERN as a standard tool to diagnose mental diseases and monitor responses to treatment.”
Error neuron firing and intracranial ERN occurred first in pre-supplementary motor area (pre-SMA), then in the dorsal anterior cingulate cortex (dACC) about 50 ms later, with significant correlations between firing and intracranial ERN in both locations. In dACC, this activity, with error-integrating neuron responses, correlated with magnitude of post-error slowing (PES).
Previous research suggested a link between “the detection of self-generated errors, as reflected in the ERN, with changes in cognitive control, as exhibited behaviorally in PES,” the investigators wrote. “However, several electroencephalogram (EEG) studies have failed to find a significant relationship between PES and ERN.”
The present study involved intracranial EEG of 29 candidates for surgical treatment of epilepsy and scalp EEG of 12 control participants, with each modality measuring activity in the frontal cortex. Both cohorts performed a rapid version of the color-word Stroop task, in which the words “red,” “green,” or “blue” were printed either in corresponding or noncorresponding colors of red, green, or blue. Subjects were presented various color-word combinations while being asked to click one of three buttons indicating the color of the word as quickly as possible. The investigators monitored neuronal activity throughout, discarding responses that were too slow.
As found in previous trials, the subjects demonstrated the “Stroop effect,” which refers to a slower response when word and color are incongruent (224.9 ms difference; P less than .001). As anticipated, correct responses following correct responses were faster than were correct responses following erroneous responses, which defines PES.
In the intracranial EEG group, the investigators isolated 1,171 neurons, of which 618 were located in dACC and 553 in pre-SMA. Using a Poisson regression model and correlations with erroneous responses, the investigators identified 99 “type I” error neurons in dACC and 118 in pre-SMA, based on higher frequency of firing during erroneous responses than during correct responses. At a single-cell level, error neuron mean spike rates were highest when intracranial ERN amplitude was greatest, such that error neuron firing in dACC and pre-SMA had maximal likelihood ratios of 7.9 (P = .01) and 15.1 (P less than .001), respectively. The strength of correlation between intracranial ERN and error neuron firing rate was directly related to PES magnitude exclusively in the dACC (maximum likelihood ratio of 13.9; P = .015). In post-error trials, faster error-integrating neuron firing rates in dACC predicted greater PES (maximal likelihood ratio of 18.3; P less than .001).
The study was funded by the National Institutes of Health, the McKnight Endowment for Neuroscience, and the National Science Foundation. The authors declared no conflicts of interest.
SOURCE: Fu Z et al. Neuron. 2018 Dec 4. doi: 10.1016/j.neuron.2018.11.016
, and this activity can be tracked through a scalp EEG pattern called error-related negativity, according to findings from experiments carried out during intracranial EEG recordings of candidates for surgical treatment of epilepsy.
“Our results suggest that coordinated neural activity can serve as a substrate for information routing that enables the performance-monitoring system to communicate the need for behavioral control to other brain regions, including those that maintain flexible goal information, such as the lateral prefrontal cortex and the frontal polar cortex,” first author Zhongzheng Fu, a PhD student at the California Institute of Technology in Pasadena, Calif., and Cedars-Sinai Medical Center, Los Angeles, and his colleagues reported in Neuron.
The findings offer insights that could lead to treatments for conditions in which the important executive function task of error self-monitoring is unbalanced, such as obsessive-compulsive disorder and schizophrenia, the authors noted in a press release.
“We discovered that the activity of error neurons correlates with the size of the ERN [error-related negativity],” Mr. Fu said. “This identifies the brain area that causes the ERN and helps explain what it signifies. This new insight might allow doctors to use the ERN as a standard tool to diagnose mental diseases and monitor responses to treatment.”
Error neuron firing and intracranial ERN occurred first in pre-supplementary motor area (pre-SMA), then in the dorsal anterior cingulate cortex (dACC) about 50 ms later, with significant correlations between firing and intracranial ERN in both locations. In dACC, this activity, with error-integrating neuron responses, correlated with magnitude of post-error slowing (PES).
Previous research suggested a link between “the detection of self-generated errors, as reflected in the ERN, with changes in cognitive control, as exhibited behaviorally in PES,” the investigators wrote. “However, several electroencephalogram (EEG) studies have failed to find a significant relationship between PES and ERN.”
The present study involved intracranial EEG of 29 candidates for surgical treatment of epilepsy and scalp EEG of 12 control participants, with each modality measuring activity in the frontal cortex. Both cohorts performed a rapid version of the color-word Stroop task, in which the words “red,” “green,” or “blue” were printed either in corresponding or noncorresponding colors of red, green, or blue. Subjects were presented various color-word combinations while being asked to click one of three buttons indicating the color of the word as quickly as possible. The investigators monitored neuronal activity throughout, discarding responses that were too slow.
As found in previous trials, the subjects demonstrated the “Stroop effect,” which refers to a slower response when word and color are incongruent (224.9 ms difference; P less than .001). As anticipated, correct responses following correct responses were faster than were correct responses following erroneous responses, which defines PES.
In the intracranial EEG group, the investigators isolated 1,171 neurons, of which 618 were located in dACC and 553 in pre-SMA. Using a Poisson regression model and correlations with erroneous responses, the investigators identified 99 “type I” error neurons in dACC and 118 in pre-SMA, based on higher frequency of firing during erroneous responses than during correct responses. At a single-cell level, error neuron mean spike rates were highest when intracranial ERN amplitude was greatest, such that error neuron firing in dACC and pre-SMA had maximal likelihood ratios of 7.9 (P = .01) and 15.1 (P less than .001), respectively. The strength of correlation between intracranial ERN and error neuron firing rate was directly related to PES magnitude exclusively in the dACC (maximum likelihood ratio of 13.9; P = .015). In post-error trials, faster error-integrating neuron firing rates in dACC predicted greater PES (maximal likelihood ratio of 18.3; P less than .001).
The study was funded by the National Institutes of Health, the McKnight Endowment for Neuroscience, and the National Science Foundation. The authors declared no conflicts of interest.
SOURCE: Fu Z et al. Neuron. 2018 Dec 4. doi: 10.1016/j.neuron.2018.11.016
, and this activity can be tracked through a scalp EEG pattern called error-related negativity, according to findings from experiments carried out during intracranial EEG recordings of candidates for surgical treatment of epilepsy.
“Our results suggest that coordinated neural activity can serve as a substrate for information routing that enables the performance-monitoring system to communicate the need for behavioral control to other brain regions, including those that maintain flexible goal information, such as the lateral prefrontal cortex and the frontal polar cortex,” first author Zhongzheng Fu, a PhD student at the California Institute of Technology in Pasadena, Calif., and Cedars-Sinai Medical Center, Los Angeles, and his colleagues reported in Neuron.
The findings offer insights that could lead to treatments for conditions in which the important executive function task of error self-monitoring is unbalanced, such as obsessive-compulsive disorder and schizophrenia, the authors noted in a press release.
“We discovered that the activity of error neurons correlates with the size of the ERN [error-related negativity],” Mr. Fu said. “This identifies the brain area that causes the ERN and helps explain what it signifies. This new insight might allow doctors to use the ERN as a standard tool to diagnose mental diseases and monitor responses to treatment.”
Error neuron firing and intracranial ERN occurred first in pre-supplementary motor area (pre-SMA), then in the dorsal anterior cingulate cortex (dACC) about 50 ms later, with significant correlations between firing and intracranial ERN in both locations. In dACC, this activity, with error-integrating neuron responses, correlated with magnitude of post-error slowing (PES).
Previous research suggested a link between “the detection of self-generated errors, as reflected in the ERN, with changes in cognitive control, as exhibited behaviorally in PES,” the investigators wrote. “However, several electroencephalogram (EEG) studies have failed to find a significant relationship between PES and ERN.”
The present study involved intracranial EEG of 29 candidates for surgical treatment of epilepsy and scalp EEG of 12 control participants, with each modality measuring activity in the frontal cortex. Both cohorts performed a rapid version of the color-word Stroop task, in which the words “red,” “green,” or “blue” were printed either in corresponding or noncorresponding colors of red, green, or blue. Subjects were presented various color-word combinations while being asked to click one of three buttons indicating the color of the word as quickly as possible. The investigators monitored neuronal activity throughout, discarding responses that were too slow.
As found in previous trials, the subjects demonstrated the “Stroop effect,” which refers to a slower response when word and color are incongruent (224.9 ms difference; P less than .001). As anticipated, correct responses following correct responses were faster than were correct responses following erroneous responses, which defines PES.
In the intracranial EEG group, the investigators isolated 1,171 neurons, of which 618 were located in dACC and 553 in pre-SMA. Using a Poisson regression model and correlations with erroneous responses, the investigators identified 99 “type I” error neurons in dACC and 118 in pre-SMA, based on higher frequency of firing during erroneous responses than during correct responses. At a single-cell level, error neuron mean spike rates were highest when intracranial ERN amplitude was greatest, such that error neuron firing in dACC and pre-SMA had maximal likelihood ratios of 7.9 (P = .01) and 15.1 (P less than .001), respectively. The strength of correlation between intracranial ERN and error neuron firing rate was directly related to PES magnitude exclusively in the dACC (maximum likelihood ratio of 13.9; P = .015). In post-error trials, faster error-integrating neuron firing rates in dACC predicted greater PES (maximal likelihood ratio of 18.3; P less than .001).
The study was funded by the National Institutes of Health, the McKnight Endowment for Neuroscience, and the National Science Foundation. The authors declared no conflicts of interest.
SOURCE: Fu Z et al. Neuron. 2018 Dec 4. doi: 10.1016/j.neuron.2018.11.016
FROM NEURON
Higher Rate of Loss in Unplanned Pregnancies for Women With Epilepsy
The risk of fetal loss is greater if the interval between pregnancies is under one year.
Unplanned pregnancy among women with epilepsy is associated with twice the risk of spontaneous fetal loss (SFL) when compared with women with epilepsy who planned their pregnancy, according to results from a retrospective study published online ahead of print October 15 in JAMA Neurology.
“This analysis adds the finding that unplanned pregnancy may increase the risk of SFL in women with epilepsy and identifies pregnancy planning, maternal age, and interpregnancy interval as significant modifiable variables,” said Andrew G. Herzog, MD, a neurologist at the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center in Wellesley, Massachusetts, and colleagues.
The Epilepsy Birth Control Registry
The researchers examined results from a web-based survey completed by 1,144 women in the Epilepsy Birth Control Registry (EBCR) between 2010 and 2014. Respondents provided data on contraception use, pregnancy history, and antiepileptic drug (AED) treatment. Patients were between ages 18 and 47 (mean, 28.5). Approximately 8.7% of the cohort were minorities, and 39.8% had household incomes of $25,000 or less.
Pregnancy history data included number of pregnancies, number of planned or unplanned pregnancies, AED type used during pregnancies, and pregnancy outcomes such as live birth, induced abortion, and SFL. Patients were categorized as receiving no therapy, monotherapy, or polytherapy. AED use was further subdivided into no AED, enzyme-inducing AED, non–enzyme-inducing AED, enzyme-inhibiting AED, glucuronidated AED, and mixed.
Most Pregnancies Were Unplanned
Of 794 pregnancies, 530 (66.8%) were unplanned and 264 (33.2%) were planned. Outcomes included 473 live births (59.6%), 141 induced abortions (17.8%), and 180 SFLs (22.7%). Among patients who did not have an induced abortion, SFL risk was higher if the pregnancy was unplanned (137 patients, 35.0%), compared with planned (43 patients, 16.4%) The risk ratio (RR) of SFL was 2.14. According to a regression analysis, SFL risk was higher for patients where “planning was entered alone” in unplanned pregnancies (odds ratio [OR], 2.75), as well as when adjusted for AED category, maternal age, and interpregnancy interval (OR, 3.57).
There was an association between maternal age (OR, 0.957) and risk of SFL. Risk was lower in the 18- to 27-year-olds (118 patients; 29.5%; RR, 0.57) and 28- to 37-year-olds (44 patients; 20.8%; RR, 0.40), compared with the under-18 group (15 patients, 51.7%). Risk of SFL was related to interpregnancy interval (OR, 2.878). This risk was greater if the interpregnancy interval was under one year (56 patients, 45.9%), compared with one year (56 patients, 22.8%) or higher (RR, 2.02).
The Epilepsy Foun-dation and Lundbeck funded the study. Dr. Herzog reports grants, and two coauthors received salary support from grants, from the two organizations.
—Jeff Craven
Suggested Reading
Herzog AG, Mandle HB, MacEachern DB. Association of unintended pregnancy with spontaneous fetal loss in women with epilepsy: findings of the Epilepsy Birth Control Registry. JAMA Neurol. 2018 Oct 15 [Epub ahead of print].
The risk of fetal loss is greater if the interval between pregnancies is under one year.
The risk of fetal loss is greater if the interval between pregnancies is under one year.
Unplanned pregnancy among women with epilepsy is associated with twice the risk of spontaneous fetal loss (SFL) when compared with women with epilepsy who planned their pregnancy, according to results from a retrospective study published online ahead of print October 15 in JAMA Neurology.
“This analysis adds the finding that unplanned pregnancy may increase the risk of SFL in women with epilepsy and identifies pregnancy planning, maternal age, and interpregnancy interval as significant modifiable variables,” said Andrew G. Herzog, MD, a neurologist at the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center in Wellesley, Massachusetts, and colleagues.
The Epilepsy Birth Control Registry
The researchers examined results from a web-based survey completed by 1,144 women in the Epilepsy Birth Control Registry (EBCR) between 2010 and 2014. Respondents provided data on contraception use, pregnancy history, and antiepileptic drug (AED) treatment. Patients were between ages 18 and 47 (mean, 28.5). Approximately 8.7% of the cohort were minorities, and 39.8% had household incomes of $25,000 or less.
Pregnancy history data included number of pregnancies, number of planned or unplanned pregnancies, AED type used during pregnancies, and pregnancy outcomes such as live birth, induced abortion, and SFL. Patients were categorized as receiving no therapy, monotherapy, or polytherapy. AED use was further subdivided into no AED, enzyme-inducing AED, non–enzyme-inducing AED, enzyme-inhibiting AED, glucuronidated AED, and mixed.
Most Pregnancies Were Unplanned
Of 794 pregnancies, 530 (66.8%) were unplanned and 264 (33.2%) were planned. Outcomes included 473 live births (59.6%), 141 induced abortions (17.8%), and 180 SFLs (22.7%). Among patients who did not have an induced abortion, SFL risk was higher if the pregnancy was unplanned (137 patients, 35.0%), compared with planned (43 patients, 16.4%) The risk ratio (RR) of SFL was 2.14. According to a regression analysis, SFL risk was higher for patients where “planning was entered alone” in unplanned pregnancies (odds ratio [OR], 2.75), as well as when adjusted for AED category, maternal age, and interpregnancy interval (OR, 3.57).
There was an association between maternal age (OR, 0.957) and risk of SFL. Risk was lower in the 18- to 27-year-olds (118 patients; 29.5%; RR, 0.57) and 28- to 37-year-olds (44 patients; 20.8%; RR, 0.40), compared with the under-18 group (15 patients, 51.7%). Risk of SFL was related to interpregnancy interval (OR, 2.878). This risk was greater if the interpregnancy interval was under one year (56 patients, 45.9%), compared with one year (56 patients, 22.8%) or higher (RR, 2.02).
The Epilepsy Foun-dation and Lundbeck funded the study. Dr. Herzog reports grants, and two coauthors received salary support from grants, from the two organizations.
—Jeff Craven
Suggested Reading
Herzog AG, Mandle HB, MacEachern DB. Association of unintended pregnancy with spontaneous fetal loss in women with epilepsy: findings of the Epilepsy Birth Control Registry. JAMA Neurol. 2018 Oct 15 [Epub ahead of print].
Unplanned pregnancy among women with epilepsy is associated with twice the risk of spontaneous fetal loss (SFL) when compared with women with epilepsy who planned their pregnancy, according to results from a retrospective study published online ahead of print October 15 in JAMA Neurology.
“This analysis adds the finding that unplanned pregnancy may increase the risk of SFL in women with epilepsy and identifies pregnancy planning, maternal age, and interpregnancy interval as significant modifiable variables,” said Andrew G. Herzog, MD, a neurologist at the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center in Wellesley, Massachusetts, and colleagues.
The Epilepsy Birth Control Registry
The researchers examined results from a web-based survey completed by 1,144 women in the Epilepsy Birth Control Registry (EBCR) between 2010 and 2014. Respondents provided data on contraception use, pregnancy history, and antiepileptic drug (AED) treatment. Patients were between ages 18 and 47 (mean, 28.5). Approximately 8.7% of the cohort were minorities, and 39.8% had household incomes of $25,000 or less.
Pregnancy history data included number of pregnancies, number of planned or unplanned pregnancies, AED type used during pregnancies, and pregnancy outcomes such as live birth, induced abortion, and SFL. Patients were categorized as receiving no therapy, monotherapy, or polytherapy. AED use was further subdivided into no AED, enzyme-inducing AED, non–enzyme-inducing AED, enzyme-inhibiting AED, glucuronidated AED, and mixed.
Most Pregnancies Were Unplanned
Of 794 pregnancies, 530 (66.8%) were unplanned and 264 (33.2%) were planned. Outcomes included 473 live births (59.6%), 141 induced abortions (17.8%), and 180 SFLs (22.7%). Among patients who did not have an induced abortion, SFL risk was higher if the pregnancy was unplanned (137 patients, 35.0%), compared with planned (43 patients, 16.4%) The risk ratio (RR) of SFL was 2.14. According to a regression analysis, SFL risk was higher for patients where “planning was entered alone” in unplanned pregnancies (odds ratio [OR], 2.75), as well as when adjusted for AED category, maternal age, and interpregnancy interval (OR, 3.57).
There was an association between maternal age (OR, 0.957) and risk of SFL. Risk was lower in the 18- to 27-year-olds (118 patients; 29.5%; RR, 0.57) and 28- to 37-year-olds (44 patients; 20.8%; RR, 0.40), compared with the under-18 group (15 patients, 51.7%). Risk of SFL was related to interpregnancy interval (OR, 2.878). This risk was greater if the interpregnancy interval was under one year (56 patients, 45.9%), compared with one year (56 patients, 22.8%) or higher (RR, 2.02).
The Epilepsy Foun-dation and Lundbeck funded the study. Dr. Herzog reports grants, and two coauthors received salary support from grants, from the two organizations.
—Jeff Craven
Suggested Reading
Herzog AG, Mandle HB, MacEachern DB. Association of unintended pregnancy with spontaneous fetal loss in women with epilepsy: findings of the Epilepsy Birth Control Registry. JAMA Neurol. 2018 Oct 15 [Epub ahead of print].
Study elicits patients’ most disturbing epilepsy symptoms
NEW ORLEANS – according to a study presented at the annual meeting of the American Epilepsy Society. The most prominent symptoms and effects on daily life may differ in the early, middle, and late stages of the disease, the results suggest.
Lead study author Jacqueline A. French, MD, professor of neurology at New York University, and her colleagues interviewed 62 patients with focal-onset epilepsy to examine patients’ experiences living with epilepsy. The investigators focused on salient symptoms and functional impacts – those that were reported by at least 50% of patients and were associated with a high degree of disturbance (patients rated them 5 or greater on a scale from 0 [no disturbance] to 10 [high disturbance]).
Of 51 symptoms that patients described during the interviews, the following 8 met the salience criteria for the total cohort: twitching or tremors, confusion, difficulty in talking, loss of awareness of others’ presence, stiffening, impaired consciousness or loss of consciousness, difficulty in remembering, and dizziness or lightheadedness. Patients reported salient functional impacts on driving and transportation, work and school, and leisure and social activities. Some symptoms met salience criteria among patients in certain stages of the disease (for example, tongue biting in patients with early-stage epilepsy and anxiety, fear, or panic in late-stage epilepsy) but not among patients in the other cohorts.
“These findings underscore the need to consider all these experiences when developing patient-reported outcome measures for use in clinical trials,” said Dr. French and her colleagues. “It may be useful to tailor measures of patient experiences to the patient’s stage of disease.”
Previous qualitative studies of epilepsy symptoms and burdens were based on small numbers of patients and interviews at a single center. For the present study, the researchers conducted qualitative, semistructured, in-person interviews with adults with focal epilepsy in different areas of the United States (such as California, Minnesota, New York, Ohio, and Pennsylvania). Patients were grouped by early, middle, or late disease stage. Patients in the early cohort (n = 19) had at least two seizures in the past year, a diagnosis of focal epilepsy in the past year, and had not yet received antiepileptic drug (AED) treatment or had received treatment with only one AED and had not failed treatment. Patients in the middle cohort (n = 17) had at least one seizure in the past year, a diagnosis of focal epilepsy within the past 5 years, and had failed one AED because of lack of efficacy or had received their first add-on AED. Patients in the late cohort (n = 26) had at least one seizure every 3 months during the past year, a diagnosis of focal epilepsy at age 12 years or older, and inadequate response to treatment of at least 3 months with two AEDs that were tolerated and appropriately chosen.
Patients’ mean age was 37 years (range, 19-60 years), 73% were female, 79% were white, 69% had a college degree as their highest level of education, and 65% were employed. Patients’ seizure types included simple partial without motor signs (52%), simple partial with motor signs (16%), complex partial (68%), or secondarily generalized (65%).
While driving or transportation was a salient impact for all three groups, memory loss was a salient impact in the early and middle cohorts only. Headaches and sadness or depression were salient impacts for the late cohort only.
This study was funded by Eisai and two of the authors are former or current employees of Eisai.
SOURCE: French JA et al. AES 2018, Abstract 1.196.
NEW ORLEANS – according to a study presented at the annual meeting of the American Epilepsy Society. The most prominent symptoms and effects on daily life may differ in the early, middle, and late stages of the disease, the results suggest.
Lead study author Jacqueline A. French, MD, professor of neurology at New York University, and her colleagues interviewed 62 patients with focal-onset epilepsy to examine patients’ experiences living with epilepsy. The investigators focused on salient symptoms and functional impacts – those that were reported by at least 50% of patients and were associated with a high degree of disturbance (patients rated them 5 or greater on a scale from 0 [no disturbance] to 10 [high disturbance]).
Of 51 symptoms that patients described during the interviews, the following 8 met the salience criteria for the total cohort: twitching or tremors, confusion, difficulty in talking, loss of awareness of others’ presence, stiffening, impaired consciousness or loss of consciousness, difficulty in remembering, and dizziness or lightheadedness. Patients reported salient functional impacts on driving and transportation, work and school, and leisure and social activities. Some symptoms met salience criteria among patients in certain stages of the disease (for example, tongue biting in patients with early-stage epilepsy and anxiety, fear, or panic in late-stage epilepsy) but not among patients in the other cohorts.
“These findings underscore the need to consider all these experiences when developing patient-reported outcome measures for use in clinical trials,” said Dr. French and her colleagues. “It may be useful to tailor measures of patient experiences to the patient’s stage of disease.”
Previous qualitative studies of epilepsy symptoms and burdens were based on small numbers of patients and interviews at a single center. For the present study, the researchers conducted qualitative, semistructured, in-person interviews with adults with focal epilepsy in different areas of the United States (such as California, Minnesota, New York, Ohio, and Pennsylvania). Patients were grouped by early, middle, or late disease stage. Patients in the early cohort (n = 19) had at least two seizures in the past year, a diagnosis of focal epilepsy in the past year, and had not yet received antiepileptic drug (AED) treatment or had received treatment with only one AED and had not failed treatment. Patients in the middle cohort (n = 17) had at least one seizure in the past year, a diagnosis of focal epilepsy within the past 5 years, and had failed one AED because of lack of efficacy or had received their first add-on AED. Patients in the late cohort (n = 26) had at least one seizure every 3 months during the past year, a diagnosis of focal epilepsy at age 12 years or older, and inadequate response to treatment of at least 3 months with two AEDs that were tolerated and appropriately chosen.
Patients’ mean age was 37 years (range, 19-60 years), 73% were female, 79% were white, 69% had a college degree as their highest level of education, and 65% were employed. Patients’ seizure types included simple partial without motor signs (52%), simple partial with motor signs (16%), complex partial (68%), or secondarily generalized (65%).
While driving or transportation was a salient impact for all three groups, memory loss was a salient impact in the early and middle cohorts only. Headaches and sadness or depression were salient impacts for the late cohort only.
This study was funded by Eisai and two of the authors are former or current employees of Eisai.
SOURCE: French JA et al. AES 2018, Abstract 1.196.
NEW ORLEANS – according to a study presented at the annual meeting of the American Epilepsy Society. The most prominent symptoms and effects on daily life may differ in the early, middle, and late stages of the disease, the results suggest.
Lead study author Jacqueline A. French, MD, professor of neurology at New York University, and her colleagues interviewed 62 patients with focal-onset epilepsy to examine patients’ experiences living with epilepsy. The investigators focused on salient symptoms and functional impacts – those that were reported by at least 50% of patients and were associated with a high degree of disturbance (patients rated them 5 or greater on a scale from 0 [no disturbance] to 10 [high disturbance]).
Of 51 symptoms that patients described during the interviews, the following 8 met the salience criteria for the total cohort: twitching or tremors, confusion, difficulty in talking, loss of awareness of others’ presence, stiffening, impaired consciousness or loss of consciousness, difficulty in remembering, and dizziness or lightheadedness. Patients reported salient functional impacts on driving and transportation, work and school, and leisure and social activities. Some symptoms met salience criteria among patients in certain stages of the disease (for example, tongue biting in patients with early-stage epilepsy and anxiety, fear, or panic in late-stage epilepsy) but not among patients in the other cohorts.
“These findings underscore the need to consider all these experiences when developing patient-reported outcome measures for use in clinical trials,” said Dr. French and her colleagues. “It may be useful to tailor measures of patient experiences to the patient’s stage of disease.”
Previous qualitative studies of epilepsy symptoms and burdens were based on small numbers of patients and interviews at a single center. For the present study, the researchers conducted qualitative, semistructured, in-person interviews with adults with focal epilepsy in different areas of the United States (such as California, Minnesota, New York, Ohio, and Pennsylvania). Patients were grouped by early, middle, or late disease stage. Patients in the early cohort (n = 19) had at least two seizures in the past year, a diagnosis of focal epilepsy in the past year, and had not yet received antiepileptic drug (AED) treatment or had received treatment with only one AED and had not failed treatment. Patients in the middle cohort (n = 17) had at least one seizure in the past year, a diagnosis of focal epilepsy within the past 5 years, and had failed one AED because of lack of efficacy or had received their first add-on AED. Patients in the late cohort (n = 26) had at least one seizure every 3 months during the past year, a diagnosis of focal epilepsy at age 12 years or older, and inadequate response to treatment of at least 3 months with two AEDs that were tolerated and appropriately chosen.
Patients’ mean age was 37 years (range, 19-60 years), 73% were female, 79% were white, 69% had a college degree as their highest level of education, and 65% were employed. Patients’ seizure types included simple partial without motor signs (52%), simple partial with motor signs (16%), complex partial (68%), or secondarily generalized (65%).
While driving or transportation was a salient impact for all three groups, memory loss was a salient impact in the early and middle cohorts only. Headaches and sadness or depression were salient impacts for the late cohort only.
This study was funded by Eisai and two of the authors are former or current employees of Eisai.
SOURCE: French JA et al. AES 2018, Abstract 1.196.
REPORTING FROM AES 2018
Key clinical point: The most prominent symptoms and functional impacts of epilepsy may differ in the early, middle, and late stages of the disease.
Major finding: More than 50% of patients reported functional impacts on driving and transportation, work and school, and leisure and social activities.
Study details: An analysis of data from semistructured interviews with 62 adults with focal epilepsy.
Disclosures: This study was funded by Eisai and two of the authors are former or current employees of Eisai.
Source: French JA et al. AES 2018, Abstract 1.196.
Nicotine patch may be an effective precision therapy for select epilepsies
NEW ORLEANS – according to research presented at the annual meeting of the American Epilepsy Society. Of four epilepsy patients at one center who received nicotine-patch treatment, three had a good clinical response, one of whom became seizure free.
“We confirm that, in select patients, treatment with a nicotine patch ... can be an effective precision therapy for epilepsy. We propose consideration of nicotine-patch treatment in refractory patients with known cholinergic nicotine receptor subunit variants, especially those with a clinical history consistent with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE),” said Jordana Fox, DO, and Alison Dolce, MD, both with the University of Texas Southwestern Medical Center in Dallas.
Gene variants in CHRAn4,CHRNA2, and CHRNB2 can cause ADNFLE. Preclinical and n-of-1 studies have suggested that nicotine may be a precision treatment for ADNFLE.
Dr. Fox and Dr. Dolce reviewed next-generation sequencing epilepsy panels from patients seen at Children’s Medical Center, Dallas, during 2011-2015 to identify patients with nAChR gene variants (CHNRA4, CHRNA2, CHRNB2, and CHRNA7). They reviewed patients’ medical and laboratory records, including genetic variant details and treatment history, and focused on patients who underwent a trial of nicotine-patch treatment.
Of the 21 patients who had nAChR gene variants, 4 tried treatment with a nicotine patch, either 7 mg or 14 mg. The patients who received nicotine-patch treatment had genetic variants in CHRNA4, CHRNB2, and CHRNA2. Three of the patients who tried nicotine-patch treatment had a greater than 50% reduction in seizures, whereas one had no treatment response.
“One patient became seizure free and is now treated with the nicotine patch as monotherapy,” Dr. Fox said.
The patient with complete resolution of seizures had a heterozygous disease–causing mutation in CHRNB2. This patient had nocturnal focal seizures, normal neuroimaging, and had been receiving treatment with oxcarbazepine and zonisamide.
The review identified four patients with nAChR gene variants and the ADNFLE phenotype who have not been treated with nicotine. Further phenotype-genotype characterizations and preclinical studies will help neurologists understand the mechanisms of these complex gene variants.
The researchers received no funding for the study and had no relevant financial disclosures.
SOURCE: Fox J et al. AES 2018, Abstract 1.230.
NEW ORLEANS – according to research presented at the annual meeting of the American Epilepsy Society. Of four epilepsy patients at one center who received nicotine-patch treatment, three had a good clinical response, one of whom became seizure free.
“We confirm that, in select patients, treatment with a nicotine patch ... can be an effective precision therapy for epilepsy. We propose consideration of nicotine-patch treatment in refractory patients with known cholinergic nicotine receptor subunit variants, especially those with a clinical history consistent with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE),” said Jordana Fox, DO, and Alison Dolce, MD, both with the University of Texas Southwestern Medical Center in Dallas.
Gene variants in CHRAn4,CHRNA2, and CHRNB2 can cause ADNFLE. Preclinical and n-of-1 studies have suggested that nicotine may be a precision treatment for ADNFLE.
Dr. Fox and Dr. Dolce reviewed next-generation sequencing epilepsy panels from patients seen at Children’s Medical Center, Dallas, during 2011-2015 to identify patients with nAChR gene variants (CHNRA4, CHRNA2, CHRNB2, and CHRNA7). They reviewed patients’ medical and laboratory records, including genetic variant details and treatment history, and focused on patients who underwent a trial of nicotine-patch treatment.
Of the 21 patients who had nAChR gene variants, 4 tried treatment with a nicotine patch, either 7 mg or 14 mg. The patients who received nicotine-patch treatment had genetic variants in CHRNA4, CHRNB2, and CHRNA2. Three of the patients who tried nicotine-patch treatment had a greater than 50% reduction in seizures, whereas one had no treatment response.
“One patient became seizure free and is now treated with the nicotine patch as monotherapy,” Dr. Fox said.
The patient with complete resolution of seizures had a heterozygous disease–causing mutation in CHRNB2. This patient had nocturnal focal seizures, normal neuroimaging, and had been receiving treatment with oxcarbazepine and zonisamide.
The review identified four patients with nAChR gene variants and the ADNFLE phenotype who have not been treated with nicotine. Further phenotype-genotype characterizations and preclinical studies will help neurologists understand the mechanisms of these complex gene variants.
The researchers received no funding for the study and had no relevant financial disclosures.
SOURCE: Fox J et al. AES 2018, Abstract 1.230.
NEW ORLEANS – according to research presented at the annual meeting of the American Epilepsy Society. Of four epilepsy patients at one center who received nicotine-patch treatment, three had a good clinical response, one of whom became seizure free.
“We confirm that, in select patients, treatment with a nicotine patch ... can be an effective precision therapy for epilepsy. We propose consideration of nicotine-patch treatment in refractory patients with known cholinergic nicotine receptor subunit variants, especially those with a clinical history consistent with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE),” said Jordana Fox, DO, and Alison Dolce, MD, both with the University of Texas Southwestern Medical Center in Dallas.
Gene variants in CHRAn4,CHRNA2, and CHRNB2 can cause ADNFLE. Preclinical and n-of-1 studies have suggested that nicotine may be a precision treatment for ADNFLE.
Dr. Fox and Dr. Dolce reviewed next-generation sequencing epilepsy panels from patients seen at Children’s Medical Center, Dallas, during 2011-2015 to identify patients with nAChR gene variants (CHNRA4, CHRNA2, CHRNB2, and CHRNA7). They reviewed patients’ medical and laboratory records, including genetic variant details and treatment history, and focused on patients who underwent a trial of nicotine-patch treatment.
Of the 21 patients who had nAChR gene variants, 4 tried treatment with a nicotine patch, either 7 mg or 14 mg. The patients who received nicotine-patch treatment had genetic variants in CHRNA4, CHRNB2, and CHRNA2. Three of the patients who tried nicotine-patch treatment had a greater than 50% reduction in seizures, whereas one had no treatment response.
“One patient became seizure free and is now treated with the nicotine patch as monotherapy,” Dr. Fox said.
The patient with complete resolution of seizures had a heterozygous disease–causing mutation in CHRNB2. This patient had nocturnal focal seizures, normal neuroimaging, and had been receiving treatment with oxcarbazepine and zonisamide.
The review identified four patients with nAChR gene variants and the ADNFLE phenotype who have not been treated with nicotine. Further phenotype-genotype characterizations and preclinical studies will help neurologists understand the mechanisms of these complex gene variants.
The researchers received no funding for the study and had no relevant financial disclosures.
SOURCE: Fox J et al. AES 2018, Abstract 1.230.
REPORTING FROM AES 2018
Key clinical point: In select patients with epilepsy, nicotine may be an effective precision therapy.
Major finding: Of four patients who received nicotine-patch treatment at one center, three had a good clinical response, one of whom became seizure free.
Study details: Single-center chart review of 21 patients with gene variants in subunits of the nicotinic acetylcholine receptor.
Disclosures: The researchers received no funding for the study and had no relevant financial disclosures.
Source: Fox J et al. AES 2018, Abstract 1.230.
Common AEDs confer modestly increased risk of major congenital malformations
NEW ORLEANS – The most commonly used antiepileptic drugs modestly increased the risk of major congenital malformations among prenatally exposed infants in the MONEAD study.
Malformations occurred among 5% of pregnancies exposed to the medications – higher than the 2% background rate – but this was still much lower than the 9%-10% rate associated with valproate.
Overall, however, the message of the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic (MONEAD) study is quite reassuring, Kimford J. Meador, MD, said at the annual meeting of the American Epilepsy Society. MONEAD is an ongoing, prospective study to determine both maternal outcomes and long-term childhood neurodevelopmental outcomes associated with the use of antiepileptic drugs (AEDs) during pregnancy.
“The rate of malformations was higher than I thought it would be, and higher than the 2% background rate, but it’s still a modest increase and most babies are born completely normal,” Dr. Meador, professor of neurology and neurosciences at Stanford (Calif.) University, said in an interview. “I think the news here is good, and it’s especially reassuring when you put it in the context that, 60 years ago, there were laws that women with epilepsy couldn’t get married, and some states even had laws to sterilize women. I think that’s absurd when most infants born to these women are without malformations and the risk of miscarriage is very low.”
Another positive finding, he said, is that valproate use among pregnant women is now practically nonexistent. Only 1 of 351 pregnant women with epilepsy and just 2 of a comparator group of 109 nonpregnant women with epilepsy were taking it. That’s great news, said Dr. Meador, who also initiated the NEAD (Neurodevelopmental Effects of Antiepileptic Drugs) study in the early 2000s. NEAD determined the drug’s serious teratogenic potential.
In addition to the cohorts of pregnant and nonpregnant women with epilepsy, 105 healthy pregnant women enrolled in the MONEAD study. Women will be monitored during pregnancy and postpartum to measure maternal outcomes and their children will be monitored from birth through age 6 years to measure their health and developmental outcomes.
The study has six primary outcomes, three for the women and three for their children.
- Determine if women with epilepsy have increased seizures during pregnancy and delineate the contributing factors.
- Determine if C-section rate is increased in women with epilepsy and delineate contributing factors.
- Determine if women with epilepsy have an increased risk for depression during pregnancy and the postpartum period and characterize risk factors.
- Determine the long-term effects of in utero AED exposure on verbal intellectual abilities and other neurobehavioral outcomes.
- Determine if small-for-gestational age and other adverse neonatal outcomes are increased.
- Determine if breastfeeding when taking AEDs impairs the child’s ultimate verbal and other cognitive outcomes.
Rates of miscarriage and neonatal malformations were not primary study outcomes, but the descriptive data were collected and are of high interest, Dr. Meador said.
At baseline, all the women had a mean age of about 30 years. Most (75%) were on monotherapy, 20% were on polytherapy, and the rest were not taking an AED. About 60% had focal epilepsy, 31% had generalized epilepsy, and the remainder had an unclassified seizure disorder. Three subjects had multiple seizure types. The most commonly used AEDs were lamotrigine and levetiracetam (both about 30%); 4% were taking zonisamide, 4% carbamazepine, and 4% oxcarbazepine. Topiramate was being used for 2% of the pregnant woman and 5% of the nonpregnant woman. The combination of lamotrigine and levetiracetam was used for 9.0% of pregnant and 5.5% of nonpregnant women, and other polytherapies in 12.0% of the pregnant and 14.0% of the nonpregnant woman. About 4% of the pregnant and 1% of the nonpregnant women were not taking any AED.
There were 10 (2.8%) spontaneous miscarriages among the pregnant women with epilepsy and none among the healthy pregnant women. Spontaneous miscarriages weren’t associated with acute seizures, and there were no major congenital malformations reported among them. There were also two elective abortions among the pregnant women with epilepsy.
There were 18 major congenital malformations among the pregnant woman with epilepsy (5%). A total of 14 were among pregnancies exposed to monotherapy, 3 were in polytherapy-exposed pregnancies, and 1 was in the group not taking any AEDs.
The malformations were:
- Carbamazepine (one case) – hydronephrosis.
- Gabapentin (one case) – inguinal hernia.
- Lamotrigine (five cases) – aortic coarctation, cryptorchidism, hydronephrosis, pectus excavatum, and morning glory syndrome (a funnel-shaped optic nerve disc associated with impaired visual acuity).
- Levetiracetam (five cases) – atrial septal defect, buried penis syndrome, cryptorchidism, hypoplastic aortic valve, ventricular septal defect.
- Topiramate (one case) – ventricular septal defect.
- Zonisamide (one case) – inguinal hernia, absent pinna.
- Lamotrigine plus clonazepam (one case) – cardiomyopathy.
- Lamotrigine plus levetiracetam (one case) – microcephaly, myelomeningocele, Chiari II malformation.
- Levetiracetam plus phenobarbital (one case) – bilateral inguinal hernia.
MONEAD is funded by the National Institutes of Health; Dr. Meador reported no financial disclosures.
SOURCE: Meador KJ et al. AES 2018, Abstract 3.231.
NEW ORLEANS – The most commonly used antiepileptic drugs modestly increased the risk of major congenital malformations among prenatally exposed infants in the MONEAD study.
Malformations occurred among 5% of pregnancies exposed to the medications – higher than the 2% background rate – but this was still much lower than the 9%-10% rate associated with valproate.
Overall, however, the message of the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic (MONEAD) study is quite reassuring, Kimford J. Meador, MD, said at the annual meeting of the American Epilepsy Society. MONEAD is an ongoing, prospective study to determine both maternal outcomes and long-term childhood neurodevelopmental outcomes associated with the use of antiepileptic drugs (AEDs) during pregnancy.
“The rate of malformations was higher than I thought it would be, and higher than the 2% background rate, but it’s still a modest increase and most babies are born completely normal,” Dr. Meador, professor of neurology and neurosciences at Stanford (Calif.) University, said in an interview. “I think the news here is good, and it’s especially reassuring when you put it in the context that, 60 years ago, there were laws that women with epilepsy couldn’t get married, and some states even had laws to sterilize women. I think that’s absurd when most infants born to these women are without malformations and the risk of miscarriage is very low.”
Another positive finding, he said, is that valproate use among pregnant women is now practically nonexistent. Only 1 of 351 pregnant women with epilepsy and just 2 of a comparator group of 109 nonpregnant women with epilepsy were taking it. That’s great news, said Dr. Meador, who also initiated the NEAD (Neurodevelopmental Effects of Antiepileptic Drugs) study in the early 2000s. NEAD determined the drug’s serious teratogenic potential.
In addition to the cohorts of pregnant and nonpregnant women with epilepsy, 105 healthy pregnant women enrolled in the MONEAD study. Women will be monitored during pregnancy and postpartum to measure maternal outcomes and their children will be monitored from birth through age 6 years to measure their health and developmental outcomes.
The study has six primary outcomes, three for the women and three for their children.
- Determine if women with epilepsy have increased seizures during pregnancy and delineate the contributing factors.
- Determine if C-section rate is increased in women with epilepsy and delineate contributing factors.
- Determine if women with epilepsy have an increased risk for depression during pregnancy and the postpartum period and characterize risk factors.
- Determine the long-term effects of in utero AED exposure on verbal intellectual abilities and other neurobehavioral outcomes.
- Determine if small-for-gestational age and other adverse neonatal outcomes are increased.
- Determine if breastfeeding when taking AEDs impairs the child’s ultimate verbal and other cognitive outcomes.
Rates of miscarriage and neonatal malformations were not primary study outcomes, but the descriptive data were collected and are of high interest, Dr. Meador said.
At baseline, all the women had a mean age of about 30 years. Most (75%) were on monotherapy, 20% were on polytherapy, and the rest were not taking an AED. About 60% had focal epilepsy, 31% had generalized epilepsy, and the remainder had an unclassified seizure disorder. Three subjects had multiple seizure types. The most commonly used AEDs were lamotrigine and levetiracetam (both about 30%); 4% were taking zonisamide, 4% carbamazepine, and 4% oxcarbazepine. Topiramate was being used for 2% of the pregnant woman and 5% of the nonpregnant woman. The combination of lamotrigine and levetiracetam was used for 9.0% of pregnant and 5.5% of nonpregnant women, and other polytherapies in 12.0% of the pregnant and 14.0% of the nonpregnant woman. About 4% of the pregnant and 1% of the nonpregnant women were not taking any AED.
There were 10 (2.8%) spontaneous miscarriages among the pregnant women with epilepsy and none among the healthy pregnant women. Spontaneous miscarriages weren’t associated with acute seizures, and there were no major congenital malformations reported among them. There were also two elective abortions among the pregnant women with epilepsy.
There were 18 major congenital malformations among the pregnant woman with epilepsy (5%). A total of 14 were among pregnancies exposed to monotherapy, 3 were in polytherapy-exposed pregnancies, and 1 was in the group not taking any AEDs.
The malformations were:
- Carbamazepine (one case) – hydronephrosis.
- Gabapentin (one case) – inguinal hernia.
- Lamotrigine (five cases) – aortic coarctation, cryptorchidism, hydronephrosis, pectus excavatum, and morning glory syndrome (a funnel-shaped optic nerve disc associated with impaired visual acuity).
- Levetiracetam (five cases) – atrial septal defect, buried penis syndrome, cryptorchidism, hypoplastic aortic valve, ventricular septal defect.
- Topiramate (one case) – ventricular septal defect.
- Zonisamide (one case) – inguinal hernia, absent pinna.
- Lamotrigine plus clonazepam (one case) – cardiomyopathy.
- Lamotrigine plus levetiracetam (one case) – microcephaly, myelomeningocele, Chiari II malformation.
- Levetiracetam plus phenobarbital (one case) – bilateral inguinal hernia.
MONEAD is funded by the National Institutes of Health; Dr. Meador reported no financial disclosures.
SOURCE: Meador KJ et al. AES 2018, Abstract 3.231.
NEW ORLEANS – The most commonly used antiepileptic drugs modestly increased the risk of major congenital malformations among prenatally exposed infants in the MONEAD study.
Malformations occurred among 5% of pregnancies exposed to the medications – higher than the 2% background rate – but this was still much lower than the 9%-10% rate associated with valproate.
Overall, however, the message of the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic (MONEAD) study is quite reassuring, Kimford J. Meador, MD, said at the annual meeting of the American Epilepsy Society. MONEAD is an ongoing, prospective study to determine both maternal outcomes and long-term childhood neurodevelopmental outcomes associated with the use of antiepileptic drugs (AEDs) during pregnancy.
“The rate of malformations was higher than I thought it would be, and higher than the 2% background rate, but it’s still a modest increase and most babies are born completely normal,” Dr. Meador, professor of neurology and neurosciences at Stanford (Calif.) University, said in an interview. “I think the news here is good, and it’s especially reassuring when you put it in the context that, 60 years ago, there were laws that women with epilepsy couldn’t get married, and some states even had laws to sterilize women. I think that’s absurd when most infants born to these women are without malformations and the risk of miscarriage is very low.”
Another positive finding, he said, is that valproate use among pregnant women is now practically nonexistent. Only 1 of 351 pregnant women with epilepsy and just 2 of a comparator group of 109 nonpregnant women with epilepsy were taking it. That’s great news, said Dr. Meador, who also initiated the NEAD (Neurodevelopmental Effects of Antiepileptic Drugs) study in the early 2000s. NEAD determined the drug’s serious teratogenic potential.
In addition to the cohorts of pregnant and nonpregnant women with epilepsy, 105 healthy pregnant women enrolled in the MONEAD study. Women will be monitored during pregnancy and postpartum to measure maternal outcomes and their children will be monitored from birth through age 6 years to measure their health and developmental outcomes.
The study has six primary outcomes, three for the women and three for their children.
- Determine if women with epilepsy have increased seizures during pregnancy and delineate the contributing factors.
- Determine if C-section rate is increased in women with epilepsy and delineate contributing factors.
- Determine if women with epilepsy have an increased risk for depression during pregnancy and the postpartum period and characterize risk factors.
- Determine the long-term effects of in utero AED exposure on verbal intellectual abilities and other neurobehavioral outcomes.
- Determine if small-for-gestational age and other adverse neonatal outcomes are increased.
- Determine if breastfeeding when taking AEDs impairs the child’s ultimate verbal and other cognitive outcomes.
Rates of miscarriage and neonatal malformations were not primary study outcomes, but the descriptive data were collected and are of high interest, Dr. Meador said.
At baseline, all the women had a mean age of about 30 years. Most (75%) were on monotherapy, 20% were on polytherapy, and the rest were not taking an AED. About 60% had focal epilepsy, 31% had generalized epilepsy, and the remainder had an unclassified seizure disorder. Three subjects had multiple seizure types. The most commonly used AEDs were lamotrigine and levetiracetam (both about 30%); 4% were taking zonisamide, 4% carbamazepine, and 4% oxcarbazepine. Topiramate was being used for 2% of the pregnant woman and 5% of the nonpregnant woman. The combination of lamotrigine and levetiracetam was used for 9.0% of pregnant and 5.5% of nonpregnant women, and other polytherapies in 12.0% of the pregnant and 14.0% of the nonpregnant woman. About 4% of the pregnant and 1% of the nonpregnant women were not taking any AED.
There were 10 (2.8%) spontaneous miscarriages among the pregnant women with epilepsy and none among the healthy pregnant women. Spontaneous miscarriages weren’t associated with acute seizures, and there were no major congenital malformations reported among them. There were also two elective abortions among the pregnant women with epilepsy.
There were 18 major congenital malformations among the pregnant woman with epilepsy (5%). A total of 14 were among pregnancies exposed to monotherapy, 3 were in polytherapy-exposed pregnancies, and 1 was in the group not taking any AEDs.
The malformations were:
- Carbamazepine (one case) – hydronephrosis.
- Gabapentin (one case) – inguinal hernia.
- Lamotrigine (five cases) – aortic coarctation, cryptorchidism, hydronephrosis, pectus excavatum, and morning glory syndrome (a funnel-shaped optic nerve disc associated with impaired visual acuity).
- Levetiracetam (five cases) – atrial septal defect, buried penis syndrome, cryptorchidism, hypoplastic aortic valve, ventricular septal defect.
- Topiramate (one case) – ventricular septal defect.
- Zonisamide (one case) – inguinal hernia, absent pinna.
- Lamotrigine plus clonazepam (one case) – cardiomyopathy.
- Lamotrigine plus levetiracetam (one case) – microcephaly, myelomeningocele, Chiari II malformation.
- Levetiracetam plus phenobarbital (one case) – bilateral inguinal hernia.
MONEAD is funded by the National Institutes of Health; Dr. Meador reported no financial disclosures.
SOURCE: Meador KJ et al. AES 2018, Abstract 3.231.
REPORTING FROM AES 2018
Key clinical point:
Major finding: The malformation rate was 5% in exposed pregnancies.
Study details: The MONEAD study comprised 351 pregnant women with epilepsy, 109 nonpregnant women with epilepsy, and 105 healthy pregnant women.
Disclosures: The National Institutes of Health funded the study; Dr. Meador reported no financial disclosures.
Source: Meador KJ et al. AES 2018, Abstract 3.231.
What constitutes a clinically meaningful reduction in seizure frequency?
NEW ORLEANS – according to a study described at the annual meeting of the American Epilepsy Society. A reduction in seizure frequency of between 60% and 68% is associated with Clinical Global Impression of Improvement (CGI-I) ratings of “very much improved,” as assessed by caregivers and investigators.
“Further analyses from other phase III studies in Dravet syndrome and other patient populations should be performed to confirm these findings and explore other potential factors that contribute to caregiver and investigator CGI-I ratings, such as nonseizure outcomes and tolerability,” said Arnold Gammaitoni, PharmD, vice president of medical and scientific affairs at Zogenix in San Diego, and his colleagues.
A 50% reduction in seizure frequency is conventionally considered to be the cutoff for a clinically meaningful change. To develop an evidence-based definition of clinically meaningful seizure reduction, Dr. Gammaitoni and colleagues examined data from a phase III, randomized, double-blind, placebo-controlled trial of fenfluramine HCl oral solution for the adjunctive treatment of seizures associated with Dravet syndrome. The investigators took an anchor-based approach and examined the percentage change in seizure frequency, along with caregiver and investigator CGI-I ratings.
A total of 119 patients with Dravet syndrome were enrolled and randomized in equal groups to placebo, 0.2 mg/kg per day of fenfluramine HCl, or 0.8 mg/kg per day of fenfluramine HCl. After a 2-week titration period, patients entered a 12-week maintenance period. Patients in the 0.8-mg/kg per day group had a 63.9% greater reduction in seizure frequency than controls did.
After the 14-week titration and maintenance period, caregivers and investigators rated the change in participants’ clinical status from baseline, using the CGI-I scale, on which responses range from 1 (very much improved) to 7 (very much worse). The investigators considered patients with CGI-I scores of 1 or 2 (much improved) to have achieved a clinically meaningful response. A score of 3 (minimally improved) was not considered meaningful. The researchers pooled the results of the three treatment groups for this analysis. They estimated the clinically meaningful percentage change in seizure frequency using receiver operating characteristic analysis of binary CGI-I score, compared with percentage change in seizure frequency, and defined it as the cut-point for which specificity and sensitivity were equal or most similar.
Caregivers and investigators provided CGI-I assessments for 112 patients and 114 patients, respectively. The receiver operating characteristic analysis identified a 44% reduction in seizure frequency as a clinically meaningful cutoff point for caregiver and investigator assessments. Using this threshold, 75%, 46%, and 12.5% of patients in the 0.8-mg/kg per day, 0.2-mg/kg per day, and placebo groups, respectively, achieved a clinically meaningful reduction from baseline in seizure frequency in the phase III study.
“The use of external anchors is one method to define a clinically meaningful change in seizure frequency,” said Dr. Gammaitoni. “Having a defined minimum clinically important difference like this allows clinicians to assess impacts of treatments on an individual patient basis.... This is a chance for others to do similar types of analyses to confirm the findings that we have had in this first study with bigger data sets, in terms of using external anchors and data to define what a clinically meaningful change is.”
Zogenix, which is developing the fenfluramine formulation examined in this study, provided funding for this research.
SOURCE: Nabbout R et al. AES 2018, Abstract 3.202.
NEW ORLEANS – according to a study described at the annual meeting of the American Epilepsy Society. A reduction in seizure frequency of between 60% and 68% is associated with Clinical Global Impression of Improvement (CGI-I) ratings of “very much improved,” as assessed by caregivers and investigators.
“Further analyses from other phase III studies in Dravet syndrome and other patient populations should be performed to confirm these findings and explore other potential factors that contribute to caregiver and investigator CGI-I ratings, such as nonseizure outcomes and tolerability,” said Arnold Gammaitoni, PharmD, vice president of medical and scientific affairs at Zogenix in San Diego, and his colleagues.
A 50% reduction in seizure frequency is conventionally considered to be the cutoff for a clinically meaningful change. To develop an evidence-based definition of clinically meaningful seizure reduction, Dr. Gammaitoni and colleagues examined data from a phase III, randomized, double-blind, placebo-controlled trial of fenfluramine HCl oral solution for the adjunctive treatment of seizures associated with Dravet syndrome. The investigators took an anchor-based approach and examined the percentage change in seizure frequency, along with caregiver and investigator CGI-I ratings.
A total of 119 patients with Dravet syndrome were enrolled and randomized in equal groups to placebo, 0.2 mg/kg per day of fenfluramine HCl, or 0.8 mg/kg per day of fenfluramine HCl. After a 2-week titration period, patients entered a 12-week maintenance period. Patients in the 0.8-mg/kg per day group had a 63.9% greater reduction in seizure frequency than controls did.
After the 14-week titration and maintenance period, caregivers and investigators rated the change in participants’ clinical status from baseline, using the CGI-I scale, on which responses range from 1 (very much improved) to 7 (very much worse). The investigators considered patients with CGI-I scores of 1 or 2 (much improved) to have achieved a clinically meaningful response. A score of 3 (minimally improved) was not considered meaningful. The researchers pooled the results of the three treatment groups for this analysis. They estimated the clinically meaningful percentage change in seizure frequency using receiver operating characteristic analysis of binary CGI-I score, compared with percentage change in seizure frequency, and defined it as the cut-point for which specificity and sensitivity were equal or most similar.
Caregivers and investigators provided CGI-I assessments for 112 patients and 114 patients, respectively. The receiver operating characteristic analysis identified a 44% reduction in seizure frequency as a clinically meaningful cutoff point for caregiver and investigator assessments. Using this threshold, 75%, 46%, and 12.5% of patients in the 0.8-mg/kg per day, 0.2-mg/kg per day, and placebo groups, respectively, achieved a clinically meaningful reduction from baseline in seizure frequency in the phase III study.
“The use of external anchors is one method to define a clinically meaningful change in seizure frequency,” said Dr. Gammaitoni. “Having a defined minimum clinically important difference like this allows clinicians to assess impacts of treatments on an individual patient basis.... This is a chance for others to do similar types of analyses to confirm the findings that we have had in this first study with bigger data sets, in terms of using external anchors and data to define what a clinically meaningful change is.”
Zogenix, which is developing the fenfluramine formulation examined in this study, provided funding for this research.
SOURCE: Nabbout R et al. AES 2018, Abstract 3.202.
NEW ORLEANS – according to a study described at the annual meeting of the American Epilepsy Society. A reduction in seizure frequency of between 60% and 68% is associated with Clinical Global Impression of Improvement (CGI-I) ratings of “very much improved,” as assessed by caregivers and investigators.
“Further analyses from other phase III studies in Dravet syndrome and other patient populations should be performed to confirm these findings and explore other potential factors that contribute to caregiver and investigator CGI-I ratings, such as nonseizure outcomes and tolerability,” said Arnold Gammaitoni, PharmD, vice president of medical and scientific affairs at Zogenix in San Diego, and his colleagues.
A 50% reduction in seizure frequency is conventionally considered to be the cutoff for a clinically meaningful change. To develop an evidence-based definition of clinically meaningful seizure reduction, Dr. Gammaitoni and colleagues examined data from a phase III, randomized, double-blind, placebo-controlled trial of fenfluramine HCl oral solution for the adjunctive treatment of seizures associated with Dravet syndrome. The investigators took an anchor-based approach and examined the percentage change in seizure frequency, along with caregiver and investigator CGI-I ratings.
A total of 119 patients with Dravet syndrome were enrolled and randomized in equal groups to placebo, 0.2 mg/kg per day of fenfluramine HCl, or 0.8 mg/kg per day of fenfluramine HCl. After a 2-week titration period, patients entered a 12-week maintenance period. Patients in the 0.8-mg/kg per day group had a 63.9% greater reduction in seizure frequency than controls did.
After the 14-week titration and maintenance period, caregivers and investigators rated the change in participants’ clinical status from baseline, using the CGI-I scale, on which responses range from 1 (very much improved) to 7 (very much worse). The investigators considered patients with CGI-I scores of 1 or 2 (much improved) to have achieved a clinically meaningful response. A score of 3 (minimally improved) was not considered meaningful. The researchers pooled the results of the three treatment groups for this analysis. They estimated the clinically meaningful percentage change in seizure frequency using receiver operating characteristic analysis of binary CGI-I score, compared with percentage change in seizure frequency, and defined it as the cut-point for which specificity and sensitivity were equal or most similar.
Caregivers and investigators provided CGI-I assessments for 112 patients and 114 patients, respectively. The receiver operating characteristic analysis identified a 44% reduction in seizure frequency as a clinically meaningful cutoff point for caregiver and investigator assessments. Using this threshold, 75%, 46%, and 12.5% of patients in the 0.8-mg/kg per day, 0.2-mg/kg per day, and placebo groups, respectively, achieved a clinically meaningful reduction from baseline in seizure frequency in the phase III study.
“The use of external anchors is one method to define a clinically meaningful change in seizure frequency,” said Dr. Gammaitoni. “Having a defined minimum clinically important difference like this allows clinicians to assess impacts of treatments on an individual patient basis.... This is a chance for others to do similar types of analyses to confirm the findings that we have had in this first study with bigger data sets, in terms of using external anchors and data to define what a clinically meaningful change is.”
Zogenix, which is developing the fenfluramine formulation examined in this study, provided funding for this research.
SOURCE: Nabbout R et al. AES 2018, Abstract 3.202.
REPORTING FROM AES 2018
Key clinical point: Data support the convention of considering a 50% reduction in seizure frequency as the cutoff for a clinically meaningful change.
Major finding: Statistical analysis indicates that a 44% reduction in seizure frequency is clinically meaningful.
Study details: A phase III, randomized, double-blind, placebo-controlled clinical trial of fenfluramine HCl that included 119 patients.
Disclosures: Zogenix provided funding for the study.
Source: Nabbout R et al. Abstract 3.202.
Addressing Mental Health Needs of Patients with Epilepsy
A community-based program that helps patients with epilepsy self-manage their condition and related psychiatric problems has proven effective in reducing the severity of depression according to a study published in Epilepsy and Behavior.
- Community Targeted Self-Management for Epilepsy and Mental Illness (C-TIME), a behavioral program, consisted of ten 60 to 90-minute sessions conducted over 12 weeks.
- The program included outreach and engagement efforts to help patients suffering from both epilepsy and mental health conditions.
- Thirty patients were enrolled in the program; four months after participating in C-TIME, 66% of the enrolled patients were available for outcome evaluation.
- Researchers reported significant reduction in depression severity, and more than 90% of the group said they were satisfied with results.
Sajatovic M, Needham K, Colón-Zimmermann K, et al. The Community-targeted Self-management of Epilepsy and Mental Illness (C-TIME) initiative: A research, community, and healthcare administration partnership to reduce epilepsy burden [published online ahead of print October 29, 2018]. Epilepsy Behav. https://doi.org/10.1016/j.yebeh.2018.10.004
A community-based program that helps patients with epilepsy self-manage their condition and related psychiatric problems has proven effective in reducing the severity of depression according to a study published in Epilepsy and Behavior.
- Community Targeted Self-Management for Epilepsy and Mental Illness (C-TIME), a behavioral program, consisted of ten 60 to 90-minute sessions conducted over 12 weeks.
- The program included outreach and engagement efforts to help patients suffering from both epilepsy and mental health conditions.
- Thirty patients were enrolled in the program; four months after participating in C-TIME, 66% of the enrolled patients were available for outcome evaluation.
- Researchers reported significant reduction in depression severity, and more than 90% of the group said they were satisfied with results.
Sajatovic M, Needham K, Colón-Zimmermann K, et al. The Community-targeted Self-management of Epilepsy and Mental Illness (C-TIME) initiative: A research, community, and healthcare administration partnership to reduce epilepsy burden [published online ahead of print October 29, 2018]. Epilepsy Behav. https://doi.org/10.1016/j.yebeh.2018.10.004
A community-based program that helps patients with epilepsy self-manage their condition and related psychiatric problems has proven effective in reducing the severity of depression according to a study published in Epilepsy and Behavior.
- Community Targeted Self-Management for Epilepsy and Mental Illness (C-TIME), a behavioral program, consisted of ten 60 to 90-minute sessions conducted over 12 weeks.
- The program included outreach and engagement efforts to help patients suffering from both epilepsy and mental health conditions.
- Thirty patients were enrolled in the program; four months after participating in C-TIME, 66% of the enrolled patients were available for outcome evaluation.
- Researchers reported significant reduction in depression severity, and more than 90% of the group said they were satisfied with results.
Sajatovic M, Needham K, Colón-Zimmermann K, et al. The Community-targeted Self-management of Epilepsy and Mental Illness (C-TIME) initiative: A research, community, and healthcare administration partnership to reduce epilepsy burden [published online ahead of print October 29, 2018]. Epilepsy Behav. https://doi.org/10.1016/j.yebeh.2018.10.004