AES 2014

SEATTLE – Cannabinoid therapy holds promise for the treatment of pediatric epilepsy, but more research is needed to rigorously assess its safety and efficacy, according to experts in the field.

Cannabis contains numerous cannabinoids, including the nonpsychoactive cannabidiol (CBD) and the psychoactive tetrahydrocannabinol (THC).

Two CBD products – an oil-based extract (Epidiolex) and an oral solution (Insys Therapeutics) – have been granted orphan drug status by the Food and Drug Administration for treatment of some forms of epilepsy. In addition, families can obtain artisanal preparations, which may contain a variety of cannabinoids as well as other chemical compounds.

However, use and study of cannabinoids in the United States has been complicated by the federal classification of marijuana as a schedule I controlled substance and the patchwork legal status of medical and recreational use across states.

Investigators reported findings of several clinical studies of cannabinoid therapy in pediatric epilepsy at the annual meeting of the American Epilepsy Society and discussed implications for clinical practice and future research, as well as legal and regulatory status of this therapy.

Benefit may be greatest in Dravet syndrome

Dr. Orrin Devinsky, director of the Comprehensive Epilepsy Center at the NYU Langone Medical Center, and his colleagues undertook a prospective, open-label, multicenter, observational study among pediatric patients with treatment-resistant epilepsy.

In the study, supported in part by GW Pharmaceuticals, 151 patients were treated with Epidiolex, added to their baseline regimen of up to three antiepileptic drugs (AEDs).

Main efficacy analyses based on the 58 patients treated for at least 3 months showed that the median reduction in seizure frequency was about 35% overall and 55% for patients with Dravet syndrome.

The 3-month rate of seizure freedom was 10% overall and 22% in the subset with Dravet syndrome. “These were much higher rates than we would expect, for example, from a placebo response alone,” Dr. Devinsky said in a press briefing.

Data from the 40 patients having longer follow-up, at least 16 weeks, showed that benefit was sustained, indicating that patients did not develop tolerance.

Safety results for all 151 patients showed the most common adverse events were somnolence, seen in 19% of patients, and fatigue, seen in 11%. A single serious adverse event, status epilepticus, was considered possibly related to the CBD. Laboratory measures did not show any noteworthy changes.

“Based on the experience at these five sites, in an open-label, nonrandomized controlled trial ... there is good evidence that the Epidiolex 98% product of CBD is an effective drug for many children with treatment-resistant epilepsy, that the patients with Dravet syndrome appear to be the most responsive ones (but again, this is a relatively small population right now), that the drug overall is quite well tolerated, and most of the side effects when they occur are relatively mild and oftentimes limited,” Dr. Devinsky said.

“The critical take-home message is that these are promising early results, but we need controlled trials to know how to move forward, he said, noting that randomized phase III trials are planned in both patients with Dravet syndrome and patients with Lennox-Gastaut syndrome.

Classifying CBD as schedule I – reserved for drugs having a high danger of abuse, lack of acceptable safety data, and no potential therapeutic benefit – presents hurdles for researchers and doesn’t make sense, according to Dr. Devinsky, who disclosed no relevant conflicts of interest.

“Cannabidiol is approved as part of Sativex, for example, in more than 25 European countries and Canada [for treatment of spasticity due to multiple sclerosis]. So we know it’s got benefit in double-blind studies, so that part ... is wrong. And cannabidiol has been tested extensively in humans. We have adult safety data; this drug’s been on the market,” he explained. So we know it’s wrong to schedule it as schedule I. And it’s not at all clear to many of us why the [Drug Enforcement Agency] is persisting in this scheduling classification.”

Impact on levels of AEDs is unpredictable

Investigators led by Dr. Daniel Friedman, director of both the ICU Epilepsy Monitoring Service and the Epilepsy Consult Service at NYU Langone Medical Center, assessed levels of coadministered AEDs in 57 patients from the above study. He noted that such research is important as preclinical data suggest that CBD inhibits enzymes that metabolize commonly used AEDs.

Results showed that over the first 2 months of CBD therapy, 33% of patients on valproate and 24% of patients on clobazam (Onfi) had their doses reduced because they experienced elevated drug levels or sedation attributed to the drugs, Dr. Friedman reported.

But none of the AEDs showed a consistent pattern of change in levels with the addition of CBD. “Many patients experienced decreases; some experienced increases. But especially for the most common drugs, we found that the ranges were pretty wide,” he said.

Data from five patients showed an average threefold increase in the level of the active metabolite of clobazam, N-desmethylclobazam, without any change in levels of the drug itself, suggesting that the CBD was interfering with clearance of the metabolite.

The findings are not definitive, given that the patients were on multiple medications that can influence levels of each other, stressed Dr. Friedman, who disclosed no relevant conflicts of interest.

“Until formal drug-drug interaction studies are done, we refrain from any specific advice, except for, make sure if your patients are on CBD, whether they are getting it through artisanal preparations or as part of a compassionate use study, that background AEDs are monitored, and if they are on clobazam, make sure to check the N-desmethyl metabolite level as well,” he recommended.

Expectations may influence perceived benefit

Dr. Kevin E. Chapman, associate professor at Children’s Hospital Colorado, Aurora, and his colleagues retrospectively reviewed data of 75 patients who reported using oral cannabis extract.

In Colorado, cannabis is legal for both medical and recreational use. However, patients must become residents, obtain a prescription from two specialized physicians, get a medical marijuana ID card (“red card”), and purchase the product from a dispensary, paying out of pocket, as it is not yet covered by insurance.

“We have had a fairly large influx of patients from out of state ever since medical marijuana became legal in our state,” Dr. Chapman noted in a press briefing. However, neurologists are often reluctant to raise the topic with patients “because of the concerns about the fact that it’s still illegal at the federal level. We worry about our own personal DEA licenses if we were to prescribe the medication.”

But when they learn patients are starting CBD therapy, “our practice is to encourage families not to make dramatic changes to seizure medications because for us, then it becomes hard to know how many of the problems that they have are from the CBD or how much of the benefit is from the CBD.”

On average, patients used their extract for 5.6 months. Overall, 33% had a response, defined as a decrease of more than half in seizure frequency as reported by parents (a rate similar to that seen with placebo). The rate was 0% among those with Doose syndrome, 25% among those with Dravet syndrome, and 89% among those with Lennox-Gastaut syndrome.

But analyses identified only a single predictor of response: moving to the state to obtain the extract. “I think it’s understandable that families have high hopes when they move to Colorado that it’s going to be effective … I don’t know if there is a bit of bias by families really wanting for it to work and that’s part of the reason we saw that,” said Dr. Chapman, who disclosed no relevant conflicts of interest.

A total of 10% of patients who had electroencephalograms (EEGs) both before and after starting extract had improvements in their interictal EEGs. However, none of them were among the group who had a response.

Use of extract was associated with some other benefits: Thirty-three percent of patients reported better alertness and/or behavior, 11% reported better language and motor skills, and 7% reported better sleep.

The most common adverse event was a worsening of seizures, seen in 13% of children, followed by somnolence, seen in 12%, and gastrointestinal symptoms, seen in 11%.

“What our study really sort of shows for us was that we really need a better study, something a little bit more controlled, because there are a lot of different strains that are being used out there, and we were not able to tease out what strain of cannabis worked best in our patient population. People are using CBD strains, THC strains, a combination of things, whereas I think we really need more of a uniform strain or preparation, and then more of a placebo-controlled trial,” Dr. Chapman said.

“At this point I think it’s a bit early to be selling the farm, so to speak, and moving to Colorado,” he concluded. “Right now there’s quite a bit of uncertainty about how effective the medication is. Also, we still have a lot of unknowns about drug interactions, adverse effects of the medication. We have no long-term data because ours is just short-term follow-up data.”

Open communication is critical

Dr. Jeffrey Gold, a pediatric neurologist at Rady Children’s Hospital in San Diego, and his colleagues reported the case of a boy with Doose syndrome whose seizures resolved after initiation of cannabinoid therapy.

“We face somewhat different challenges in California, where recreational marijuana is not legal. Medical marijuana has some acceptance, but it exists in a nebulous legal area,” he noted in the press briefing.

The boy’s seizures were refractory to medical therapy and video EEG features suggested a high risk of progression. His parents opted to try CBD instead of the ketogenic diet, the standard of care in such cases.

“They obtained the product from the local family group, which is challenging for us because we don’t really know what’s in it. We don’t know what the composition is. The family doesn’t know what the composition of the product is,” Dr. Gold said. However, the boy’s mother obtained independent testing, which showed that it was sometimes high in CBD, other times high in THC.

After starting therapy, the boy had apparent worsening of seizures. Testing revealed that his valproic acid level had risen from 115 to 178 mcg/mL, suggesting the CBD was interfering with the drug’s clearance.

The valproic acid dose was lowered, and over a 4-month period, the patient became seizure free. “We obtained another EEG which was completely normal, honestly to our surprise,” reported Dr. Gold, who disclosed no relevant conflicts of interest. “And I don’t know why that was, if that was because he got some extra valproic acid and that tripped a mechanism that set off improvement, or if that’s because of the CBD. Resolution of seizures and normalization of the EEG has been reported before in Doose syndrome and can happen spontaneously or as a result of medication.

“We wanted to get this report out to the community so that they would know, if families choose to start CBD therapy, we strongly advocate that they share that information with their physicians and that physicians manage the other antiseizure treatments the child is receiving,” Dr. Gold said. “We have heard from parents and from other providers that once they told their provider that they were doing CBD, they were told to not come back to the office because they were doing a nonapproved therapy, and we don’t support that. We want families to feel like they can share their treatments with their physicians and receive the help they need because we don’t know what these medications do to other treatments that the patient might be receiving, and it’s imperative that families stay in contact with their physicians.”

Families often tinker with artisanal cannabis products themselves, hoping to find just the right combination, Dr. Gold noted. “It emphasizes both the difficulties of doing the artisanal preparations but more specifically, the difficulties of not doing it scientifically. Science is hard, it’s very difficult, it’s expensive, and it’s time consuming. But it’s the right way to do it. And studies ... that are coming up are the right way to do it,” he maintained.

“So we encourage families to pursue conventional treatment, enroll in clinical trials when they are offered, to get involved with the scientific community as you can, and we will get an answer to these questions. But it is going to take time. We need to do it the right way,” he concluded.

SEATTLE – Cannabinoid therapy holds promise for the treatment of pediatric epilepsy, but more research is needed to rigorously assess its safety and efficacy, according to experts in the field.

Cannabis contains numerous cannabinoids, including the nonpsychoactive cannabidiol (CBD) and the psychoactive tetrahydrocannabinol (THC).

Two CBD products – an oil-based extract (Epidiolex) and an oral solution (Insys Therapeutics) – have been granted orphan drug status by the Food and Drug Administration for treatment of some forms of epilepsy. In addition, families can obtain artisanal preparations, which may contain a variety of cannabinoids as well as other chemical compounds.

However, use and study of cannabinoids in the United States has been complicated by the federal classification of marijuana as a schedule I controlled substance and the patchwork legal status of medical and recreational use across states.

Investigators reported findings of several clinical studies of cannabinoid therapy in pediatric epilepsy at the annual meeting of the American Epilepsy Society and discussed implications for clinical practice and future research, as well as legal and regulatory status of this therapy.

Benefit may be greatest in Dravet syndrome

Dr. Orrin Devinsky, director of the Comprehensive Epilepsy Center at the NYU Langone Medical Center, and his colleagues undertook a prospective, open-label, multicenter, observational study among pediatric patients with treatment-resistant epilepsy.

In the study, supported in part by GW Pharmaceuticals, 151 patients were treated with Epidiolex, added to their baseline regimen of up to three antiepileptic drugs (AEDs).

Main efficacy analyses based on the 58 patients treated for at least 3 months showed that the median reduction in seizure frequency was about 35% overall and 55% for patients with Dravet syndrome.

The 3-month rate of seizure freedom was 10% overall and 22% in the subset with Dravet syndrome. “These were much higher rates than we would expect, for example, from a placebo response alone,” Dr. Devinsky said in a press briefing.

Data from the 40 patients having longer follow-up, at least 16 weeks, showed that benefit was sustained, indicating that patients did not develop tolerance.

Safety results for all 151 patients showed the most common adverse events were somnolence, seen in 19% of patients, and fatigue, seen in 11%. A single serious adverse event, status epilepticus, was considered possibly related to the CBD. Laboratory measures did not show any noteworthy changes.

“Based on the experience at these five sites, in an open-label, nonrandomized controlled trial ... there is good evidence that the Epidiolex 98% product of CBD is an effective drug for many children with treatment-resistant epilepsy, that the patients with Dravet syndrome appear to be the most responsive ones (but again, this is a relatively small population right now), that the drug overall is quite well tolerated, and most of the side effects when they occur are relatively mild and oftentimes limited,” Dr. Devinsky said.

“The critical take-home message is that these are promising early results, but we need controlled trials to know how to move forward, he said, noting that randomized phase III trials are planned in both patients with Dravet syndrome and patients with Lennox-Gastaut syndrome.

Classifying CBD as schedule I – reserved for drugs having a high danger of abuse, lack of acceptable safety data, and no potential therapeutic benefit – presents hurdles for researchers and doesn’t make sense, according to Dr. Devinsky, who disclosed no relevant conflicts of interest.

“Cannabidiol is approved as part of Sativex, for example, in more than 25 European countries and Canada [for treatment of spasticity due to multiple sclerosis]. So we know it’s got benefit in double-blind studies, so that part ... is wrong. And cannabidiol has been tested extensively in humans. We have adult safety data; this drug’s been on the market,” he explained. So we know it’s wrong to schedule it as schedule I. And it’s not at all clear to many of us why the [Drug Enforcement Agency] is persisting in this scheduling classification.”

Impact on levels of AEDs is unpredictable

Investigators led by Dr. Daniel Friedman, director of both the ICU Epilepsy Monitoring Service and the Epilepsy Consult Service at NYU Langone Medical Center, assessed levels of coadministered AEDs in 57 patients from the above study. He noted that such research is important as preclinical data suggest that CBD inhibits enzymes that metabolize commonly used AEDs.

Results showed that over the first 2 months of CBD therapy, 33% of patients on valproate and 24% of patients on clobazam (Onfi) had their doses reduced because they experienced elevated drug levels or sedation attributed to the drugs, Dr. Friedman reported.

But none of the AEDs showed a consistent pattern of change in levels with the addition of CBD. “Many patients experienced decreases; some experienced increases. But especially for the most common drugs, we found that the ranges were pretty wide,” he said.

Data from five patients showed an average threefold increase in the level of the active metabolite of clobazam, N-desmethylclobazam, without any change in levels of the drug itself, suggesting that the CBD was interfering with clearance of the metabolite.

The findings are not definitive, given that the patients were on multiple medications that can influence levels of each other, stressed Dr. Friedman, who disclosed no relevant conflicts of interest.

“Until formal drug-drug interaction studies are done, we refrain from any specific advice, except for, make sure if your patients are on CBD, whether they are getting it through artisanal preparations or as part of a compassionate use study, that background AEDs are monitored, and if they are on clobazam, make sure to check the N-desmethyl metabolite level as well,” he recommended.

Expectations may influence perceived benefit

Dr. Kevin E. Chapman, associate professor at Children’s Hospital Colorado, Aurora, and his colleagues retrospectively reviewed data of 75 patients who reported using oral cannabis extract.

In Colorado, cannabis is legal for both medical and recreational use. However, patients must become residents, obtain a prescription from two specialized physicians, get a medical marijuana ID card (“red card”), and purchase the product from a dispensary, paying out of pocket, as it is not yet covered by insurance.

“We have had a fairly large influx of patients from out of state ever since medical marijuana became legal in our state,” Dr. Chapman noted in a press briefing. However, neurologists are often reluctant to raise the topic with patients “because of the concerns about the fact that it’s still illegal at the federal level. We worry about our own personal DEA licenses if we were to prescribe the medication.”

But when they learn patients are starting CBD therapy, “our practice is to encourage families not to make dramatic changes to seizure medications because for us, then it becomes hard to know how many of the problems that they have are from the CBD or how much of the benefit is from the CBD.”

On average, patients used their extract for 5.6 months. Overall, 33% had a response, defined as a decrease of more than half in seizure frequency as reported by parents (a rate similar to that seen with placebo). The rate was 0% among those with Doose syndrome, 25% among those with Dravet syndrome, and 89% among those with Lennox-Gastaut syndrome.

But analyses identified only a single predictor of response: moving to the state to obtain the extract. “I think it’s understandable that families have high hopes when they move to Colorado that it’s going to be effective … I don’t know if there is a bit of bias by families really wanting for it to work and that’s part of the reason we saw that,” said Dr. Chapman, who disclosed no relevant conflicts of interest.

A total of 10% of patients who had electroencephalograms (EEGs) both before and after starting extract had improvements in their interictal EEGs. However, none of them were among the group who had a response.

Use of extract was associated with some other benefits: Thirty-three percent of patients reported better alertness and/or behavior, 11% reported better language and motor skills, and 7% reported better sleep.

The most common adverse event was a worsening of seizures, seen in 13% of children, followed by somnolence, seen in 12%, and gastrointestinal symptoms, seen in 11%.

“What our study really sort of shows for us was that we really need a better study, something a little bit more controlled, because there are a lot of different strains that are being used out there, and we were not able to tease out what strain of cannabis worked best in our patient population. People are using CBD strains, THC strains, a combination of things, whereas I think we really need more of a uniform strain or preparation, and then more of a placebo-controlled trial,” Dr. Chapman said.

“At this point I think it’s a bit early to be selling the farm, so to speak, and moving to Colorado,” he concluded. “Right now there’s quite a bit of uncertainty about how effective the medication is. Also, we still have a lot of unknowns about drug interactions, adverse effects of the medication. We have no long-term data because ours is just short-term follow-up data.”

Open communication is critical

Dr. Jeffrey Gold, a pediatric neurologist at Rady Children’s Hospital in San Diego, and his colleagues reported the case of a boy with Doose syndrome whose seizures resolved after initiation of cannabinoid therapy.

“We face somewhat different challenges in California, where recreational marijuana is not legal. Medical marijuana has some acceptance, but it exists in a nebulous legal area,” he noted in the press briefing.

The boy’s seizures were refractory to medical therapy and video EEG features suggested a high risk of progression. His parents opted to try CBD instead of the ketogenic diet, the standard of care in such cases.

“They obtained the product from the local family group, which is challenging for us because we don’t really know what’s in it. We don’t know what the composition is. The family doesn’t know what the composition of the product is,” Dr. Gold said. However, the boy’s mother obtained independent testing, which showed that it was sometimes high in CBD, other times high in THC.

After starting therapy, the boy had apparent worsening of seizures. Testing revealed that his valproic acid level had risen from 115 to 178 mcg/mL, suggesting the CBD was interfering with the drug’s clearance.

The valproic acid dose was lowered, and over a 4-month period, the patient became seizure free. “We obtained another EEG which was completely normal, honestly to our surprise,” reported Dr. Gold, who disclosed no relevant conflicts of interest. “And I don’t know why that was, if that was because he got some extra valproic acid and that tripped a mechanism that set off improvement, or if that’s because of the CBD. Resolution of seizures and normalization of the EEG has been reported before in Doose syndrome and can happen spontaneously or as a result of medication.

“We wanted to get this report out to the community so that they would know, if families choose to start CBD therapy, we strongly advocate that they share that information with their physicians and that physicians manage the other antiseizure treatments the child is receiving,” Dr. Gold said. “We have heard from parents and from other providers that once they told their provider that they were doing CBD, they were told to not come back to the office because they were doing a nonapproved therapy, and we don’t support that. We want families to feel like they can share their treatments with their physicians and receive the help they need because we don’t know what these medications do to other treatments that the patient might be receiving, and it’s imperative that families stay in contact with their physicians.”

Families often tinker with artisanal cannabis products themselves, hoping to find just the right combination, Dr. Gold noted. “It emphasizes both the difficulties of doing the artisanal preparations but more specifically, the difficulties of not doing it scientifically. Science is hard, it’s very difficult, it’s expensive, and it’s time consuming. But it’s the right way to do it. And studies ... that are coming up are the right way to do it,” he maintained.

“So we encourage families to pursue conventional treatment, enroll in clinical trials when they are offered, to get involved with the scientific community as you can, and we will get an answer to these questions. But it is going to take time. We need to do it the right way,” he concluded.

SEATTLE – Cannabinoid therapy holds promise for the treatment of pediatric epilepsy, but more research is needed to rigorously assess its safety and efficacy, according to experts in the field.

Cannabis contains numerous cannabinoids, including the nonpsychoactive cannabidiol (CBD) and the psychoactive tetrahydrocannabinol (THC).

Two CBD products – an oil-based extract (Epidiolex) and an oral solution (Insys Therapeutics) – have been granted orphan drug status by the Food and Drug Administration for treatment of some forms of epilepsy. In addition, families can obtain artisanal preparations, which may contain a variety of cannabinoids as well as other chemical compounds.

However, use and study of cannabinoids in the United States has been complicated by the federal classification of marijuana as a schedule I controlled substance and the patchwork legal status of medical and recreational use across states.

Investigators reported findings of several clinical studies of cannabinoid therapy in pediatric epilepsy at the annual meeting of the American Epilepsy Society and discussed implications for clinical practice and future research, as well as legal and regulatory status of this therapy.

Benefit may be greatest in Dravet syndrome

Dr. Orrin Devinsky, director of the Comprehensive Epilepsy Center at the NYU Langone Medical Center, and his colleagues undertook a prospective, open-label, multicenter, observational study among pediatric patients with treatment-resistant epilepsy.

In the study, supported in part by GW Pharmaceuticals, 151 patients were treated with Epidiolex, added to their baseline regimen of up to three antiepileptic drugs (AEDs).

Main efficacy analyses based on the 58 patients treated for at least 3 months showed that the median reduction in seizure frequency was about 35% overall and 55% for patients with Dravet syndrome.

The 3-month rate of seizure freedom was 10% overall and 22% in the subset with Dravet syndrome. “These were much higher rates than we would expect, for example, from a placebo response alone,” Dr. Devinsky said in a press briefing.

Data from the 40 patients having longer follow-up, at least 16 weeks, showed that benefit was sustained, indicating that patients did not develop tolerance.

Safety results for all 151 patients showed the most common adverse events were somnolence, seen in 19% of patients, and fatigue, seen in 11%. A single serious adverse event, status epilepticus, was considered possibly related to the CBD. Laboratory measures did not show any noteworthy changes.

“Based on the experience at these five sites, in an open-label, nonrandomized controlled trial ... there is good evidence that the Epidiolex 98% product of CBD is an effective drug for many children with treatment-resistant epilepsy, that the patients with Dravet syndrome appear to be the most responsive ones (but again, this is a relatively small population right now), that the drug overall is quite well tolerated, and most of the side effects when they occur are relatively mild and oftentimes limited,” Dr. Devinsky said.

“The critical take-home message is that these are promising early results, but we need controlled trials to know how to move forward, he said, noting that randomized phase III trials are planned in both patients with Dravet syndrome and patients with Lennox-Gastaut syndrome.

Classifying CBD as schedule I – reserved for drugs having a high danger of abuse, lack of acceptable safety data, and no potential therapeutic benefit – presents hurdles for researchers and doesn’t make sense, according to Dr. Devinsky, who disclosed no relevant conflicts of interest.

“Cannabidiol is approved as part of Sativex, for example, in more than 25 European countries and Canada [for treatment of spasticity due to multiple sclerosis]. So we know it’s got benefit in double-blind studies, so that part ... is wrong. And cannabidiol has been tested extensively in humans. We have adult safety data; this drug’s been on the market,” he explained. So we know it’s wrong to schedule it as schedule I. And it’s not at all clear to many of us why the [Drug Enforcement Agency] is persisting in this scheduling classification.”

Impact on levels of AEDs is unpredictable

Investigators led by Dr. Daniel Friedman, director of both the ICU Epilepsy Monitoring Service and the Epilepsy Consult Service at NYU Langone Medical Center, assessed levels of coadministered AEDs in 57 patients from the above study. He noted that such research is important as preclinical data suggest that CBD inhibits enzymes that metabolize commonly used AEDs.

Results showed that over the first 2 months of CBD therapy, 33% of patients on valproate and 24% of patients on clobazam (Onfi) had their doses reduced because they experienced elevated drug levels or sedation attributed to the drugs, Dr. Friedman reported.

But none of the AEDs showed a consistent pattern of change in levels with the addition of CBD. “Many patients experienced decreases; some experienced increases. But especially for the most common drugs, we found that the ranges were pretty wide,” he said.

Data from five patients showed an average threefold increase in the level of the active metabolite of clobazam, N-desmethylclobazam, without any change in levels of the drug itself, suggesting that the CBD was interfering with clearance of the metabolite.

The findings are not definitive, given that the patients were on multiple medications that can influence levels of each other, stressed Dr. Friedman, who disclosed no relevant conflicts of interest.

“Until formal drug-drug interaction studies are done, we refrain from any specific advice, except for, make sure if your patients are on CBD, whether they are getting it through artisanal preparations or as part of a compassionate use study, that background AEDs are monitored, and if they are on clobazam, make sure to check the N-desmethyl metabolite level as well,” he recommended.

Expectations may influence perceived benefit

Dr. Kevin E. Chapman, associate professor at Children’s Hospital Colorado, Aurora, and his colleagues retrospectively reviewed data of 75 patients who reported using oral cannabis extract.

In Colorado, cannabis is legal for both medical and recreational use. However, patients must become residents, obtain a prescription from two specialized physicians, get a medical marijuana ID card (“red card”), and purchase the product from a dispensary, paying out of pocket, as it is not yet covered by insurance.

“We have had a fairly large influx of patients from out of state ever since medical marijuana became legal in our state,” Dr. Chapman noted in a press briefing. However, neurologists are often reluctant to raise the topic with patients “because of the concerns about the fact that it’s still illegal at the federal level. We worry about our own personal DEA licenses if we were to prescribe the medication.”

But when they learn patients are starting CBD therapy, “our practice is to encourage families not to make dramatic changes to seizure medications because for us, then it becomes hard to know how many of the problems that they have are from the CBD or how much of the benefit is from the CBD.”

On average, patients used their extract for 5.6 months. Overall, 33% had a response, defined as a decrease of more than half in seizure frequency as reported by parents (a rate similar to that seen with placebo). The rate was 0% among those with Doose syndrome, 25% among those with Dravet syndrome, and 89% among those with Lennox-Gastaut syndrome.

But analyses identified only a single predictor of response: moving to the state to obtain the extract. “I think it’s understandable that families have high hopes when they move to Colorado that it’s going to be effective … I don’t know if there is a bit of bias by families really wanting for it to work and that’s part of the reason we saw that,” said Dr. Chapman, who disclosed no relevant conflicts of interest.

A total of 10% of patients who had electroencephalograms (EEGs) both before and after starting extract had improvements in their interictal EEGs. However, none of them were among the group who had a response.

Use of extract was associated with some other benefits: Thirty-three percent of patients reported better alertness and/or behavior, 11% reported better language and motor skills, and 7% reported better sleep.

The most common adverse event was a worsening of seizures, seen in 13% of children, followed by somnolence, seen in 12%, and gastrointestinal symptoms, seen in 11%.

“What our study really sort of shows for us was that we really need a better study, something a little bit more controlled, because there are a lot of different strains that are being used out there, and we were not able to tease out what strain of cannabis worked best in our patient population. People are using CBD strains, THC strains, a combination of things, whereas I think we really need more of a uniform strain or preparation, and then more of a placebo-controlled trial,” Dr. Chapman said.

“At this point I think it’s a bit early to be selling the farm, so to speak, and moving to Colorado,” he concluded. “Right now there’s quite a bit of uncertainty about how effective the medication is. Also, we still have a lot of unknowns about drug interactions, adverse effects of the medication. We have no long-term data because ours is just short-term follow-up data.”

Open communication is critical

Dr. Jeffrey Gold, a pediatric neurologist at Rady Children’s Hospital in San Diego, and his colleagues reported the case of a boy with Doose syndrome whose seizures resolved after initiation of cannabinoid therapy.

“We face somewhat different challenges in California, where recreational marijuana is not legal. Medical marijuana has some acceptance, but it exists in a nebulous legal area,” he noted in the press briefing.

The boy’s seizures were refractory to medical therapy and video EEG features suggested a high risk of progression. His parents opted to try CBD instead of the ketogenic diet, the standard of care in such cases.

“They obtained the product from the local family group, which is challenging for us because we don’t really know what’s in it. We don’t know what the composition is. The family doesn’t know what the composition of the product is,” Dr. Gold said. However, the boy’s mother obtained independent testing, which showed that it was sometimes high in CBD, other times high in THC.

After starting therapy, the boy had apparent worsening of seizures. Testing revealed that his valproic acid level had risen from 115 to 178 mcg/mL, suggesting the CBD was interfering with the drug’s clearance.

The valproic acid dose was lowered, and over a 4-month period, the patient became seizure free. “We obtained another EEG which was completely normal, honestly to our surprise,” reported Dr. Gold, who disclosed no relevant conflicts of interest. “And I don’t know why that was, if that was because he got some extra valproic acid and that tripped a mechanism that set off improvement, or if that’s because of the CBD. Resolution of seizures and normalization of the EEG has been reported before in Doose syndrome and can happen spontaneously or as a result of medication.

“We wanted to get this report out to the community so that they would know, if families choose to start CBD therapy, we strongly advocate that they share that information with their physicians and that physicians manage the other antiseizure treatments the child is receiving,” Dr. Gold said. “We have heard from parents and from other providers that once they told their provider that they were doing CBD, they were told to not come back to the office because they were doing a nonapproved therapy, and we don’t support that. We want families to feel like they can share their treatments with their physicians and receive the help they need because we don’t know what these medications do to other treatments that the patient might be receiving, and it’s imperative that families stay in contact with their physicians.”

Families often tinker with artisanal cannabis products themselves, hoping to find just the right combination, Dr. Gold noted. “It emphasizes both the difficulties of doing the artisanal preparations but more specifically, the difficulties of not doing it scientifically. Science is hard, it’s very difficult, it’s expensive, and it’s time consuming. But it’s the right way to do it. And studies ... that are coming up are the right way to do it,” he maintained.

“So we encourage families to pursue conventional treatment, enroll in clinical trials when they are offered, to get involved with the scientific community as you can, and we will get an answer to these questions. But it is going to take time. We need to do it the right way,” he concluded.

SEATTLE – UCB will likely submit brivaracetam – its follow-up to levetiracetam – to the Food and Drug Administration for approval in the not-so-distant future.

Brivaracetam is a molecular analog of levetiracetam (Keppra), a widely used epilepsy drug that’s now available as a generic. The company has reported that it binds synaptic vesicle protein 2A with greater affinity than does levetiracetam, which suggests greater potency. However, phase III testing compared brivaracetam to placebo, so it’s unclear if the analog has advantages over the older drug, according to Dr. Pavel Klein, an epileptologist and director of the Mid-Atlantic Epilepsy and Sleep Center in Bethesda, Md.

“Levetiracetam is a great medication, but its psychiatric side effects,” which can include aggression, depression, and even psychosis, are “limiting. If brivaracetam turns out to be a friendlier version of levetiracetam, that would be helpful, but we don’t know that yet,” he said at the annual meeting of the American Epilepsy Society.

Dr. Klein was the principal investigator on brivaracetam’s final phase III trial, and he presented the results at the meeting. With testing complete, UCB said it plans to submit brivaracetam to the FDA in early 2015.

His study randomized 768 adult patients with refractory partial onset seizures to placebo or 100 or 200 mg/day brivaracetam by mouth for 12 weeks as an adjunct; the subjects were also taking one or two other antiepileptic drugs, although not levetiracetam; the trial excluded patients taking levetiracetam and those who had taken it within 3 months. The study group was about 40 years old on average, and evenly split between men and women.

Brivaracetam 100 mg/day reduced 28-day adjusted seizure frequency by 22.8% over placebo, and 200 mg/day reduced it 23.2% over placebo. The responder rate – a reduction of at least 50% in seizure frequency – was 21.6% for placebo, 38.9% for brivaracetam 100 mg, and 37.8% for brivaracetam 200 mg. About 4.5% of brivaracetam patients went the entire 12 weeks without a seizure, versus less than 1% in the placebo group.

“Efficacy was seen in both levetiracetam-naive patients and patients previously exposed to levetiracetam, but there wasn’t really any significant difference in efficacy between the 100- and 200-mg doses. Neither was superior,” Dr. Klein said.

The efficacy outcomes are comparable to levetiracetam’s phase III results against placebo, as described in the older drug’s FDA labeling. However, brivaracetam seems to help some patients at a smaller dose, which is a potential selling point for UCB.

The study dropout rate was 6.5% for placebo patients and about 11% in the brivaracetam group. About two-thirds of brivaracetam patients reported side effects, most commonly – and also similar to levetiracetam – somnolence, dizziness, and fatigue.

Self-reported “irritability occurred relatively little” in the study, perhaps in about 2% of brivaracetam patients and 1% of the placebo group. Postmarketing data shows that irritability occurs in “somewhere around 10%” of levetiracetam patients, Dr. Klein said.

The earlier phase III trials also compared brivaracetam against placebo as an adjunct, but mostly at smaller doses; the results for 100 and 200 mg tended to be more robust.

UCB funded the work. Dr. Klein said he investigated the drug on the company’s behalf. He is also a speaker and adviser for UCB.

aotto@frontlinemedcom.com

SEATTLE – UCB will likely submit brivaracetam – its follow-up to levetiracetam – to the Food and Drug Administration for approval in the not-so-distant future.

Brivaracetam is a molecular analog of levetiracetam (Keppra), a widely used epilepsy drug that’s now available as a generic. The company has reported that it binds synaptic vesicle protein 2A with greater affinity than does levetiracetam, which suggests greater potency. However, phase III testing compared brivaracetam to placebo, so it’s unclear if the analog has advantages over the older drug, according to Dr. Pavel Klein, an epileptologist and director of the Mid-Atlantic Epilepsy and Sleep Center in Bethesda, Md.

“Levetiracetam is a great medication, but its psychiatric side effects,” which can include aggression, depression, and even psychosis, are “limiting. If brivaracetam turns out to be a friendlier version of levetiracetam, that would be helpful, but we don’t know that yet,” he said at the annual meeting of the American Epilepsy Society.

Dr. Klein was the principal investigator on brivaracetam’s final phase III trial, and he presented the results at the meeting. With testing complete, UCB said it plans to submit brivaracetam to the FDA in early 2015.

His study randomized 768 adult patients with refractory partial onset seizures to placebo or 100 or 200 mg/day brivaracetam by mouth for 12 weeks as an adjunct; the subjects were also taking one or two other antiepileptic drugs, although not levetiracetam; the trial excluded patients taking levetiracetam and those who had taken it within 3 months. The study group was about 40 years old on average, and evenly split between men and women.

Brivaracetam 100 mg/day reduced 28-day adjusted seizure frequency by 22.8% over placebo, and 200 mg/day reduced it 23.2% over placebo. The responder rate – a reduction of at least 50% in seizure frequency – was 21.6% for placebo, 38.9% for brivaracetam 100 mg, and 37.8% for brivaracetam 200 mg. About 4.5% of brivaracetam patients went the entire 12 weeks without a seizure, versus less than 1% in the placebo group.

“Efficacy was seen in both levetiracetam-naive patients and patients previously exposed to levetiracetam, but there wasn’t really any significant difference in efficacy between the 100- and 200-mg doses. Neither was superior,” Dr. Klein said.

The efficacy outcomes are comparable to levetiracetam’s phase III results against placebo, as described in the older drug’s FDA labeling. However, brivaracetam seems to help some patients at a smaller dose, which is a potential selling point for UCB.

The study dropout rate was 6.5% for placebo patients and about 11% in the brivaracetam group. About two-thirds of brivaracetam patients reported side effects, most commonly – and also similar to levetiracetam – somnolence, dizziness, and fatigue.

Self-reported “irritability occurred relatively little” in the study, perhaps in about 2% of brivaracetam patients and 1% of the placebo group. Postmarketing data shows that irritability occurs in “somewhere around 10%” of levetiracetam patients, Dr. Klein said.

The earlier phase III trials also compared brivaracetam against placebo as an adjunct, but mostly at smaller doses; the results for 100 and 200 mg tended to be more robust.

UCB funded the work. Dr. Klein said he investigated the drug on the company’s behalf. He is also a speaker and adviser for UCB.

aotto@frontlinemedcom.com

SEATTLE – UCB will likely submit brivaracetam – its follow-up to levetiracetam – to the Food and Drug Administration for approval in the not-so-distant future.

Brivaracetam is a molecular analog of levetiracetam (Keppra), a widely used epilepsy drug that’s now available as a generic. The company has reported that it binds synaptic vesicle protein 2A with greater affinity than does levetiracetam, which suggests greater potency. However, phase III testing compared brivaracetam to placebo, so it’s unclear if the analog has advantages over the older drug, according to Dr. Pavel Klein, an epileptologist and director of the Mid-Atlantic Epilepsy and Sleep Center in Bethesda, Md.

“Levetiracetam is a great medication, but its psychiatric side effects,” which can include aggression, depression, and even psychosis, are “limiting. If brivaracetam turns out to be a friendlier version of levetiracetam, that would be helpful, but we don’t know that yet,” he said at the annual meeting of the American Epilepsy Society.

Dr. Klein was the principal investigator on brivaracetam’s final phase III trial, and he presented the results at the meeting. With testing complete, UCB said it plans to submit brivaracetam to the FDA in early 2015.

His study randomized 768 adult patients with refractory partial onset seizures to placebo or 100 or 200 mg/day brivaracetam by mouth for 12 weeks as an adjunct; the subjects were also taking one or two other antiepileptic drugs, although not levetiracetam; the trial excluded patients taking levetiracetam and those who had taken it within 3 months. The study group was about 40 years old on average, and evenly split between men and women.

Brivaracetam 100 mg/day reduced 28-day adjusted seizure frequency by 22.8% over placebo, and 200 mg/day reduced it 23.2% over placebo. The responder rate – a reduction of at least 50% in seizure frequency – was 21.6% for placebo, 38.9% for brivaracetam 100 mg, and 37.8% for brivaracetam 200 mg. About 4.5% of brivaracetam patients went the entire 12 weeks without a seizure, versus less than 1% in the placebo group.

“Efficacy was seen in both levetiracetam-naive patients and patients previously exposed to levetiracetam, but there wasn’t really any significant difference in efficacy between the 100- and 200-mg doses. Neither was superior,” Dr. Klein said.

The efficacy outcomes are comparable to levetiracetam’s phase III results against placebo, as described in the older drug’s FDA labeling. However, brivaracetam seems to help some patients at a smaller dose, which is a potential selling point for UCB.

The study dropout rate was 6.5% for placebo patients and about 11% in the brivaracetam group. About two-thirds of brivaracetam patients reported side effects, most commonly – and also similar to levetiracetam – somnolence, dizziness, and fatigue.

Self-reported “irritability occurred relatively little” in the study, perhaps in about 2% of brivaracetam patients and 1% of the placebo group. Postmarketing data shows that irritability occurs in “somewhere around 10%” of levetiracetam patients, Dr. Klein said.

The earlier phase III trials also compared brivaracetam against placebo as an adjunct, but mostly at smaller doses; the results for 100 and 200 mg tended to be more robust.

UCB funded the work. Dr. Klein said he investigated the drug on the company’s behalf. He is also a speaker and adviser for UCB.

aotto@frontlinemedcom.com

SEATTLE – Pediatric epileptologists require a longer seizure-free duration when it comes to a second attempt at discontinuing antiepileptic drugs (AEDs) in epileptic children after a failed first attempt, new data show.

Researchers conducted a survey by e-mail of 94 U.S. and Canadian pediatric epileptologists in 2014, asking about their usual approach to weaning patients off AEDs. Additionally, they presented the epileptologists with real-life cases in which discontinuation of AEDs might be more difficult.

Michele G. Sullivan/Frontline Medical News

Main results reported in a poster session at the annual meeting of the American Epilepsy Society showed that a majority of epileptologists required that children have a seizure-free period of 2-3 years before a first attempt at discontinuation (62%) and before a second attempt at discontinuation (62%), although there was considerable variability.

Overall, there was a shift toward a longer required seizure-free period going from a first to a second attempt: the proportion of epileptologists requiring less than 2 years fell from 38% to 21%, while the proportion requiring 3 or more years rose from 0% to 17%.

This shift was greater among those who were more experienced, defined as having practiced pediatric epilepsy for at least 10 years after finishing their fellowship: 56% of these more experienced epileptologists required a longer duration the second time, compared with 26% of less experienced epileptologists.

“There is a lot of disagreement how people do this [discontinue AEDs on the second attempt],” presenting researcher Dr. Ignacio Valencia, an attending neurologist and associate professor of pediatrics at St. Christopher’s Hospital for Children, Philadelphia, commented in an interview. “Epileptologists in general are more cautious the second time, and even more so the people who have more experience compared to the less experienced.”

“There are no guidelines or statements from the American Epilepsy Society about how to wean down the second time,” he added. The next step will be to analyze the characteristics of second attempts and patients outcomes. “Then we could try to make a consensus statement from one of the epilepsy societies, like a recommendation for people who treat children with epilepsy, how to do it the second time.”

The more experienced epileptologists likely wait longer because “they have just been burned before. They know for a fact that when they wean down earlier, the kids have a seizure again. They have been burned and then they are probably more cautious and conservative the second time,” speculated Dr. Valencia, who disclosed that he had no relevant conflicts of interest.

Overall, the epileptologists ordered more electroencephalograms and more anti-epileptic drug (AED) levels (but not more MRIs) with a second attempt as well. And they tapered the drugs more slowly.

Comparing attempts, epileptologists had a shift in perspective, viewing all of a variety of factors, syndromes, and etiologies (e.g., polytherapy, age younger than 2 at seizure onset, and focal seizures) as more unfavorable to AED discontinuation the second time around.

For example, “benign Rolandic epilepsy is still viewed as a favorable factor, but it moves down from the first attempt to the second attempt, making it a little less favorable the second time,” Dr. Valencia noted.

Dr. Valencia disclosed that he had no relevant conflicts of interest.

SEATTLE – Pediatric epileptologists require a longer seizure-free duration when it comes to a second attempt at discontinuing antiepileptic drugs (AEDs) in epileptic children after a failed first attempt, new data show.

Researchers conducted a survey by e-mail of 94 U.S. and Canadian pediatric epileptologists in 2014, asking about their usual approach to weaning patients off AEDs. Additionally, they presented the epileptologists with real-life cases in which discontinuation of AEDs might be more difficult.

Michele G. Sullivan/Frontline Medical News

Main results reported in a poster session at the annual meeting of the American Epilepsy Society showed that a majority of epileptologists required that children have a seizure-free period of 2-3 years before a first attempt at discontinuation (62%) and before a second attempt at discontinuation (62%), although there was considerable variability.

Overall, there was a shift toward a longer required seizure-free period going from a first to a second attempt: the proportion of epileptologists requiring less than 2 years fell from 38% to 21%, while the proportion requiring 3 or more years rose from 0% to 17%.

This shift was greater among those who were more experienced, defined as having practiced pediatric epilepsy for at least 10 years after finishing their fellowship: 56% of these more experienced epileptologists required a longer duration the second time, compared with 26% of less experienced epileptologists.

“There is a lot of disagreement how people do this [discontinue AEDs on the second attempt],” presenting researcher Dr. Ignacio Valencia, an attending neurologist and associate professor of pediatrics at St. Christopher’s Hospital for Children, Philadelphia, commented in an interview. “Epileptologists in general are more cautious the second time, and even more so the people who have more experience compared to the less experienced.”

“There are no guidelines or statements from the American Epilepsy Society about how to wean down the second time,” he added. The next step will be to analyze the characteristics of second attempts and patients outcomes. “Then we could try to make a consensus statement from one of the epilepsy societies, like a recommendation for people who treat children with epilepsy, how to do it the second time.”

The more experienced epileptologists likely wait longer because “they have just been burned before. They know for a fact that when they wean down earlier, the kids have a seizure again. They have been burned and then they are probably more cautious and conservative the second time,” speculated Dr. Valencia, who disclosed that he had no relevant conflicts of interest.

Overall, the epileptologists ordered more electroencephalograms and more anti-epileptic drug (AED) levels (but not more MRIs) with a second attempt as well. And they tapered the drugs more slowly.

Comparing attempts, epileptologists had a shift in perspective, viewing all of a variety of factors, syndromes, and etiologies (e.g., polytherapy, age younger than 2 at seizure onset, and focal seizures) as more unfavorable to AED discontinuation the second time around.

For example, “benign Rolandic epilepsy is still viewed as a favorable factor, but it moves down from the first attempt to the second attempt, making it a little less favorable the second time,” Dr. Valencia noted.

Dr. Valencia disclosed that he had no relevant conflicts of interest.

SEATTLE – Pediatric epileptologists require a longer seizure-free duration when it comes to a second attempt at discontinuing antiepileptic drugs (AEDs) in epileptic children after a failed first attempt, new data show.

Researchers conducted a survey by e-mail of 94 U.S. and Canadian pediatric epileptologists in 2014, asking about their usual approach to weaning patients off AEDs. Additionally, they presented the epileptologists with real-life cases in which discontinuation of AEDs might be more difficult.

Michele G. Sullivan/Frontline Medical News

Main results reported in a poster session at the annual meeting of the American Epilepsy Society showed that a majority of epileptologists required that children have a seizure-free period of 2-3 years before a first attempt at discontinuation (62%) and before a second attempt at discontinuation (62%), although there was considerable variability.

Overall, there was a shift toward a longer required seizure-free period going from a first to a second attempt: the proportion of epileptologists requiring less than 2 years fell from 38% to 21%, while the proportion requiring 3 or more years rose from 0% to 17%.

This shift was greater among those who were more experienced, defined as having practiced pediatric epilepsy for at least 10 years after finishing their fellowship: 56% of these more experienced epileptologists required a longer duration the second time, compared with 26% of less experienced epileptologists.

“There is a lot of disagreement how people do this [discontinue AEDs on the second attempt],” presenting researcher Dr. Ignacio Valencia, an attending neurologist and associate professor of pediatrics at St. Christopher’s Hospital for Children, Philadelphia, commented in an interview. “Epileptologists in general are more cautious the second time, and even more so the people who have more experience compared to the less experienced.”

“There are no guidelines or statements from the American Epilepsy Society about how to wean down the second time,” he added. The next step will be to analyze the characteristics of second attempts and patients outcomes. “Then we could try to make a consensus statement from one of the epilepsy societies, like a recommendation for people who treat children with epilepsy, how to do it the second time.”

The more experienced epileptologists likely wait longer because “they have just been burned before. They know for a fact that when they wean down earlier, the kids have a seizure again. They have been burned and then they are probably more cautious and conservative the second time,” speculated Dr. Valencia, who disclosed that he had no relevant conflicts of interest.

Overall, the epileptologists ordered more electroencephalograms and more anti-epileptic drug (AED) levels (but not more MRIs) with a second attempt as well. And they tapered the drugs more slowly.

Comparing attempts, epileptologists had a shift in perspective, viewing all of a variety of factors, syndromes, and etiologies (e.g., polytherapy, age younger than 2 at seizure onset, and focal seizures) as more unfavorable to AED discontinuation the second time around.

For example, “benign Rolandic epilepsy is still viewed as a favorable factor, but it moves down from the first attempt to the second attempt, making it a little less favorable the second time,” Dr. Valencia noted.

Dr. Valencia disclosed that he had no relevant conflicts of interest.

SEATTLE - It is unclear whether drivers with epilepsy have an elevated risk of motor vehicle accidents (MVAs), according to a systematic review reported at the annual meeting of the American Epilepsy Society. And conditions such as diabetes and cardiac problems appear riskier than epilepsy.

“Driving and epilepsy is an extremely controversial topic where we do have rules and regulations in place around the country, but they are really not based on any evidence, they are just based basically based on what the state legislature decides,” lead investigator Dr. Puja Naik commented in an interview.

“People walk around preaching about not driving for a year, not driving for 6 months [after the last seizure] for state regulations, but we don’t have anything that shows why they should or shouldn’t. It’s really important for the patient because quality of life can suffer from not being able to drive,” she added.

Susan London/Frontline Medical News

To determine whether the evidence supports driving restrictions, Dr. Naik and her colleagues systematically reviewed eight studies assessing the risk of MVAs among individuals with epilepsy. As classified according to American Academy of Neurology criteria, one study had class I (highest-quality) evidence, six had class II evidence, and one had class III evidence.

Results reported in a poster session showed that the relative risk of MVAs comparing drivers who did versus did not have epilepsy ranged from about 0.86 to 7.01 across the studies. The studies differed with respect to methods of MVA ascertainment, sample sizes, study durations, denominators used, and specific outcomes, noted Dr. Naik, who is a clinical neurophysiology fellow at the Hofstra North Shore–LIJ School of Medicine in Manhasset, N.Y.

Overall, two of the studies found trends toward a decreased rate of MVAs among drivers with epilepsy, but both used self-reports. “If it’s self-reported, then how objective can the evidence be, because patients may not want to identify themselves as having accidents on the road because then that will restrict their driving,” she commented. Three studies found an increased risk for epileptic drivers.

“It’s really important to have the appropriate methodology,” Dr. Naik asserted, endorsing use of a rigorous measure of driving exposure (such as the actual number of miles driven instead of the holding of a driver’s license or simple person-year of time) and a rigorous measure of MVAs (such as emergency department records giving International Classification of Diseases codes).

In other results of note, one study found that seizure-related crashes were rare, accounting for just 1 in every 2,800 MVAs (Mayo Clin. Proc. 2003;78:819-25). And another found that the rate of fatal crashes due to alcohol and alcoholism was 156 times higher and the rate due to conditions such as diabetes or cardiac disease was 26 times than that due to epilepsy (Neurology 2004;63:1002-7).

The investigators did not assess antiepileptic drug use or compliance, acknowledged Dr. Naik, who disclosed that she had no relevant conflicts of interest. “We were looking simply for the history of epilepsy or having an epilepsy disorder and whether or not it increases your risk, and we couldn’t conclude…in one particular way or the other based on this information,” she said.

SEATTLE - It is unclear whether drivers with epilepsy have an elevated risk of motor vehicle accidents (MVAs), according to a systematic review reported at the annual meeting of the American Epilepsy Society. And conditions such as diabetes and cardiac problems appear riskier than epilepsy.

“Driving and epilepsy is an extremely controversial topic where we do have rules and regulations in place around the country, but they are really not based on any evidence, they are just based basically based on what the state legislature decides,” lead investigator Dr. Puja Naik commented in an interview.

“People walk around preaching about not driving for a year, not driving for 6 months [after the last seizure] for state regulations, but we don’t have anything that shows why they should or shouldn’t. It’s really important for the patient because quality of life can suffer from not being able to drive,” she added.

Susan London/Frontline Medical News

To determine whether the evidence supports driving restrictions, Dr. Naik and her colleagues systematically reviewed eight studies assessing the risk of MVAs among individuals with epilepsy. As classified according to American Academy of Neurology criteria, one study had class I (highest-quality) evidence, six had class II evidence, and one had class III evidence.

Results reported in a poster session showed that the relative risk of MVAs comparing drivers who did versus did not have epilepsy ranged from about 0.86 to 7.01 across the studies. The studies differed with respect to methods of MVA ascertainment, sample sizes, study durations, denominators used, and specific outcomes, noted Dr. Naik, who is a clinical neurophysiology fellow at the Hofstra North Shore–LIJ School of Medicine in Manhasset, N.Y.

Overall, two of the studies found trends toward a decreased rate of MVAs among drivers with epilepsy, but both used self-reports. “If it’s self-reported, then how objective can the evidence be, because patients may not want to identify themselves as having accidents on the road because then that will restrict their driving,” she commented. Three studies found an increased risk for epileptic drivers.

“It’s really important to have the appropriate methodology,” Dr. Naik asserted, endorsing use of a rigorous measure of driving exposure (such as the actual number of miles driven instead of the holding of a driver’s license or simple person-year of time) and a rigorous measure of MVAs (such as emergency department records giving International Classification of Diseases codes).

In other results of note, one study found that seizure-related crashes were rare, accounting for just 1 in every 2,800 MVAs (Mayo Clin. Proc. 2003;78:819-25). And another found that the rate of fatal crashes due to alcohol and alcoholism was 156 times higher and the rate due to conditions such as diabetes or cardiac disease was 26 times than that due to epilepsy (Neurology 2004;63:1002-7).

The investigators did not assess antiepileptic drug use or compliance, acknowledged Dr. Naik, who disclosed that she had no relevant conflicts of interest. “We were looking simply for the history of epilepsy or having an epilepsy disorder and whether or not it increases your risk, and we couldn’t conclude…in one particular way or the other based on this information,” she said.

SEATTLE - It is unclear whether drivers with epilepsy have an elevated risk of motor vehicle accidents (MVAs), according to a systematic review reported at the annual meeting of the American Epilepsy Society. And conditions such as diabetes and cardiac problems appear riskier than epilepsy.

“Driving and epilepsy is an extremely controversial topic where we do have rules and regulations in place around the country, but they are really not based on any evidence, they are just based basically based on what the state legislature decides,” lead investigator Dr. Puja Naik commented in an interview.

“People walk around preaching about not driving for a year, not driving for 6 months [after the last seizure] for state regulations, but we don’t have anything that shows why they should or shouldn’t. It’s really important for the patient because quality of life can suffer from not being able to drive,” she added.

Susan London/Frontline Medical News

To determine whether the evidence supports driving restrictions, Dr. Naik and her colleagues systematically reviewed eight studies assessing the risk of MVAs among individuals with epilepsy. As classified according to American Academy of Neurology criteria, one study had class I (highest-quality) evidence, six had class II evidence, and one had class III evidence.

Results reported in a poster session showed that the relative risk of MVAs comparing drivers who did versus did not have epilepsy ranged from about 0.86 to 7.01 across the studies. The studies differed with respect to methods of MVA ascertainment, sample sizes, study durations, denominators used, and specific outcomes, noted Dr. Naik, who is a clinical neurophysiology fellow at the Hofstra North Shore–LIJ School of Medicine in Manhasset, N.Y.

Overall, two of the studies found trends toward a decreased rate of MVAs among drivers with epilepsy, but both used self-reports. “If it’s self-reported, then how objective can the evidence be, because patients may not want to identify themselves as having accidents on the road because then that will restrict their driving,” she commented. Three studies found an increased risk for epileptic drivers.

“It’s really important to have the appropriate methodology,” Dr. Naik asserted, endorsing use of a rigorous measure of driving exposure (such as the actual number of miles driven instead of the holding of a driver’s license or simple person-year of time) and a rigorous measure of MVAs (such as emergency department records giving International Classification of Diseases codes).

In other results of note, one study found that seizure-related crashes were rare, accounting for just 1 in every 2,800 MVAs (Mayo Clin. Proc. 2003;78:819-25). And another found that the rate of fatal crashes due to alcohol and alcoholism was 156 times higher and the rate due to conditions such as diabetes or cardiac disease was 26 times than that due to epilepsy (Neurology 2004;63:1002-7).

The investigators did not assess antiepileptic drug use or compliance, acknowledged Dr. Naik, who disclosed that she had no relevant conflicts of interest. “We were looking simply for the history of epilepsy or having an epilepsy disorder and whether or not it increases your risk, and we couldn’t conclude…in one particular way or the other based on this information,” she said.

SEATTLE – Adults want to know about the risk of sudden death when they are diagnosed with epilepsy, or shortly thereafter, and they want to hear the news face-to-face from their diagnosing neurologist, according to surveys of 23 epilepsy patients at McMaster University in Hamilton, Ont.

Doctors often struggle about how – or even if – to explain Sudden Unexpected Death in Epilepsy (SUDEP) to patients because the risk of SUDEP is small – perhaps 1 in 1,000 per year overall – but the potential for unwarranted anxiety about sudden death is large. There’s concern that patients will obsess about SUDEP and forget everything they hear about epilepsy management.

Instead of trying to guess what patients want, the investigators turned to “the experts” on how to broach difficult medical issues, the patients themselves, said epileptologist and lead investigator Dr. Rajesh RamachandranNair, an associate professor of pediatrics at McMaster.

They interviewed 19 epilepsy patients aged 18-65 years over the phone for almost an hour, and listened to what four others had to say in a focus group. All of the subjects had focal or generalized convulsive seizures and about half were well controlled with medication. Most had been diagnosed for more than a year, but two patients had been diagnosed within the previous 12 months. Thirteen (57%) hadn’t heard about SUDEP before being invited into the study, the others didn’t know much about the problem; 16 of the 23 patients were women. “There was 100% agreement that all of them wanted to know about SUDEP. Several people actually overestimated the risk, so this could be a positive discussion” for patients, Dr. RamachandranNair said at the American Epilepsy Society annual meeting.

Fifteen (65%) wanted to hear about SUDEP at the time of diagnosis; the rest wanted the discussion shortly thereafter at follow-up. All of the patients wanted to hear the news from a physician, primarily face-to-face from a neurologist who could accurately answer their questions. The patients said the conversation should focus mostly on the actual risk of sudden death, general information about the problem, prevention, and perhaps support group contacts. Most wanted to leave the office with supplmental written materials.

Most thought it was a good idea for all epilepsy patents to know about SUDEP, so that they and their loved ones could prepare for the possibility. Most also wanted a close relative in the room when they learned of SUDEP, and many thought it was a good idea to have a nurse or social worker present for extra support. Fourteen (61%) did not think knowing about SUDEP would change their lives, but a handful said it would make them take better care of themselves and be more compliant with their medications.

The McMaster team had a social worker on standby for their study, “but none of the patients contacted the social worker, which indirectly tell us that patients were probably not [too] worried” about the news, Dr. RamachandranNair said.

Dr. RamachandranNair and his colleagues have been tackling SUDEP awareness for several years. They previously found that parents of children with epilepsy want a similarly frank discussion of the issue.

“One word of caution is that this is a highly selective group.” They agreed to participate in the study, “so that tells us they are probably information seekers who want to know about their health status,” Dr. RamachandranNair said.

The team is planning future work to check the generalizability of their results, and assess how well patients live with the news of SUDEP.

Dr. RamachandranNair said he has no relevant financial disclosures. The work was funded by the Ontario Ministry of Health and Long-Term Care.

aotto@frontlinemedcom.com

SEATTLE – Adults want to know about the risk of sudden death when they are diagnosed with epilepsy, or shortly thereafter, and they want to hear the news face-to-face from their diagnosing neurologist, according to surveys of 23 epilepsy patients at McMaster University in Hamilton, Ont.

Doctors often struggle about how – or even if – to explain Sudden Unexpected Death in Epilepsy (SUDEP) to patients because the risk of SUDEP is small – perhaps 1 in 1,000 per year overall – but the potential for unwarranted anxiety about sudden death is large. There’s concern that patients will obsess about SUDEP and forget everything they hear about epilepsy management.

Instead of trying to guess what patients want, the investigators turned to “the experts” on how to broach difficult medical issues, the patients themselves, said epileptologist and lead investigator Dr. Rajesh RamachandranNair, an associate professor of pediatrics at McMaster.

They interviewed 19 epilepsy patients aged 18-65 years over the phone for almost an hour, and listened to what four others had to say in a focus group. All of the subjects had focal or generalized convulsive seizures and about half were well controlled with medication. Most had been diagnosed for more than a year, but two patients had been diagnosed within the previous 12 months. Thirteen (57%) hadn’t heard about SUDEP before being invited into the study, the others didn’t know much about the problem; 16 of the 23 patients were women. “There was 100% agreement that all of them wanted to know about SUDEP. Several people actually overestimated the risk, so this could be a positive discussion” for patients, Dr. RamachandranNair said at the American Epilepsy Society annual meeting.

Fifteen (65%) wanted to hear about SUDEP at the time of diagnosis; the rest wanted the discussion shortly thereafter at follow-up. All of the patients wanted to hear the news from a physician, primarily face-to-face from a neurologist who could accurately answer their questions. The patients said the conversation should focus mostly on the actual risk of sudden death, general information about the problem, prevention, and perhaps support group contacts. Most wanted to leave the office with supplmental written materials.

Most thought it was a good idea for all epilepsy patents to know about SUDEP, so that they and their loved ones could prepare for the possibility. Most also wanted a close relative in the room when they learned of SUDEP, and many thought it was a good idea to have a nurse or social worker present for extra support. Fourteen (61%) did not think knowing about SUDEP would change their lives, but a handful said it would make them take better care of themselves and be more compliant with their medications.

The McMaster team had a social worker on standby for their study, “but none of the patients contacted the social worker, which indirectly tell us that patients were probably not [too] worried” about the news, Dr. RamachandranNair said.

Dr. RamachandranNair and his colleagues have been tackling SUDEP awareness for several years. They previously found that parents of children with epilepsy want a similarly frank discussion of the issue.

“One word of caution is that this is a highly selective group.” They agreed to participate in the study, “so that tells us they are probably information seekers who want to know about their health status,” Dr. RamachandranNair said.

The team is planning future work to check the generalizability of their results, and assess how well patients live with the news of SUDEP.

Dr. RamachandranNair said he has no relevant financial disclosures. The work was funded by the Ontario Ministry of Health and Long-Term Care.

aotto@frontlinemedcom.com

SEATTLE – Adults want to know about the risk of sudden death when they are diagnosed with epilepsy, or shortly thereafter, and they want to hear the news face-to-face from their diagnosing neurologist, according to surveys of 23 epilepsy patients at McMaster University in Hamilton, Ont.

Doctors often struggle about how – or even if – to explain Sudden Unexpected Death in Epilepsy (SUDEP) to patients because the risk of SUDEP is small – perhaps 1 in 1,000 per year overall – but the potential for unwarranted anxiety about sudden death is large. There’s concern that patients will obsess about SUDEP and forget everything they hear about epilepsy management.

Instead of trying to guess what patients want, the investigators turned to “the experts” on how to broach difficult medical issues, the patients themselves, said epileptologist and lead investigator Dr. Rajesh RamachandranNair, an associate professor of pediatrics at McMaster.

They interviewed 19 epilepsy patients aged 18-65 years over the phone for almost an hour, and listened to what four others had to say in a focus group. All of the subjects had focal or generalized convulsive seizures and about half were well controlled with medication. Most had been diagnosed for more than a year, but two patients had been diagnosed within the previous 12 months. Thirteen (57%) hadn’t heard about SUDEP before being invited into the study, the others didn’t know much about the problem; 16 of the 23 patients were women. “There was 100% agreement that all of them wanted to know about SUDEP. Several people actually overestimated the risk, so this could be a positive discussion” for patients, Dr. RamachandranNair said at the American Epilepsy Society annual meeting.

Fifteen (65%) wanted to hear about SUDEP at the time of diagnosis; the rest wanted the discussion shortly thereafter at follow-up. All of the patients wanted to hear the news from a physician, primarily face-to-face from a neurologist who could accurately answer their questions. The patients said the conversation should focus mostly on the actual risk of sudden death, general information about the problem, prevention, and perhaps support group contacts. Most wanted to leave the office with supplmental written materials.

Most thought it was a good idea for all epilepsy patents to know about SUDEP, so that they and their loved ones could prepare for the possibility. Most also wanted a close relative in the room when they learned of SUDEP, and many thought it was a good idea to have a nurse or social worker present for extra support. Fourteen (61%) did not think knowing about SUDEP would change their lives, but a handful said it would make them take better care of themselves and be more compliant with their medications.

The McMaster team had a social worker on standby for their study, “but none of the patients contacted the social worker, which indirectly tell us that patients were probably not [too] worried” about the news, Dr. RamachandranNair said.

Dr. RamachandranNair and his colleagues have been tackling SUDEP awareness for several years. They previously found that parents of children with epilepsy want a similarly frank discussion of the issue.

“One word of caution is that this is a highly selective group.” They agreed to participate in the study, “so that tells us they are probably information seekers who want to know about their health status,” Dr. RamachandranNair said.

The team is planning future work to check the generalizability of their results, and assess how well patients live with the news of SUDEP.

Dr. RamachandranNair said he has no relevant financial disclosures. The work was funded by the Ontario Ministry of Health and Long-Term Care.

aotto@frontlinemedcom.com

SEATTLE – Auras don’t keep epilepsy patients safe while driving, according to a Yale University review of 215 medically-refractory epilepsy patients who had seizures behind the wheel.

Patients who have auras before their seizures are just as likely to get into accidents as are those who do not. “Our findings question the assumed protective benefit of reliable auras against motor vehicle accidents,” said Dr. Vineet Punia, a fellow in clinical neurophysiology, EEG, and epilepsy at the Cleveland Clinic.

It’s widely assumed that auras give patients enough time to pull off the road before a seizure. Many states have codified that belief into their driving laws based on advice from the American Academy of Neurology and American Epilepsy Society to use “consistent and prolonged auras” as a favorable factor when deciding if epilepsy patients should be licensed to drive (Epilepsia 1994;35:696-705).

That assumption has led to “a false sense of security,” Dr. Punia said at the annual meeting of the American Epilepsy Society. Even when they last more than a minute, “auras do not decrease the risk of motor vehicle accidents. We need to educate” people about this, he said, and, perhaps, rethink the laws.

He and his team looked for differences between the 141 patients who said their seizures caused car accidents, and the 74 who said they did not. The patients in the study were culled from the Multicenter Study of Epilepsy Surgery database.

If auras kept patients safe, the team reasoned that they would be more common in the accident-free group, but that’s not what they found. About 66% of the accident-free group reported having reliable auras before their attacks, the same as in the group that had seizure-related crashes. About 20% in both groups estimated that their auras lasted more than a minute, and about 41% in both thought that their auras were almost always long enough to prevent accidents.

“The presence of a reliable aura did not differ between the two groups. Having a longer aura did not prevent accidents. This would definitely affect how I counsel patients who want to drive,” Dr. Punia said.

The two groups were evenly matched. In both, about 86% had temporal lobe epilepsy; the majority had complex partial seizures (CPS); 45% were women; and the average age was 40 years.

There were a few factors that increased the odds of being involved in a motor vehicle accident, including having a history of CPS (odds ratio, 2.83; 95% confidence interval, 1.14-7.09; P = .029), at least one CPS per month in the last 3 months (OR, 2.52; 95% CI, 1.22-5.21; P = .01), and postictal periods of a minute or more (OR, 2.53; 95% CI, 1.04-6.19; P = .05) .

“CPS and longer postictal state are the most salient features of seizures” that increase the risk of accidents, suggesting that “impairment of consciousness may be a key factor,” they said.

The work was funded internally, and the investigators said they have no relevant industry disclosures.

aotto@frontlinemedcom.com

SEATTLE – Auras don’t keep epilepsy patients safe while driving, according to a Yale University review of 215 medically-refractory epilepsy patients who had seizures behind the wheel.

Patients who have auras before their seizures are just as likely to get into accidents as are those who do not. “Our findings question the assumed protective benefit of reliable auras against motor vehicle accidents,” said Dr. Vineet Punia, a fellow in clinical neurophysiology, EEG, and epilepsy at the Cleveland Clinic.

It’s widely assumed that auras give patients enough time to pull off the road before a seizure. Many states have codified that belief into their driving laws based on advice from the American Academy of Neurology and American Epilepsy Society to use “consistent and prolonged auras” as a favorable factor when deciding if epilepsy patients should be licensed to drive (Epilepsia 1994;35:696-705).

That assumption has led to “a false sense of security,” Dr. Punia said at the annual meeting of the American Epilepsy Society. Even when they last more than a minute, “auras do not decrease the risk of motor vehicle accidents. We need to educate” people about this, he said, and, perhaps, rethink the laws.

He and his team looked for differences between the 141 patients who said their seizures caused car accidents, and the 74 who said they did not. The patients in the study were culled from the Multicenter Study of Epilepsy Surgery database.

If auras kept patients safe, the team reasoned that they would be more common in the accident-free group, but that’s not what they found. About 66% of the accident-free group reported having reliable auras before their attacks, the same as in the group that had seizure-related crashes. About 20% in both groups estimated that their auras lasted more than a minute, and about 41% in both thought that their auras were almost always long enough to prevent accidents.

“The presence of a reliable aura did not differ between the two groups. Having a longer aura did not prevent accidents. This would definitely affect how I counsel patients who want to drive,” Dr. Punia said.

The two groups were evenly matched. In both, about 86% had temporal lobe epilepsy; the majority had complex partial seizures (CPS); 45% were women; and the average age was 40 years.

There were a few factors that increased the odds of being involved in a motor vehicle accident, including having a history of CPS (odds ratio, 2.83; 95% confidence interval, 1.14-7.09; P = .029), at least one CPS per month in the last 3 months (OR, 2.52; 95% CI, 1.22-5.21; P = .01), and postictal periods of a minute or more (OR, 2.53; 95% CI, 1.04-6.19; P = .05) .

“CPS and longer postictal state are the most salient features of seizures” that increase the risk of accidents, suggesting that “impairment of consciousness may be a key factor,” they said.

The work was funded internally, and the investigators said they have no relevant industry disclosures.

aotto@frontlinemedcom.com

SEATTLE – Auras don’t keep epilepsy patients safe while driving, according to a Yale University review of 215 medically-refractory epilepsy patients who had seizures behind the wheel.

Patients who have auras before their seizures are just as likely to get into accidents as are those who do not. “Our findings question the assumed protective benefit of reliable auras against motor vehicle accidents,” said Dr. Vineet Punia, a fellow in clinical neurophysiology, EEG, and epilepsy at the Cleveland Clinic.

It’s widely assumed that auras give patients enough time to pull off the road before a seizure. Many states have codified that belief into their driving laws based on advice from the American Academy of Neurology and American Epilepsy Society to use “consistent and prolonged auras” as a favorable factor when deciding if epilepsy patients should be licensed to drive (Epilepsia 1994;35:696-705).

That assumption has led to “a false sense of security,” Dr. Punia said at the annual meeting of the American Epilepsy Society. Even when they last more than a minute, “auras do not decrease the risk of motor vehicle accidents. We need to educate” people about this, he said, and, perhaps, rethink the laws.

He and his team looked for differences between the 141 patients who said their seizures caused car accidents, and the 74 who said they did not. The patients in the study were culled from the Multicenter Study of Epilepsy Surgery database.

If auras kept patients safe, the team reasoned that they would be more common in the accident-free group, but that’s not what they found. About 66% of the accident-free group reported having reliable auras before their attacks, the same as in the group that had seizure-related crashes. About 20% in both groups estimated that their auras lasted more than a minute, and about 41% in both thought that their auras were almost always long enough to prevent accidents.

“The presence of a reliable aura did not differ between the two groups. Having a longer aura did not prevent accidents. This would definitely affect how I counsel patients who want to drive,” Dr. Punia said.

The two groups were evenly matched. In both, about 86% had temporal lobe epilepsy; the majority had complex partial seizures (CPS); 45% were women; and the average age was 40 years.

There were a few factors that increased the odds of being involved in a motor vehicle accident, including having a history of CPS (odds ratio, 2.83; 95% confidence interval, 1.14-7.09; P = .029), at least one CPS per month in the last 3 months (OR, 2.52; 95% CI, 1.22-5.21; P = .01), and postictal periods of a minute or more (OR, 2.53; 95% CI, 1.04-6.19; P = .05) .

“CPS and longer postictal state are the most salient features of seizures” that increase the risk of accidents, suggesting that “impairment of consciousness may be a key factor,” they said.

The work was funded internally, and the investigators said they have no relevant industry disclosures.

aotto@frontlinemedcom.com

SEATTLE – Nearly a third of patients who experience a generalized convulsive seizure develop pulmonary edema, suggests a small cohort study reported at the annual meeting of the American Epilepsy Society. The longer the seizure lasts, the higher the probability of this complication.

“There are a few theories about how pulmonary edema can develop” in this context, noted first author Dr. Jeffrey Kennedy of the UC Davis Health System in Sacramento, Calif. Neurogenic mechanisms, hypoxemia, and prolonged negative intrathoracic pressure have all been implicated.

As far as the clinical implications, “postictal pulmonary edema may play a role in the mechanisms of SUDEP (sudden unexpected death in epilepsy),” he proposed at the annual meeting of the American Epilepsy Society.

Session attendee Dr. Kevin Chapman of the child neurology section in the department of pediatrics at Children’s Hospital Colorado, Aurora, asked, “If you identify somebody who has pulmonary edema, what do you do with them?”

“We have been following the patients who are clinically stable,” Dr. Kennedy replied. “We had a patient we identified with Takotsubo cardiomyopathy, which triggered some additional patient care from our cardiology department.”

“I think it just identifies patients who are at higher risk” for poor outcomes, he speculated. “In the EMU [epilepsy monitoring unit], when it comes to letting patients have more seizures, it does make us conservative as far as restarting medications and maybe trying to start giving them some benzodiazepines to try to shut things down.”

Another attendee commented, “Some of my patients’ relatives are very alarmed when the patient suffers severe cyanosis after a seizure. The first thing that our emergency staff will do when they arrive will be to clasp an oxygen mask over them. So our patients ask us, ‘Please, will we provide them with oxygen?’ I have a sneaking suspicion from your data that they may be justified in that. What would you advise?”

Another study done by the UC Davis group looked at a variety of peri-ictal interventions and found simple nursing practices worked about as well as oxygen, according to Dr. Kennedy (Epilepsia 2013;54:377-82). “It seems like just doing something – stimulating the patient, turning them on their side – is enough, rather than just administering oxygen.”

In an interview, session comoderator Dr. Amy Crepeau, a neurologist at the Mayo Clinic Arizona in Phoenix, said the observed incidence of pulmonary edema raises important questions: “Is this something we need to be more conscientious about and really intervene more closely? Should we be shortening the duration of time before we stop seizures and not letting them go as long? It seems as though they have done that at UC Davis – kind of limited the number of seizures that they allow patients to have in the epilepsy monitoring unit.”

“This study comes back to this issue of who’s at risk for SUDEP, what are the causes for SUDEP, and what are the interventions we can use to try to prevent that or lessen the risk for it,” she added. “We are looking forward to seeing whether these patients have any increased risk of SUDEP that associates with the pulmonary edema.”

Dr. Kennedy and colleagues studied 24 consecutive adult patients, mean age 32, who experienced generalized convulsive seizures while undergoing monitoring in the UC Davis EMU, where all patients with such seizures receive a chest x-ray soon afterward as a safety measure.

Overall, 29% of the patients were found to have pulmonary edema, with or without focal infiltrates, on their chest x-ray, and another 17% were found to have focal infiltrates only.

The mean time elapsed between the seizure and the chest x-ray acquisition was 225 minutes in the patients with abnormal findings and 196 minutes in the patients with normal findings, a nonsignificant difference, reported Dr. Kennedy, who disclosed that he had no relevant conflicts of interest.

The seizure duration was more than twice as long among patients with chest x-ray abnormalities as among counterparts without these abnormalities (250 vs. 101 seconds; P = .002), and the probability of abnormalities increased with seizure duration.

The groups with and without chest x-rays abnormalities did not differ significantly with respect to a variety of demographic and cardiorespiratory and other clinical factors, however.

SEATTLE – Nearly a third of patients who experience a generalized convulsive seizure develop pulmonary edema, suggests a small cohort study reported at the annual meeting of the American Epilepsy Society. The longer the seizure lasts, the higher the probability of this complication.

“There are a few theories about how pulmonary edema can develop” in this context, noted first author Dr. Jeffrey Kennedy of the UC Davis Health System in Sacramento, Calif. Neurogenic mechanisms, hypoxemia, and prolonged negative intrathoracic pressure have all been implicated.

As far as the clinical implications, “postictal pulmonary edema may play a role in the mechanisms of SUDEP (sudden unexpected death in epilepsy),” he proposed at the annual meeting of the American Epilepsy Society.

Session attendee Dr. Kevin Chapman of the child neurology section in the department of pediatrics at Children’s Hospital Colorado, Aurora, asked, “If you identify somebody who has pulmonary edema, what do you do with them?”

“We have been following the patients who are clinically stable,” Dr. Kennedy replied. “We had a patient we identified with Takotsubo cardiomyopathy, which triggered some additional patient care from our cardiology department.”

“I think it just identifies patients who are at higher risk” for poor outcomes, he speculated. “In the EMU [epilepsy monitoring unit], when it comes to letting patients have more seizures, it does make us conservative as far as restarting medications and maybe trying to start giving them some benzodiazepines to try to shut things down.”

Another attendee commented, “Some of my patients’ relatives are very alarmed when the patient suffers severe cyanosis after a seizure. The first thing that our emergency staff will do when they arrive will be to clasp an oxygen mask over them. So our patients ask us, ‘Please, will we provide them with oxygen?’ I have a sneaking suspicion from your data that they may be justified in that. What would you advise?”

Another study done by the UC Davis group looked at a variety of peri-ictal interventions and found simple nursing practices worked about as well as oxygen, according to Dr. Kennedy (Epilepsia 2013;54:377-82). “It seems like just doing something – stimulating the patient, turning them on their side – is enough, rather than just administering oxygen.”

In an interview, session comoderator Dr. Amy Crepeau, a neurologist at the Mayo Clinic Arizona in Phoenix, said the observed incidence of pulmonary edema raises important questions: “Is this something we need to be more conscientious about and really intervene more closely? Should we be shortening the duration of time before we stop seizures and not letting them go as long? It seems as though they have done that at UC Davis – kind of limited the number of seizures that they allow patients to have in the epilepsy monitoring unit.”

“This study comes back to this issue of who’s at risk for SUDEP, what are the causes for SUDEP, and what are the interventions we can use to try to prevent that or lessen the risk for it,” she added. “We are looking forward to seeing whether these patients have any increased risk of SUDEP that associates with the pulmonary edema.”

Dr. Kennedy and colleagues studied 24 consecutive adult patients, mean age 32, who experienced generalized convulsive seizures while undergoing monitoring in the UC Davis EMU, where all patients with such seizures receive a chest x-ray soon afterward as a safety measure.

Overall, 29% of the patients were found to have pulmonary edema, with or without focal infiltrates, on their chest x-ray, and another 17% were found to have focal infiltrates only.

The mean time elapsed between the seizure and the chest x-ray acquisition was 225 minutes in the patients with abnormal findings and 196 minutes in the patients with normal findings, a nonsignificant difference, reported Dr. Kennedy, who disclosed that he had no relevant conflicts of interest.

The seizure duration was more than twice as long among patients with chest x-ray abnormalities as among counterparts without these abnormalities (250 vs. 101 seconds; P = .002), and the probability of abnormalities increased with seizure duration.

The groups with and without chest x-rays abnormalities did not differ significantly with respect to a variety of demographic and cardiorespiratory and other clinical factors, however.

SEATTLE – Nearly a third of patients who experience a generalized convulsive seizure develop pulmonary edema, suggests a small cohort study reported at the annual meeting of the American Epilepsy Society. The longer the seizure lasts, the higher the probability of this complication.

“There are a few theories about how pulmonary edema can develop” in this context, noted first author Dr. Jeffrey Kennedy of the UC Davis Health System in Sacramento, Calif. Neurogenic mechanisms, hypoxemia, and prolonged negative intrathoracic pressure have all been implicated.

As far as the clinical implications, “postictal pulmonary edema may play a role in the mechanisms of SUDEP (sudden unexpected death in epilepsy),” he proposed at the annual meeting of the American Epilepsy Society.

Session attendee Dr. Kevin Chapman of the child neurology section in the department of pediatrics at Children’s Hospital Colorado, Aurora, asked, “If you identify somebody who has pulmonary edema, what do you do with them?”

“We have been following the patients who are clinically stable,” Dr. Kennedy replied. “We had a patient we identified with Takotsubo cardiomyopathy, which triggered some additional patient care from our cardiology department.”

“I think it just identifies patients who are at higher risk” for poor outcomes, he speculated. “In the EMU [epilepsy monitoring unit], when it comes to letting patients have more seizures, it does make us conservative as far as restarting medications and maybe trying to start giving them some benzodiazepines to try to shut things down.”

Another attendee commented, “Some of my patients’ relatives are very alarmed when the patient suffers severe cyanosis after a seizure. The first thing that our emergency staff will do when they arrive will be to clasp an oxygen mask over them. So our patients ask us, ‘Please, will we provide them with oxygen?’ I have a sneaking suspicion from your data that they may be justified in that. What would you advise?”

Another study done by the UC Davis group looked at a variety of peri-ictal interventions and found simple nursing practices worked about as well as oxygen, according to Dr. Kennedy (Epilepsia 2013;54:377-82). “It seems like just doing something – stimulating the patient, turning them on their side – is enough, rather than just administering oxygen.”

In an interview, session comoderator Dr. Amy Crepeau, a neurologist at the Mayo Clinic Arizona in Phoenix, said the observed incidence of pulmonary edema raises important questions: “Is this something we need to be more conscientious about and really intervene more closely? Should we be shortening the duration of time before we stop seizures and not letting them go as long? It seems as though they have done that at UC Davis – kind of limited the number of seizures that they allow patients to have in the epilepsy monitoring unit.”

“This study comes back to this issue of who’s at risk for SUDEP, what are the causes for SUDEP, and what are the interventions we can use to try to prevent that or lessen the risk for it,” she added. “We are looking forward to seeing whether these patients have any increased risk of SUDEP that associates with the pulmonary edema.”

Dr. Kennedy and colleagues studied 24 consecutive adult patients, mean age 32, who experienced generalized convulsive seizures while undergoing monitoring in the UC Davis EMU, where all patients with such seizures receive a chest x-ray soon afterward as a safety measure.

Overall, 29% of the patients were found to have pulmonary edema, with or without focal infiltrates, on their chest x-ray, and another 17% were found to have focal infiltrates only.

The mean time elapsed between the seizure and the chest x-ray acquisition was 225 minutes in the patients with abnormal findings and 196 minutes in the patients with normal findings, a nonsignificant difference, reported Dr. Kennedy, who disclosed that he had no relevant conflicts of interest.

The seizure duration was more than twice as long among patients with chest x-ray abnormalities as among counterparts without these abnormalities (250 vs. 101 seconds; P = .002), and the probability of abnormalities increased with seizure duration.

The groups with and without chest x-rays abnormalities did not differ significantly with respect to a variety of demographic and cardiorespiratory and other clinical factors, however.

SEATTLE– Most pediatric patients with intractable epilepsy fare similarly well if they follow the less-restrictive modified Atkins diet instead of the classic ketogenic diet, new data suggest. The former may be better in patients with kidney disease, whereas the latter may be better for very young children.

“The modified Atkins diet is much easier to follow, and many physicians think that it shows much lower [rates of] complications. But until now, there have been very few studies comparing the ketogenic diet and modified Atkins diet,” lead investigator Dr. Jeong-A Kim commented in an interview at the annual meeting of the American Epilepsy Society, where she presented the findings.

The investigators conducted a randomized trial pitting the two diets against each other among 104 patients aged 1-18 years who had drug-refractory epilepsy and had never received dietary therapy.

The proportion of patients free of seizures, defined as having none for at least the past month, did not differ significantly overall between the ketogenic diet and modified Atkins diet groups at 3 months (32.7% vs. 26.4%) or at 6 months (29.4% vs. 20.7%), according to results reported in a poster session. There was also no significant difference in the proportions achieving a greater than 50% reduction and a greater than 90% reduction in seizures.

In stratified analyses, the findings were similar for most age groups, except for children 1 or 2 years old, who had a significantly higher rate of freedom from seizures at 3 months if they were on the ketogenic diet (17.6% vs. 7.5%; P = .047).

The diets were statistically indistinguishable with respect to rates of most adverse effects, but hypercalciuria was twice as common with the ketogenic diet (35.3% vs. 13.2%; P = .01). Also, a larger share of patients in the ketogenic diet group stopped their diet because of adverse effects.

“I usually first try the ketogenic diet, but if the patients show some side effects such as hypercalciuria or GI trouble, something like that, then I usually change it to the modified Atkins diet,” commented Dr. Kim, who is a pediatric neurologist at Severance Children’s Hospital, Yonsei University Health System, in Seoul, South Korea.

Clinicians should know “You have choices when you think about dietary therapy: It’s not just the ketogenic diet, you also have choices such as the modified Atkins diet,” she maintained. “So if a patient has kidney problems or some other problems, then you can try the modified Atkins diet instead of the ketogenic diet. You don’t have to have prejudices or misconceptions about dietary therapy; you also have other options for dietary therapy.”

“For younger patients who have Lennox-Gastaut syndrome or infantile spasms, it would be better to try the ketogenic diet first,” advised Dr. Kim, who disclosed that she had no relevant conflicts of interest.

SEATTLE– Most pediatric patients with intractable epilepsy fare similarly well if they follow the less-restrictive modified Atkins diet instead of the classic ketogenic diet, new data suggest. The former may be better in patients with kidney disease, whereas the latter may be better for very young children.

“The modified Atkins diet is much easier to follow, and many physicians think that it shows much lower [rates of] complications. But until now, there have been very few studies comparing the ketogenic diet and modified Atkins diet,” lead investigator Dr. Jeong-A Kim commented in an interview at the annual meeting of the American Epilepsy Society, where she presented the findings.

The investigators conducted a randomized trial pitting the two diets against each other among 104 patients aged 1-18 years who had drug-refractory epilepsy and had never received dietary therapy.

The proportion of patients free of seizures, defined as having none for at least the past month, did not differ significantly overall between the ketogenic diet and modified Atkins diet groups at 3 months (32.7% vs. 26.4%) or at 6 months (29.4% vs. 20.7%), according to results reported in a poster session. There was also no significant difference in the proportions achieving a greater than 50% reduction and a greater than 90% reduction in seizures.

In stratified analyses, the findings were similar for most age groups, except for children 1 or 2 years old, who had a significantly higher rate of freedom from seizures at 3 months if they were on the ketogenic diet (17.6% vs. 7.5%; P = .047).

The diets were statistically indistinguishable with respect to rates of most adverse effects, but hypercalciuria was twice as common with the ketogenic diet (35.3% vs. 13.2%; P = .01). Also, a larger share of patients in the ketogenic diet group stopped their diet because of adverse effects.

“I usually first try the ketogenic diet, but if the patients show some side effects such as hypercalciuria or GI trouble, something like that, then I usually change it to the modified Atkins diet,” commented Dr. Kim, who is a pediatric neurologist at Severance Children’s Hospital, Yonsei University Health System, in Seoul, South Korea.

Clinicians should know “You have choices when you think about dietary therapy: It’s not just the ketogenic diet, you also have choices such as the modified Atkins diet,” she maintained. “So if a patient has kidney problems or some other problems, then you can try the modified Atkins diet instead of the ketogenic diet. You don’t have to have prejudices or misconceptions about dietary therapy; you also have other options for dietary therapy.”

“For younger patients who have Lennox-Gastaut syndrome or infantile spasms, it would be better to try the ketogenic diet first,” advised Dr. Kim, who disclosed that she had no relevant conflicts of interest.

SEATTLE– Most pediatric patients with intractable epilepsy fare similarly well if they follow the less-restrictive modified Atkins diet instead of the classic ketogenic diet, new data suggest. The former may be better in patients with kidney disease, whereas the latter may be better for very young children.

“The modified Atkins diet is much easier to follow, and many physicians think that it shows much lower [rates of] complications. But until now, there have been very few studies comparing the ketogenic diet and modified Atkins diet,” lead investigator Dr. Jeong-A Kim commented in an interview at the annual meeting of the American Epilepsy Society, where she presented the findings.

The investigators conducted a randomized trial pitting the two diets against each other among 104 patients aged 1-18 years who had drug-refractory epilepsy and had never received dietary therapy.

The proportion of patients free of seizures, defined as having none for at least the past month, did not differ significantly overall between the ketogenic diet and modified Atkins diet groups at 3 months (32.7% vs. 26.4%) or at 6 months (29.4% vs. 20.7%), according to results reported in a poster session. There was also no significant difference in the proportions achieving a greater than 50% reduction and a greater than 90% reduction in seizures.

In stratified analyses, the findings were similar for most age groups, except for children 1 or 2 years old, who had a significantly higher rate of freedom from seizures at 3 months if they were on the ketogenic diet (17.6% vs. 7.5%; P = .047).

The diets were statistically indistinguishable with respect to rates of most adverse effects, but hypercalciuria was twice as common with the ketogenic diet (35.3% vs. 13.2%; P = .01). Also, a larger share of patients in the ketogenic diet group stopped their diet because of adverse effects.

“I usually first try the ketogenic diet, but if the patients show some side effects such as hypercalciuria or GI trouble, something like that, then I usually change it to the modified Atkins diet,” commented Dr. Kim, who is a pediatric neurologist at Severance Children’s Hospital, Yonsei University Health System, in Seoul, South Korea.

Clinicians should know “You have choices when you think about dietary therapy: It’s not just the ketogenic diet, you also have choices such as the modified Atkins diet,” she maintained. “So if a patient has kidney problems or some other problems, then you can try the modified Atkins diet instead of the ketogenic diet. You don’t have to have prejudices or misconceptions about dietary therapy; you also have other options for dietary therapy.”

“For younger patients who have Lennox-Gastaut syndrome or infantile spasms, it would be better to try the ketogenic diet first,” advised Dr. Kim, who disclosed that she had no relevant conflicts of interest.

SEATTLE – When history, physical, and brain MRI fail to find a cause for infantile spasms, genetic studies – not specialized metabolic testing – should be the next diagnostic step, according to investigators from the National Infantile Spasms Consortium.

In a prospective study of 251 children with West syndrome at 21 pediatric epilepsy centers in the United States, they found that genetic studies – especially epilepsy gene panels and array comparative genomic hybridization (aCGH) – were more likely than specialized metabolic tests were to reveal the cause of infantile spasms. They were also a bit less expensive, and sometimes caught genes associated with mitochondrial disorders, glucose transporter deficiencies, and other metabolic issues.

“If your MRI looks normal, you are better off spending your money on genetic studies. Think about doing [an aCGH] microarray and an epilepsy gene panel if the microarray is negative.” If answers are still elusive, metabolic screening is in order, but “you can probably limit it to serum lactate, pyruvate amino acids, and urine organic acids,” said study leader Dr. Elaine Wirrell, director of the pediatric epilepsy fellowship program at the Mayo Clinic in Rochester, Minn.History, physical, and MRI found congenital or acquired structural brain abnormalities or other obvious causes for spasms in 138 children (55%). Three months of follow-up testing identified the cause in another 23 (9%). The kids in the study were an average of 7 months old at presentation and were about evenly split between boys and girls.

Almost all the children in the study had extensive metabolic evaluations of their blood and urine, and about half had cerebrospinal fluid testing. Even so, the diagnostic yield of metabolic workups was “very low” among children with no clear etiology for their spasms after their initial evaluations. “Very rarely did metabolic testing come up with any sort of etiological answer,” Dr. Wirrell said, and in the few times it did, abnormalities were found only on serum lactate, pyruvate amino acids, and urine organic acid testing.

About half of the kids had genetic testing. In the group with no clear etiology, 20 had an epilepsy gene panel; its diagnostic yield was 30%. If the variants of uncertain significance (VUS) were included, the yield rose to more than 50%. Among the 60-plus children screened with aCGH microarray, the diagnostic yield was 10%, but with the VUS, it was 20%. Chromosome 15 abnormalities were found in a number of children.

“We had a significant yield of clear pathogenic changes and variants” with genetic testing. With more widespread use, “I think we would pick up a lot more children who have genetic causes” for infantile spasms, Dr. Wirrell said.

There’s not a lot that can be done for those children at present. “For most cases that have a genetic etiology, we are not at the point where we can say ‘this etiology equals that treatment,’ but I think we’ll get there,” she said.

The study was funded by the American Epilepsy Society and the Pediatric Epilepsy Research Foundation. Dr. Wirrell said she has no industry disclosures.

aotto@frontlinemedcom.com

SEATTLE – When history, physical, and brain MRI fail to find a cause for infantile spasms, genetic studies – not specialized metabolic testing – should be the next diagnostic step, according to investigators from the National Infantile Spasms Consortium.

In a prospective study of 251 children with West syndrome at 21 pediatric epilepsy centers in the United States, they found that genetic studies – especially epilepsy gene panels and array comparative genomic hybridization (aCGH) – were more likely than specialized metabolic tests were to reveal the cause of infantile spasms. They were also a bit less expensive, and sometimes caught genes associated with mitochondrial disorders, glucose transporter deficiencies, and other metabolic issues.

“If your MRI looks normal, you are better off spending your money on genetic studies. Think about doing [an aCGH] microarray and an epilepsy gene panel if the microarray is negative.” If answers are still elusive, metabolic screening is in order, but “you can probably limit it to serum lactate, pyruvate amino acids, and urine organic acids,” said study leader Dr. Elaine Wirrell, director of the pediatric epilepsy fellowship program at the Mayo Clinic in Rochester, Minn.History, physical, and MRI found congenital or acquired structural brain abnormalities or other obvious causes for spasms in 138 children (55%). Three months of follow-up testing identified the cause in another 23 (9%). The kids in the study were an average of 7 months old at presentation and were about evenly split between boys and girls.

Almost all the children in the study had extensive metabolic evaluations of their blood and urine, and about half had cerebrospinal fluid testing. Even so, the diagnostic yield of metabolic workups was “very low” among children with no clear etiology for their spasms after their initial evaluations. “Very rarely did metabolic testing come up with any sort of etiological answer,” Dr. Wirrell said, and in the few times it did, abnormalities were found only on serum lactate, pyruvate amino acids, and urine organic acid testing.

About half of the kids had genetic testing. In the group with no clear etiology, 20 had an epilepsy gene panel; its diagnostic yield was 30%. If the variants of uncertain significance (VUS) were included, the yield rose to more than 50%. Among the 60-plus children screened with aCGH microarray, the diagnostic yield was 10%, but with the VUS, it was 20%. Chromosome 15 abnormalities were found in a number of children.

“We had a significant yield of clear pathogenic changes and variants” with genetic testing. With more widespread use, “I think we would pick up a lot more children who have genetic causes” for infantile spasms, Dr. Wirrell said.

There’s not a lot that can be done for those children at present. “For most cases that have a genetic etiology, we are not at the point where we can say ‘this etiology equals that treatment,’ but I think we’ll get there,” she said.

The study was funded by the American Epilepsy Society and the Pediatric Epilepsy Research Foundation. Dr. Wirrell said she has no industry disclosures.

aotto@frontlinemedcom.com

SEATTLE – When history, physical, and brain MRI fail to find a cause for infantile spasms, genetic studies – not specialized metabolic testing – should be the next diagnostic step, according to investigators from the National Infantile Spasms Consortium.

In a prospective study of 251 children with West syndrome at 21 pediatric epilepsy centers in the United States, they found that genetic studies – especially epilepsy gene panels and array comparative genomic hybridization (aCGH) – were more likely than specialized metabolic tests were to reveal the cause of infantile spasms. They were also a bit less expensive, and sometimes caught genes associated with mitochondrial disorders, glucose transporter deficiencies, and other metabolic issues.

“If your MRI looks normal, you are better off spending your money on genetic studies. Think about doing [an aCGH] microarray and an epilepsy gene panel if the microarray is negative.” If answers are still elusive, metabolic screening is in order, but “you can probably limit it to serum lactate, pyruvate amino acids, and urine organic acids,” said study leader Dr. Elaine Wirrell, director of the pediatric epilepsy fellowship program at the Mayo Clinic in Rochester, Minn.History, physical, and MRI found congenital or acquired structural brain abnormalities or other obvious causes for spasms in 138 children (55%). Three months of follow-up testing identified the cause in another 23 (9%). The kids in the study were an average of 7 months old at presentation and were about evenly split between boys and girls.

Almost all the children in the study had extensive metabolic evaluations of their blood and urine, and about half had cerebrospinal fluid testing. Even so, the diagnostic yield of metabolic workups was “very low” among children with no clear etiology for their spasms after their initial evaluations. “Very rarely did metabolic testing come up with any sort of etiological answer,” Dr. Wirrell said, and in the few times it did, abnormalities were found only on serum lactate, pyruvate amino acids, and urine organic acid testing.

About half of the kids had genetic testing. In the group with no clear etiology, 20 had an epilepsy gene panel; its diagnostic yield was 30%. If the variants of uncertain significance (VUS) were included, the yield rose to more than 50%. Among the 60-plus children screened with aCGH microarray, the diagnostic yield was 10%, but with the VUS, it was 20%. Chromosome 15 abnormalities were found in a number of children.

“We had a significant yield of clear pathogenic changes and variants” with genetic testing. With more widespread use, “I think we would pick up a lot more children who have genetic causes” for infantile spasms, Dr. Wirrell said.

There’s not a lot that can be done for those children at present. “For most cases that have a genetic etiology, we are not at the point where we can say ‘this etiology equals that treatment,’ but I think we’ll get there,” she said.

The study was funded by the American Epilepsy Society and the Pediatric Epilepsy Research Foundation. Dr. Wirrell said she has no industry disclosures.

aotto@frontlinemedcom.com

SEATTLE – Different generic versions of lamotrigine had essentially the same pharmacokinetics, safety, and efficacy in controlling seizures in a randomized, head-to-head cross-over trial reported at the annual meeting of the American Epilepsy Society.

“There is all this worry about generics, even though the FDA [Food and Drug Administration] says, ‘We do rigorous testing, and these generics are beautiful, and you don’t have to worry, and you don’t have to measure blood levels of anything,’” lead investigator Dr. Michael D. Privitera commented in an interview. And pharmacies often switch patients with epilepsy between generic antiepileptic drug products with little or no notice.

“What we tried to do here was sort of a worst-case scenario [comparison] with two different generics that would be the most different, and we demonstrated that they were extremely close,” he said. “Although there are other studies that you need to look at too, from this study, I would say that the risks of switching from generic to generic are probably less than one might anticipate from reading the nonrigorous studies that are out there in the literature.”

To capture real-world conditions, Dr. Privitera and his colleagues of the EQUIGEN (Equivalence Among Generic AEDs) study group designed a practical trial using repeated dosing among epilepsy patients who could be taking other medications. “The FDA does all their studies in normal volunteers using single doses, never people with epilepsy, never somebody taking a drug,” he noted.

In the study, the investigators chose for comparison the two generic lamotrigine products on the market having the most disparate dissolution and content characteristics based on testing, and the most disparate pharmacokinetic profiles based on data submitted to the FDA by the manufacturers for approval. For the latter, the products had the lowest and highest values for the total drug exposure as assessed from the area under the curve (AUC) and for the peak blood concentration (Cmax) that still fell within the permitted 90% confidence interval of 80% to 120% relative to the brand-name drug.

Study participants were 35 adults with epilepsy, with or without comorbidities, who were receiving lamotrigine in a dose that was a multiple of 100 mg, with equal morning and evening doses, as either monotherapy or polytherapy. The sample was enriched in that five of the patients reported experiencing troubles when switching between generics in the past.

“In general, these were not people with high seizure frequency because we really wanted them to be stable and compliant, because compliance is the single most important thing in getting these kinds of numbers,” noted Dr. Privitera, professor of neurology at the University of Cincinnati and director of the Epilepsy Center at the University of Cincinnati Neuroscience Institute.

After randomization to the order of products, patients took the low and high generic products on a blinded basis for four alternating 2-week periods. Compliance was assessed with tablet counts, patient diaries, and computerized compliance caps on bottles. Pharmacokinetics were assessed in each period with serial blood measurements.

Results presented in a poster session showed that none of the patients experienced adverse events or lost seizure control, as assessed from self-reported seizure frequency, when switching between the two generic products, reported Dr. Privitera, who disclosed that he had no relevant conflicts of interest.

Additionally, the two products did not differ significantly in pharmacokinetics, meeting the FDA standards for bioequivalence for both the ratio of their AUC values (90% confidence interval, 98%-103%) and the ratio of their Cmax values (90% confidence interval, 99%-105%). “We didn’t find any outlier group here,” he added.

Findings were essentially the same after controlling for concomitant use of enzyme-inducing antiepileptic drugs, sex, dose, and missing data.

Dr. Privitera speculated that reported difficulties after switches of generic antiepileptic drugs have been because of compliance issues and not the drug products. That is, the differing appearance of various generics may confuse patients, causing them to stop taking the medication, as suggested by recent research (JAMA Intern. Med. 2013;173:202-8), or to take too much.

“The FDA actually wants generic drugs [from different manufacturers] to look different,” he noted. But there has recently been a push from clinicians “to say look, if you are making generic lamotrigine, no matter who manufactures it, it should all look the same, and then people won’t get confused when they go from a blue triangle to a white round to a yellow round.”

The investigators are conducting a similar trial that is comparing brand name drug lamotrigine (Lamictal) with generic versions in patients with epilepsy, but using single doses.

SEATTLE – Different generic versions of lamotrigine had essentially the same pharmacokinetics, safety, and efficacy in controlling seizures in a randomized, head-to-head cross-over trial reported at the annual meeting of the American Epilepsy Society.

“There is all this worry about generics, even though the FDA [Food and Drug Administration] says, ‘We do rigorous testing, and these generics are beautiful, and you don’t have to worry, and you don’t have to measure blood levels of anything,’” lead investigator Dr. Michael D. Privitera commented in an interview. And pharmacies often switch patients with epilepsy between generic antiepileptic drug products with little or no notice.

“What we tried to do here was sort of a worst-case scenario [comparison] with two different generics that would be the most different, and we demonstrated that they were extremely close,” he said. “Although there are other studies that you need to look at too, from this study, I would say that the risks of switching from generic to generic are probably less than one might anticipate from reading the nonrigorous studies that are out there in the literature.”

To capture real-world conditions, Dr. Privitera and his colleagues of the EQUIGEN (Equivalence Among Generic AEDs) study group designed a practical trial using repeated dosing among epilepsy patients who could be taking other medications. “The FDA does all their studies in normal volunteers using single doses, never people with epilepsy, never somebody taking a drug,” he noted.

In the study, the investigators chose for comparison the two generic lamotrigine products on the market having the most disparate dissolution and content characteristics based on testing, and the most disparate pharmacokinetic profiles based on data submitted to the FDA by the manufacturers for approval. For the latter, the products had the lowest and highest values for the total drug exposure as assessed from the area under the curve (AUC) and for the peak blood concentration (Cmax) that still fell within the permitted 90% confidence interval of 80% to 120% relative to the brand-name drug.

Study participants were 35 adults with epilepsy, with or without comorbidities, who were receiving lamotrigine in a dose that was a multiple of 100 mg, with equal morning and evening doses, as either monotherapy or polytherapy. The sample was enriched in that five of the patients reported experiencing troubles when switching between generics in the past.

“In general, these were not people with high seizure frequency because we really wanted them to be stable and compliant, because compliance is the single most important thing in getting these kinds of numbers,” noted Dr. Privitera, professor of neurology at the University of Cincinnati and director of the Epilepsy Center at the University of Cincinnati Neuroscience Institute.

After randomization to the order of products, patients took the low and high generic products on a blinded basis for four alternating 2-week periods. Compliance was assessed with tablet counts, patient diaries, and computerized compliance caps on bottles. Pharmacokinetics were assessed in each period with serial blood measurements.

Results presented in a poster session showed that none of the patients experienced adverse events or lost seizure control, as assessed from self-reported seizure frequency, when switching between the two generic products, reported Dr. Privitera, who disclosed that he had no relevant conflicts of interest.

Additionally, the two products did not differ significantly in pharmacokinetics, meeting the FDA standards for bioequivalence for both the ratio of their AUC values (90% confidence interval, 98%-103%) and the ratio of their Cmax values (90% confidence interval, 99%-105%). “We didn’t find any outlier group here,” he added.

Findings were essentially the same after controlling for concomitant use of enzyme-inducing antiepileptic drugs, sex, dose, and missing data.

Dr. Privitera speculated that reported difficulties after switches of generic antiepileptic drugs have been because of compliance issues and not the drug products. That is, the differing appearance of various generics may confuse patients, causing them to stop taking the medication, as suggested by recent research (JAMA Intern. Med. 2013;173:202-8), or to take too much.

“The FDA actually wants generic drugs [from different manufacturers] to look different,” he noted. But there has recently been a push from clinicians “to say look, if you are making generic lamotrigine, no matter who manufactures it, it should all look the same, and then people won’t get confused when they go from a blue triangle to a white round to a yellow round.”

The investigators are conducting a similar trial that is comparing brand name drug lamotrigine (Lamictal) with generic versions in patients with epilepsy, but using single doses.

SEATTLE – Different generic versions of lamotrigine had essentially the same pharmacokinetics, safety, and efficacy in controlling seizures in a randomized, head-to-head cross-over trial reported at the annual meeting of the American Epilepsy Society.

“There is all this worry about generics, even though the FDA [Food and Drug Administration] says, ‘We do rigorous testing, and these generics are beautiful, and you don’t have to worry, and you don’t have to measure blood levels of anything,’” lead investigator Dr. Michael D. Privitera commented in an interview. And pharmacies often switch patients with epilepsy between generic antiepileptic drug products with little or no notice.

“What we tried to do here was sort of a worst-case scenario [comparison] with two different generics that would be the most different, and we demonstrated that they were extremely close,” he said. “Although there are other studies that you need to look at too, from this study, I would say that the risks of switching from generic to generic are probably less than one might anticipate from reading the nonrigorous studies that are out there in the literature.”

To capture real-world conditions, Dr. Privitera and his colleagues of the EQUIGEN (Equivalence Among Generic AEDs) study group designed a practical trial using repeated dosing among epilepsy patients who could be taking other medications. “The FDA does all their studies in normal volunteers using single doses, never people with epilepsy, never somebody taking a drug,” he noted.

In the study, the investigators chose for comparison the two generic lamotrigine products on the market having the most disparate dissolution and content characteristics based on testing, and the most disparate pharmacokinetic profiles based on data submitted to the FDA by the manufacturers for approval. For the latter, the products had the lowest and highest values for the total drug exposure as assessed from the area under the curve (AUC) and for the peak blood concentration (Cmax) that still fell within the permitted 90% confidence interval of 80% to 120% relative to the brand-name drug.

Study participants were 35 adults with epilepsy, with or without comorbidities, who were receiving lamotrigine in a dose that was a multiple of 100 mg, with equal morning and evening doses, as either monotherapy or polytherapy. The sample was enriched in that five of the patients reported experiencing troubles when switching between generics in the past.

“In general, these were not people with high seizure frequency because we really wanted them to be stable and compliant, because compliance is the single most important thing in getting these kinds of numbers,” noted Dr. Privitera, professor of neurology at the University of Cincinnati and director of the Epilepsy Center at the University of Cincinnati Neuroscience Institute.

After randomization to the order of products, patients took the low and high generic products on a blinded basis for four alternating 2-week periods. Compliance was assessed with tablet counts, patient diaries, and computerized compliance caps on bottles. Pharmacokinetics were assessed in each period with serial blood measurements.

Results presented in a poster session showed that none of the patients experienced adverse events or lost seizure control, as assessed from self-reported seizure frequency, when switching between the two generic products, reported Dr. Privitera, who disclosed that he had no relevant conflicts of interest.

Additionally, the two products did not differ significantly in pharmacokinetics, meeting the FDA standards for bioequivalence for both the ratio of their AUC values (90% confidence interval, 98%-103%) and the ratio of their Cmax values (90% confidence interval, 99%-105%). “We didn’t find any outlier group here,” he added.

Findings were essentially the same after controlling for concomitant use of enzyme-inducing antiepileptic drugs, sex, dose, and missing data.

Dr. Privitera speculated that reported difficulties after switches of generic antiepileptic drugs have been because of compliance issues and not the drug products. That is, the differing appearance of various generics may confuse patients, causing them to stop taking the medication, as suggested by recent research (JAMA Intern. Med. 2013;173:202-8), or to take too much.

“The FDA actually wants generic drugs [from different manufacturers] to look different,” he noted. But there has recently been a push from clinicians “to say look, if you are making generic lamotrigine, no matter who manufactures it, it should all look the same, and then people won’t get confused when they go from a blue triangle to a white round to a yellow round.”

The investigators are conducting a similar trial that is comparing brand name drug lamotrigine (Lamictal) with generic versions in patients with epilepsy, but using single doses.