Epilepsy Resource Center

A large Danish study supports a robust and long-term bidirectional relationship between epilepsy and depression, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.

“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.

The study was published online in Neurology.
 

Epilepsy then depression

The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.

In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).

The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).

The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.

The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.

The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
 

Depression then epilepsy

The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).

As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.

The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.

The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.

For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.

Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.

“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.

“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
 

Clinical implications

Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”

“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.

“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.

The findings do have implications for care, he said.

“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.

“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.

“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.

The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A large Danish study supports a robust and long-term bidirectional relationship between epilepsy and depression, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.

“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.

The study was published online in Neurology.
 

Epilepsy then depression

The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.

In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).

The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).

The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.

The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.

The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
 

Depression then epilepsy

The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).

As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.

The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.

The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.

For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.

Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.

“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.

“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
 

Clinical implications

Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”

“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.

“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.

The findings do have implications for care, he said.

“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.

“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.

“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.

The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A large Danish study supports a robust and long-term bidirectional relationship between epilepsy and depression, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.

“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.

The study was published online in Neurology.
 

Epilepsy then depression

The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.

In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).

The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).

The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.

The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.

The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
 

Depression then epilepsy

The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).

As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.

The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.

The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.

For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.

Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.

“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.

“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
 

Clinical implications

Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”

“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.

“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.

The findings do have implications for care, he said.

“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.

“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.

“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.

The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CINCINNATI – A new analysis of data from a phase 3 clinical trial suggests that an inhaled diazepam nasal spray (Valtoco, Neurelis Inc.) works about as well among patients with Lennox-Gastaut Syndrome (LGS) as it does with other patients with pediatric encephalopathies.

LGS is a severe form of epilepsy that generally begins in early childhood and has a poor prognosis and seizures that are often treatment refractory. The findings of the analysis should be encouraging to physicians who may view patients with LGS as not benefiting from treatment, said Daniel C. Tarquinio, DO, who presented the results at the 2022 annual meeting of the Child Neurology Society.

“Their response to their first appropriate weight-based rescue dose of Valtoco was essentially no different. They were subtly different, but they’re not really meaningful differences. Very few needed a second dose. In practice this is helpful because we know that kids with LGS, we think of them as having worse epilepsy, if you will. But if they need rescue, if we prescribe an appropriate rescue dose based on their weight, that the same rescue will work for them as it will for a kid that doesn’t have – quote unquote – as bad epilepsy that needs rescue,” said Dr. Tarquinio, a child neurologist and epileptologist and founder of the Center for Rare Neurological Diseases.

During the Q&A, Dr. Tarquinio was asked if there is something about the biology of LGS that would suggest it might respond differently to the drug. Dr. Tarquinio said no. “The reason we even looked at this is because many clinicians told us that their sense was [that patients with LGS] did not respond as well to rescue in general no matter what they use. This allowed us to go back and look at a controlled data set and say, at least in our controlled dataset, they respond the same,” he said.

Grace Gombolay, MD, who moderated the session, agreed that the results should be encouraging. “It seems like a lot of clinicians have the sense that Lennox-Gastaut Syndrome is a very terrible refractory epilepsy syndrome, and so doing rescue doesn’t seem to make sense if they don’t really respond. I think it’s helpful to know because there are actually studies showing that Valtoco seems to actually work in those patients, so it’s actually useful clinically to prescribe those patients and give it a shot,” said Dr. Gombolay, director of the Pediatric Neuroimmunology and Multiple Sclerosis Clinic at Emory University, Atlanta.

LGS patients may experience hundreds of seizures per day. “It’s really hard for parents to quantify, did they get better? Did the rescue help or not, because they’re still having some seizures. I think the sense is, ‘oh, this isn’t working.’ That’s probably the bias. I think this is good data that if you are able to get Valtoco for your patients, I think it’s worth a shot even in Lennox-Gastaut,” said Dr. Gombolay.

The researchers conducted a post hoc analysis of the phase 3, open-label, repeat-dose safety study of Valtoco. The study included a 12-month treatment period with visits at day 30 and every 60 days following. Patients had the option of staying on the drug following the end of the treatment period. Seizure and dosing information were obtained from a diary. The study enrolled 163 patients whose physicians believed they would need to be treated with a benzodiazepine at least once every other month to achieve seizure control. Dosing was determined by a combination of age and weight. If a second dose was required, caregivers were instructed to provide it 4-12 hours after the first dose.

In the study cohort, 47.9% of patients were aged 6-17 years. The researchers looked specifically at 73 cases of seizure clusters. In nine cases, the patient had LGS (five male, four female). Nearly all (95.9%) of LGS cluster cases were treated with a single dose and 4.1% were exposed to a second dose. Among 64 cases involving a patient with pediatric epileptic encephalopathies, 89.4% were treated with a single dose and 10.6% received a second. The safety profile was similar between patients with LGS and those with pediatric encephalopathies.

Dr. Gombolay has no relevant financial disclosures.

CINCINNATI – A new analysis of data from a phase 3 clinical trial suggests that an inhaled diazepam nasal spray (Valtoco, Neurelis Inc.) works about as well among patients with Lennox-Gastaut Syndrome (LGS) as it does with other patients with pediatric encephalopathies.

LGS is a severe form of epilepsy that generally begins in early childhood and has a poor prognosis and seizures that are often treatment refractory. The findings of the analysis should be encouraging to physicians who may view patients with LGS as not benefiting from treatment, said Daniel C. Tarquinio, DO, who presented the results at the 2022 annual meeting of the Child Neurology Society.

“Their response to their first appropriate weight-based rescue dose of Valtoco was essentially no different. They were subtly different, but they’re not really meaningful differences. Very few needed a second dose. In practice this is helpful because we know that kids with LGS, we think of them as having worse epilepsy, if you will. But if they need rescue, if we prescribe an appropriate rescue dose based on their weight, that the same rescue will work for them as it will for a kid that doesn’t have – quote unquote – as bad epilepsy that needs rescue,” said Dr. Tarquinio, a child neurologist and epileptologist and founder of the Center for Rare Neurological Diseases.

During the Q&A, Dr. Tarquinio was asked if there is something about the biology of LGS that would suggest it might respond differently to the drug. Dr. Tarquinio said no. “The reason we even looked at this is because many clinicians told us that their sense was [that patients with LGS] did not respond as well to rescue in general no matter what they use. This allowed us to go back and look at a controlled data set and say, at least in our controlled dataset, they respond the same,” he said.

Grace Gombolay, MD, who moderated the session, agreed that the results should be encouraging. “It seems like a lot of clinicians have the sense that Lennox-Gastaut Syndrome is a very terrible refractory epilepsy syndrome, and so doing rescue doesn’t seem to make sense if they don’t really respond. I think it’s helpful to know because there are actually studies showing that Valtoco seems to actually work in those patients, so it’s actually useful clinically to prescribe those patients and give it a shot,” said Dr. Gombolay, director of the Pediatric Neuroimmunology and Multiple Sclerosis Clinic at Emory University, Atlanta.

LGS patients may experience hundreds of seizures per day. “It’s really hard for parents to quantify, did they get better? Did the rescue help or not, because they’re still having some seizures. I think the sense is, ‘oh, this isn’t working.’ That’s probably the bias. I think this is good data that if you are able to get Valtoco for your patients, I think it’s worth a shot even in Lennox-Gastaut,” said Dr. Gombolay.

The researchers conducted a post hoc analysis of the phase 3, open-label, repeat-dose safety study of Valtoco. The study included a 12-month treatment period with visits at day 30 and every 60 days following. Patients had the option of staying on the drug following the end of the treatment period. Seizure and dosing information were obtained from a diary. The study enrolled 163 patients whose physicians believed they would need to be treated with a benzodiazepine at least once every other month to achieve seizure control. Dosing was determined by a combination of age and weight. If a second dose was required, caregivers were instructed to provide it 4-12 hours after the first dose.

In the study cohort, 47.9% of patients were aged 6-17 years. The researchers looked specifically at 73 cases of seizure clusters. In nine cases, the patient had LGS (five male, four female). Nearly all (95.9%) of LGS cluster cases were treated with a single dose and 4.1% were exposed to a second dose. Among 64 cases involving a patient with pediatric epileptic encephalopathies, 89.4% were treated with a single dose and 10.6% received a second. The safety profile was similar between patients with LGS and those with pediatric encephalopathies.

Dr. Gombolay has no relevant financial disclosures.

CINCINNATI – A new analysis of data from a phase 3 clinical trial suggests that an inhaled diazepam nasal spray (Valtoco, Neurelis Inc.) works about as well among patients with Lennox-Gastaut Syndrome (LGS) as it does with other patients with pediatric encephalopathies.

LGS is a severe form of epilepsy that generally begins in early childhood and has a poor prognosis and seizures that are often treatment refractory. The findings of the analysis should be encouraging to physicians who may view patients with LGS as not benefiting from treatment, said Daniel C. Tarquinio, DO, who presented the results at the 2022 annual meeting of the Child Neurology Society.

“Their response to their first appropriate weight-based rescue dose of Valtoco was essentially no different. They were subtly different, but they’re not really meaningful differences. Very few needed a second dose. In practice this is helpful because we know that kids with LGS, we think of them as having worse epilepsy, if you will. But if they need rescue, if we prescribe an appropriate rescue dose based on their weight, that the same rescue will work for them as it will for a kid that doesn’t have – quote unquote – as bad epilepsy that needs rescue,” said Dr. Tarquinio, a child neurologist and epileptologist and founder of the Center for Rare Neurological Diseases.

During the Q&A, Dr. Tarquinio was asked if there is something about the biology of LGS that would suggest it might respond differently to the drug. Dr. Tarquinio said no. “The reason we even looked at this is because many clinicians told us that their sense was [that patients with LGS] did not respond as well to rescue in general no matter what they use. This allowed us to go back and look at a controlled data set and say, at least in our controlled dataset, they respond the same,” he said.

Grace Gombolay, MD, who moderated the session, agreed that the results should be encouraging. “It seems like a lot of clinicians have the sense that Lennox-Gastaut Syndrome is a very terrible refractory epilepsy syndrome, and so doing rescue doesn’t seem to make sense if they don’t really respond. I think it’s helpful to know because there are actually studies showing that Valtoco seems to actually work in those patients, so it’s actually useful clinically to prescribe those patients and give it a shot,” said Dr. Gombolay, director of the Pediatric Neuroimmunology and Multiple Sclerosis Clinic at Emory University, Atlanta.

LGS patients may experience hundreds of seizures per day. “It’s really hard for parents to quantify, did they get better? Did the rescue help or not, because they’re still having some seizures. I think the sense is, ‘oh, this isn’t working.’ That’s probably the bias. I think this is good data that if you are able to get Valtoco for your patients, I think it’s worth a shot even in Lennox-Gastaut,” said Dr. Gombolay.

The researchers conducted a post hoc analysis of the phase 3, open-label, repeat-dose safety study of Valtoco. The study included a 12-month treatment period with visits at day 30 and every 60 days following. Patients had the option of staying on the drug following the end of the treatment period. Seizure and dosing information were obtained from a diary. The study enrolled 163 patients whose physicians believed they would need to be treated with a benzodiazepine at least once every other month to achieve seizure control. Dosing was determined by a combination of age and weight. If a second dose was required, caregivers were instructed to provide it 4-12 hours after the first dose.

In the study cohort, 47.9% of patients were aged 6-17 years. The researchers looked specifically at 73 cases of seizure clusters. In nine cases, the patient had LGS (five male, four female). Nearly all (95.9%) of LGS cluster cases were treated with a single dose and 4.1% were exposed to a second dose. Among 64 cases involving a patient with pediatric epileptic encephalopathies, 89.4% were treated with a single dose and 10.6% received a second. The safety profile was similar between patients with LGS and those with pediatric encephalopathies.

Dr. Gombolay has no relevant financial disclosures.

POMONA, CALIF. – When you first meet 17-month-old Aaron Martinez, it’s not obvious that something is catastrophically wrong.

What you see is a beautiful little boy with smooth, lustrous skin, an abundance of glossy brown hair, and a disarming smile. What you hear are coos and cries that don’t immediately signal anything is horribly awry.

But his parents, Adriana Pinedo and Hector Martinez, know the truth painfully well.

Although Ms. Pinedo’s doctors and midwife had described the pregnancy as “perfect” for all 9 months, Aaron was born with most of his brain cells dead, the result of two strokes and a massive bleed he sustained while in utero.

Doctors aren’t sure what caused the anomalies that left Aaron with virtually no cognitive function or physical mobility. His voluminous hair hides a head whose circumference is too small for his age. He has epilepsy that triggers multiple seizures each day, and his smile is not always what it seems. “It could be a smile; it could be a seizure,” Ms. Pinedo said.

Shortly after Aaron was born, doctors told Ms. Pinedo, 34, and Mr. Martinez, 35, there was no hope and they should “let nature take its course.” They would learn months later that the doctors had not expected the boy to live more than 5 days. It was on Day 5 that his parents put him in home hospice care, an arrangement that has continued into his second year of life.

The family gets weekly visits from hospice nurses, therapists, social workers, and a chaplain in the cramped one-bedroom apartment they rent from the people who live in the main house on the same lot on a quiet residential street in this Inland Empire city.

One of the main criteria for hospice care, established by Medicare largely for seniors but also applied to children, is a diagnosis of 6 months or less to live. Yet over the course of 17 months, Aaron’s medical team has repeatedly recertified his hospice eligibility.

Under a provision of the 2010 Affordable Care Act, children enrolled in Medicaid or the Children’s Health Insurance Program are allowed, unlike adults, to be in hospice while continuing to receive curative or life-extending care. Commercial insurers are not required to cover this “concurrent care,” but many now do.

More than a decade since its inception, concurrent care is widely credited with improving the quality of life for many terminally ill children, easing stress on the family and, in some cases, sustaining hope for a cure. But the arrangement can contribute to a painful dilemma for parents like Ms. Pinedo and Mr. Martinez, who are torn between their fierce commitment to their son and the futility of knowing that his condition leaves him with no future worth hoping for.

“We could lose a life, but if he continues to live this way, we’ll lose three,” said Ms. Pinedo. “There’s no quality of life for him or for us.”

Aaron’s doctors now say he could conceivably live for years. His body hasn’t stopped growing since he was born. He’s in the 96th percentile for height for his age, and his weight is about average.

His parents have talked about “graduating” him from hospice. But he is never stable for long, and they welcome the visits from their hospice team. The seizures, sometimes 30 a day, are a persistent assault on his brain and, as he grows, the medications intended to control them must be changed or the doses recalibrated. He is at continual risk of gastrointestinal problems and potentially deadly fluid buildup in his lungs.

Ms. Pinedo, who works from home for a nonprofit public health organization, spends much of her time with Aaron, while Mr. Martinez works as a landscaper. She has chosen to live in the moment, she said, because otherwise her mind wanders to a future in which either “he could die – or he won’t, and I’ll end up changing the diapers of a 40-year-old man.” Either of those “are going to suck.”

While cancer is one of the major illnesses afflicting children in hospice, many others, like Aaron, have rare congenital defects, severe neurological impairments, or uncommon metabolic deficiencies.

“We have diseases that families tell us are 1 of 10 cases in the world,” said Glen Komatsu, MD, medical director of Torrance, Calif.–based TrinityKids Care, which provides home hospice services to Aaron and more than 70 other kids in Los Angeles and Orange counties.

In the years leading up to the ACA’s implementation, pediatric health advocates lobbied hard for the concurrent care provision. Without the possibility of life-extending care or hope for a cure, many parents refused to put their terminally ill kids in hospice, thinking it was tantamount to giving up on them. That meant the whole family missed out on the support hospice can provide, not just pain relief and comfort for the dying child, but emotional and spiritual care for parents and siblings under extreme duress.

TrinityKids Care, run by the large national Catholic health system Providence, doesn’t just send nurses, social workers, and chaplains into homes. For patients able to participate, and their siblings, it also offers art and science projects, exercise classes, movies, and music. During the pandemic, these activities have been conducted via Zoom, and volunteers deliver needed supplies to the children’s homes.

The ability to get treatments that prolong their lives is a major reason children in concurrent care are more likely than adults to outlive the 6-months-to-live diagnosis required for hospice.

“Concurrent care, by its very intention, very clearly is going to extend their lives, and by extending their lives they’re no longer going to be hospice-eligible if you use the 6-month life expectancy criteria,” said David Steinhorn, MD, a pediatric intensive care physician in Virginia, who has helped develop numerous children’s hospice programs across the United States.

Another factor is that kids, even sick ones, are simply more robust than many older people.

“Sick kids are often otherwise healthy, except for one organ,” said Debra Lotstein, MD, chief of the division of comfort and palliative care at Children’s Hospital Los Angeles. “They may have cancer in their body, but their hearts are good and their lungs are good, compared to a 90-year-old who at baseline is just not as resilient.”

All of Aaron Martinez’s vital organs, except for his brain, seem to be working. “There have been times when we’ve brought him in, and the nurse looks at the chart and looks at him, and she can’t believe it’s that child,” said Mr. Martinez.

When kids live past the 6-month life expectancy, they must be recertified to stay in hospice. In many cases, Dr. Steinhorn said, he is willing to recertify his pediatric patients indefinitely.

Even with doctors advocating for them, it’s not always easy for children to get into hospice care. Most hospices care primarily for adults and are reluctant to take kids.

“The hospice will say: ‘We don’t have the capacity to treat children. Our nurses aren’t trained. It’s different. We just can’t do it,’ ” said Lori Butterworth, cofounder of the Children’s Hospice and Palliative Care Coalition of California in Watsonville. “The other reason is not wanting to, because it’s existentially devastating and sad and hard.”

Finances also play a role. Home hospice care is paid at a per diem rate set by Medicare – slightly over $200 a day for the first 2 months, about $161 a day after that – and it is typically the same for kids and adults. Children, particularly those with rare conditions, often require more intensive and innovative care, so the per diem doesn’t stretch as far.

The concurrent care provision has made taking pediatric patients more viable for hospice organizations, Dr. Steinhorn and others said. Under the ACA, many of the expenses for certain medications and medical services can be shifted to the patient’s primary insurance, leaving hospices responsible for pain relief and comfort care.

Even so, the relatively small number of kids who die each year from protracted ailments hardly makes pediatric hospice an appealing line of business in an industry craving growth, especially one in which private equity investors are active and seeking a big payday.

In California, only 21 of 1,336 hospices reported having a specialized pediatric hospice program, and 59 said they served at least one patient under age 21, according to an analysis of 2020 state data by Cordt Kassner, CEO of Hospice Analytics in Colorado Springs.

Hospice providers that do cater to children often face a more basic challenge: Even with the possibility of concurrent care, many parents still equate hospice with acceptance of death. That was the case initially for Matt and Reese Sonnen, Los Angeles residents whose daughter, Layla, was born with a seizure disorder that had no name: Her brain had simply failed to develop in the womb, and an MRI showed “fluid taking up space where the brain wasn’t,” her mother said.

When Layla’s team first mentioned hospice, “I was in the car on my phone, and I almost crashed the car,” Mrs. Sonnen recalled. “The first thought that came to mind was: ‘It is just the end,’ but we felt she was nowhere near it, because she was strong, she was mighty. She was my little girl. She was going to get through this.”

About 3 months later, as Layla’s nervous system deteriorated, causing her to writhe in pain, her parents agreed to enroll her in hospice with TrinityKids Care. She died weeks later, not long after her second birthday. She was in her mother’s arms, with Mr. Sonnen close by.

“All of a sudden, Layla breathed out a big rush of air. The nurse looked at me and said: ‘That was her last breath.’ I was literally breathing in her last breath,” Mrs. Sonnen recounted. “I never wanted to breathe again, because now I felt I had her in my lungs. Don’t make me laugh, don’t make me exhale.”

Layla’s parents have no regrets about their decision to put her in hospice. “It was the absolute right decision, and in hindsight we should have done it sooner,” Mr. Sonnen said. “She was suffering, and we had blinders on.”

Ms. Pinedo said she is “infinitely grateful” for hospice, despite the heartache of Aaron’s condition. Sometimes the social worker will stop by, she said, just to say hello and drop off a latte, a small gesture that can feel very uplifting. “They’ve been our lifeline,” she said.

Ms. Pinedo talks about a friend of hers with a healthy baby, also named Aaron, who is pregnant with her second child. “All the stuff that was on our list, they’re living. And I love them dearly. But it’s almost hard to look, because it’s like looking at the stuff that you didn’t get. It’s like Christmas Day, staring through the window at the neighbor’s house, and you’re sitting there in the cold.”

Yet she seems palpably torn between that bleak remorse and the unconditional love parents feel toward their children. At one point, Ms. Pinedo interrupted herself midsentence and turned to her son, who was in Mr. Martinez’s arms: “Yes, Papi, you are so stinking cute, and you are still my dream come true.”

This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

POMONA, CALIF. – When you first meet 17-month-old Aaron Martinez, it’s not obvious that something is catastrophically wrong.

What you see is a beautiful little boy with smooth, lustrous skin, an abundance of glossy brown hair, and a disarming smile. What you hear are coos and cries that don’t immediately signal anything is horribly awry.

But his parents, Adriana Pinedo and Hector Martinez, know the truth painfully well.

Although Ms. Pinedo’s doctors and midwife had described the pregnancy as “perfect” for all 9 months, Aaron was born with most of his brain cells dead, the result of two strokes and a massive bleed he sustained while in utero.

Doctors aren’t sure what caused the anomalies that left Aaron with virtually no cognitive function or physical mobility. His voluminous hair hides a head whose circumference is too small for his age. He has epilepsy that triggers multiple seizures each day, and his smile is not always what it seems. “It could be a smile; it could be a seizure,” Ms. Pinedo said.

Shortly after Aaron was born, doctors told Ms. Pinedo, 34, and Mr. Martinez, 35, there was no hope and they should “let nature take its course.” They would learn months later that the doctors had not expected the boy to live more than 5 days. It was on Day 5 that his parents put him in home hospice care, an arrangement that has continued into his second year of life.

The family gets weekly visits from hospice nurses, therapists, social workers, and a chaplain in the cramped one-bedroom apartment they rent from the people who live in the main house on the same lot on a quiet residential street in this Inland Empire city.

One of the main criteria for hospice care, established by Medicare largely for seniors but also applied to children, is a diagnosis of 6 months or less to live. Yet over the course of 17 months, Aaron’s medical team has repeatedly recertified his hospice eligibility.

Under a provision of the 2010 Affordable Care Act, children enrolled in Medicaid or the Children’s Health Insurance Program are allowed, unlike adults, to be in hospice while continuing to receive curative or life-extending care. Commercial insurers are not required to cover this “concurrent care,” but many now do.

More than a decade since its inception, concurrent care is widely credited with improving the quality of life for many terminally ill children, easing stress on the family and, in some cases, sustaining hope for a cure. But the arrangement can contribute to a painful dilemma for parents like Ms. Pinedo and Mr. Martinez, who are torn between their fierce commitment to their son and the futility of knowing that his condition leaves him with no future worth hoping for.

“We could lose a life, but if he continues to live this way, we’ll lose three,” said Ms. Pinedo. “There’s no quality of life for him or for us.”

Aaron’s doctors now say he could conceivably live for years. His body hasn’t stopped growing since he was born. He’s in the 96th percentile for height for his age, and his weight is about average.

His parents have talked about “graduating” him from hospice. But he is never stable for long, and they welcome the visits from their hospice team. The seizures, sometimes 30 a day, are a persistent assault on his brain and, as he grows, the medications intended to control them must be changed or the doses recalibrated. He is at continual risk of gastrointestinal problems and potentially deadly fluid buildup in his lungs.

Ms. Pinedo, who works from home for a nonprofit public health organization, spends much of her time with Aaron, while Mr. Martinez works as a landscaper. She has chosen to live in the moment, she said, because otherwise her mind wanders to a future in which either “he could die – or he won’t, and I’ll end up changing the diapers of a 40-year-old man.” Either of those “are going to suck.”

While cancer is one of the major illnesses afflicting children in hospice, many others, like Aaron, have rare congenital defects, severe neurological impairments, or uncommon metabolic deficiencies.

“We have diseases that families tell us are 1 of 10 cases in the world,” said Glen Komatsu, MD, medical director of Torrance, Calif.–based TrinityKids Care, which provides home hospice services to Aaron and more than 70 other kids in Los Angeles and Orange counties.

In the years leading up to the ACA’s implementation, pediatric health advocates lobbied hard for the concurrent care provision. Without the possibility of life-extending care or hope for a cure, many parents refused to put their terminally ill kids in hospice, thinking it was tantamount to giving up on them. That meant the whole family missed out on the support hospice can provide, not just pain relief and comfort for the dying child, but emotional and spiritual care for parents and siblings under extreme duress.

TrinityKids Care, run by the large national Catholic health system Providence, doesn’t just send nurses, social workers, and chaplains into homes. For patients able to participate, and their siblings, it also offers art and science projects, exercise classes, movies, and music. During the pandemic, these activities have been conducted via Zoom, and volunteers deliver needed supplies to the children’s homes.

The ability to get treatments that prolong their lives is a major reason children in concurrent care are more likely than adults to outlive the 6-months-to-live diagnosis required for hospice.

“Concurrent care, by its very intention, very clearly is going to extend their lives, and by extending their lives they’re no longer going to be hospice-eligible if you use the 6-month life expectancy criteria,” said David Steinhorn, MD, a pediatric intensive care physician in Virginia, who has helped develop numerous children’s hospice programs across the United States.

Another factor is that kids, even sick ones, are simply more robust than many older people.

“Sick kids are often otherwise healthy, except for one organ,” said Debra Lotstein, MD, chief of the division of comfort and palliative care at Children’s Hospital Los Angeles. “They may have cancer in their body, but their hearts are good and their lungs are good, compared to a 90-year-old who at baseline is just not as resilient.”

All of Aaron Martinez’s vital organs, except for his brain, seem to be working. “There have been times when we’ve brought him in, and the nurse looks at the chart and looks at him, and she can’t believe it’s that child,” said Mr. Martinez.

When kids live past the 6-month life expectancy, they must be recertified to stay in hospice. In many cases, Dr. Steinhorn said, he is willing to recertify his pediatric patients indefinitely.

Even with doctors advocating for them, it’s not always easy for children to get into hospice care. Most hospices care primarily for adults and are reluctant to take kids.

“The hospice will say: ‘We don’t have the capacity to treat children. Our nurses aren’t trained. It’s different. We just can’t do it,’ ” said Lori Butterworth, cofounder of the Children’s Hospice and Palliative Care Coalition of California in Watsonville. “The other reason is not wanting to, because it’s existentially devastating and sad and hard.”

Finances also play a role. Home hospice care is paid at a per diem rate set by Medicare – slightly over $200 a day for the first 2 months, about $161 a day after that – and it is typically the same for kids and adults. Children, particularly those with rare conditions, often require more intensive and innovative care, so the per diem doesn’t stretch as far.

The concurrent care provision has made taking pediatric patients more viable for hospice organizations, Dr. Steinhorn and others said. Under the ACA, many of the expenses for certain medications and medical services can be shifted to the patient’s primary insurance, leaving hospices responsible for pain relief and comfort care.

Even so, the relatively small number of kids who die each year from protracted ailments hardly makes pediatric hospice an appealing line of business in an industry craving growth, especially one in which private equity investors are active and seeking a big payday.

In California, only 21 of 1,336 hospices reported having a specialized pediatric hospice program, and 59 said they served at least one patient under age 21, according to an analysis of 2020 state data by Cordt Kassner, CEO of Hospice Analytics in Colorado Springs.

Hospice providers that do cater to children often face a more basic challenge: Even with the possibility of concurrent care, many parents still equate hospice with acceptance of death. That was the case initially for Matt and Reese Sonnen, Los Angeles residents whose daughter, Layla, was born with a seizure disorder that had no name: Her brain had simply failed to develop in the womb, and an MRI showed “fluid taking up space where the brain wasn’t,” her mother said.

When Layla’s team first mentioned hospice, “I was in the car on my phone, and I almost crashed the car,” Mrs. Sonnen recalled. “The first thought that came to mind was: ‘It is just the end,’ but we felt she was nowhere near it, because she was strong, she was mighty. She was my little girl. She was going to get through this.”

About 3 months later, as Layla’s nervous system deteriorated, causing her to writhe in pain, her parents agreed to enroll her in hospice with TrinityKids Care. She died weeks later, not long after her second birthday. She was in her mother’s arms, with Mr. Sonnen close by.

“All of a sudden, Layla breathed out a big rush of air. The nurse looked at me and said: ‘That was her last breath.’ I was literally breathing in her last breath,” Mrs. Sonnen recounted. “I never wanted to breathe again, because now I felt I had her in my lungs. Don’t make me laugh, don’t make me exhale.”

Layla’s parents have no regrets about their decision to put her in hospice. “It was the absolute right decision, and in hindsight we should have done it sooner,” Mr. Sonnen said. “She was suffering, and we had blinders on.”

Ms. Pinedo said she is “infinitely grateful” for hospice, despite the heartache of Aaron’s condition. Sometimes the social worker will stop by, she said, just to say hello and drop off a latte, a small gesture that can feel very uplifting. “They’ve been our lifeline,” she said.

Ms. Pinedo talks about a friend of hers with a healthy baby, also named Aaron, who is pregnant with her second child. “All the stuff that was on our list, they’re living. And I love them dearly. But it’s almost hard to look, because it’s like looking at the stuff that you didn’t get. It’s like Christmas Day, staring through the window at the neighbor’s house, and you’re sitting there in the cold.”

Yet she seems palpably torn between that bleak remorse and the unconditional love parents feel toward their children. At one point, Ms. Pinedo interrupted herself midsentence and turned to her son, who was in Mr. Martinez’s arms: “Yes, Papi, you are so stinking cute, and you are still my dream come true.”

This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

POMONA, CALIF. – When you first meet 17-month-old Aaron Martinez, it’s not obvious that something is catastrophically wrong.

What you see is a beautiful little boy with smooth, lustrous skin, an abundance of glossy brown hair, and a disarming smile. What you hear are coos and cries that don’t immediately signal anything is horribly awry.

But his parents, Adriana Pinedo and Hector Martinez, know the truth painfully well.

Although Ms. Pinedo’s doctors and midwife had described the pregnancy as “perfect” for all 9 months, Aaron was born with most of his brain cells dead, the result of two strokes and a massive bleed he sustained while in utero.

Doctors aren’t sure what caused the anomalies that left Aaron with virtually no cognitive function or physical mobility. His voluminous hair hides a head whose circumference is too small for his age. He has epilepsy that triggers multiple seizures each day, and his smile is not always what it seems. “It could be a smile; it could be a seizure,” Ms. Pinedo said.

Shortly after Aaron was born, doctors told Ms. Pinedo, 34, and Mr. Martinez, 35, there was no hope and they should “let nature take its course.” They would learn months later that the doctors had not expected the boy to live more than 5 days. It was on Day 5 that his parents put him in home hospice care, an arrangement that has continued into his second year of life.

The family gets weekly visits from hospice nurses, therapists, social workers, and a chaplain in the cramped one-bedroom apartment they rent from the people who live in the main house on the same lot on a quiet residential street in this Inland Empire city.

One of the main criteria for hospice care, established by Medicare largely for seniors but also applied to children, is a diagnosis of 6 months or less to live. Yet over the course of 17 months, Aaron’s medical team has repeatedly recertified his hospice eligibility.

Under a provision of the 2010 Affordable Care Act, children enrolled in Medicaid or the Children’s Health Insurance Program are allowed, unlike adults, to be in hospice while continuing to receive curative or life-extending care. Commercial insurers are not required to cover this “concurrent care,” but many now do.

More than a decade since its inception, concurrent care is widely credited with improving the quality of life for many terminally ill children, easing stress on the family and, in some cases, sustaining hope for a cure. But the arrangement can contribute to a painful dilemma for parents like Ms. Pinedo and Mr. Martinez, who are torn between their fierce commitment to their son and the futility of knowing that his condition leaves him with no future worth hoping for.

“We could lose a life, but if he continues to live this way, we’ll lose three,” said Ms. Pinedo. “There’s no quality of life for him or for us.”

Aaron’s doctors now say he could conceivably live for years. His body hasn’t stopped growing since he was born. He’s in the 96th percentile for height for his age, and his weight is about average.

His parents have talked about “graduating” him from hospice. But he is never stable for long, and they welcome the visits from their hospice team. The seizures, sometimes 30 a day, are a persistent assault on his brain and, as he grows, the medications intended to control them must be changed or the doses recalibrated. He is at continual risk of gastrointestinal problems and potentially deadly fluid buildup in his lungs.

Ms. Pinedo, who works from home for a nonprofit public health organization, spends much of her time with Aaron, while Mr. Martinez works as a landscaper. She has chosen to live in the moment, she said, because otherwise her mind wanders to a future in which either “he could die – or he won’t, and I’ll end up changing the diapers of a 40-year-old man.” Either of those “are going to suck.”

While cancer is one of the major illnesses afflicting children in hospice, many others, like Aaron, have rare congenital defects, severe neurological impairments, or uncommon metabolic deficiencies.

“We have diseases that families tell us are 1 of 10 cases in the world,” said Glen Komatsu, MD, medical director of Torrance, Calif.–based TrinityKids Care, which provides home hospice services to Aaron and more than 70 other kids in Los Angeles and Orange counties.

In the years leading up to the ACA’s implementation, pediatric health advocates lobbied hard for the concurrent care provision. Without the possibility of life-extending care or hope for a cure, many parents refused to put their terminally ill kids in hospice, thinking it was tantamount to giving up on them. That meant the whole family missed out on the support hospice can provide, not just pain relief and comfort for the dying child, but emotional and spiritual care for parents and siblings under extreme duress.

TrinityKids Care, run by the large national Catholic health system Providence, doesn’t just send nurses, social workers, and chaplains into homes. For patients able to participate, and their siblings, it also offers art and science projects, exercise classes, movies, and music. During the pandemic, these activities have been conducted via Zoom, and volunteers deliver needed supplies to the children’s homes.

The ability to get treatments that prolong their lives is a major reason children in concurrent care are more likely than adults to outlive the 6-months-to-live diagnosis required for hospice.

“Concurrent care, by its very intention, very clearly is going to extend their lives, and by extending their lives they’re no longer going to be hospice-eligible if you use the 6-month life expectancy criteria,” said David Steinhorn, MD, a pediatric intensive care physician in Virginia, who has helped develop numerous children’s hospice programs across the United States.

Another factor is that kids, even sick ones, are simply more robust than many older people.

“Sick kids are often otherwise healthy, except for one organ,” said Debra Lotstein, MD, chief of the division of comfort and palliative care at Children’s Hospital Los Angeles. “They may have cancer in their body, but their hearts are good and their lungs are good, compared to a 90-year-old who at baseline is just not as resilient.”

All of Aaron Martinez’s vital organs, except for his brain, seem to be working. “There have been times when we’ve brought him in, and the nurse looks at the chart and looks at him, and she can’t believe it’s that child,” said Mr. Martinez.

When kids live past the 6-month life expectancy, they must be recertified to stay in hospice. In many cases, Dr. Steinhorn said, he is willing to recertify his pediatric patients indefinitely.

Even with doctors advocating for them, it’s not always easy for children to get into hospice care. Most hospices care primarily for adults and are reluctant to take kids.

“The hospice will say: ‘We don’t have the capacity to treat children. Our nurses aren’t trained. It’s different. We just can’t do it,’ ” said Lori Butterworth, cofounder of the Children’s Hospice and Palliative Care Coalition of California in Watsonville. “The other reason is not wanting to, because it’s existentially devastating and sad and hard.”

Finances also play a role. Home hospice care is paid at a per diem rate set by Medicare – slightly over $200 a day for the first 2 months, about $161 a day after that – and it is typically the same for kids and adults. Children, particularly those with rare conditions, often require more intensive and innovative care, so the per diem doesn’t stretch as far.

The concurrent care provision has made taking pediatric patients more viable for hospice organizations, Dr. Steinhorn and others said. Under the ACA, many of the expenses for certain medications and medical services can be shifted to the patient’s primary insurance, leaving hospices responsible for pain relief and comfort care.

Even so, the relatively small number of kids who die each year from protracted ailments hardly makes pediatric hospice an appealing line of business in an industry craving growth, especially one in which private equity investors are active and seeking a big payday.

In California, only 21 of 1,336 hospices reported having a specialized pediatric hospice program, and 59 said they served at least one patient under age 21, according to an analysis of 2020 state data by Cordt Kassner, CEO of Hospice Analytics in Colorado Springs.

Hospice providers that do cater to children often face a more basic challenge: Even with the possibility of concurrent care, many parents still equate hospice with acceptance of death. That was the case initially for Matt and Reese Sonnen, Los Angeles residents whose daughter, Layla, was born with a seizure disorder that had no name: Her brain had simply failed to develop in the womb, and an MRI showed “fluid taking up space where the brain wasn’t,” her mother said.

When Layla’s team first mentioned hospice, “I was in the car on my phone, and I almost crashed the car,” Mrs. Sonnen recalled. “The first thought that came to mind was: ‘It is just the end,’ but we felt she was nowhere near it, because she was strong, she was mighty. She was my little girl. She was going to get through this.”

About 3 months later, as Layla’s nervous system deteriorated, causing her to writhe in pain, her parents agreed to enroll her in hospice with TrinityKids Care. She died weeks later, not long after her second birthday. She was in her mother’s arms, with Mr. Sonnen close by.

“All of a sudden, Layla breathed out a big rush of air. The nurse looked at me and said: ‘That was her last breath.’ I was literally breathing in her last breath,” Mrs. Sonnen recounted. “I never wanted to breathe again, because now I felt I had her in my lungs. Don’t make me laugh, don’t make me exhale.”

Layla’s parents have no regrets about their decision to put her in hospice. “It was the absolute right decision, and in hindsight we should have done it sooner,” Mr. Sonnen said. “She was suffering, and we had blinders on.”

Ms. Pinedo said she is “infinitely grateful” for hospice, despite the heartache of Aaron’s condition. Sometimes the social worker will stop by, she said, just to say hello and drop off a latte, a small gesture that can feel very uplifting. “They’ve been our lifeline,” she said.

Ms. Pinedo talks about a friend of hers with a healthy baby, also named Aaron, who is pregnant with her second child. “All the stuff that was on our list, they’re living. And I love them dearly. But it’s almost hard to look, because it’s like looking at the stuff that you didn’t get. It’s like Christmas Day, staring through the window at the neighbor’s house, and you’re sitting there in the cold.”

Yet she seems palpably torn between that bleak remorse and the unconditional love parents feel toward their children. At one point, Ms. Pinedo interrupted herself midsentence and turned to her son, who was in Mr. Martinez’s arms: “Yes, Papi, you are so stinking cute, and you are still my dream come true.”

This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Most patients with drug-resistant epilepsy should receive a referral for a surgical evaluation as soon as it’s clear their disease is drug resistant, according to expert consensus recommendations from the International League Against Epilepsy (ILAE) published in the journal Epilepsia.

Comprehensive epilepsy care

Such a referral is not ”a commitment to undergo brain surgery,” wrote the authors of the new recommendations study, but surgical evaluations offer patients an opportunity to learn about the range of therapies available to them and to have their diagnosis verified, as well as learning about the cause and type of epilepsy they have, even if they ultimately do not pursue surgery.

”In fact, most patients with drug-resistant epilepsy do not end up undergoing surgery after referral, but still benefit from comprehensive epilepsy care improving quality of life and lowering mortality,” wrote lead author Lara Jehi, MD, professor of neurology and epilepsy specialist at Cleveland Clinic, and her colleagues. “A better characterization of the epilepsy can also help optimize medical therapy and address somatic, cognitive, behavioral, and psychiatric comorbidities.”
 

Is the diagnosis correct?

They noted that about one-third of patients referred to epilepsy centers with an apparent diagnosis of drug-resistant epilepsy actually have psychogenic nonepileptic seizures (PNES) – not epilepsy – and an early, accurate diagnosis of PNES can ensure they receive psychotherapy, stop taking antiseizure medications, and have better outcomes.

“These recommendations are necessary, as the delay to surgery and the overall underutilization of surgery have not improved much over the last 20 years,” said Selim R. Benbadis, MD, professor of neurology and director of the comprehensive epilepsy program at the University of South Florida and Tampa General Hospital. “Comprehensive epilepsy centers offer more than surgery, including correct and precise diagnosis, drug options, three [Food and Drug Administration]–approved neurostimulation options, and more,” said Dr. Benbadis, who was not involved in the development of these recommendations.
 

Consensus recommendations

On behalf of the the ILAE’s Surgical Therapies Commission, the authors used the Delphi consensus process to develop expert consensus recommendations on when to refer patients with epilepsy to surgery. They conducted three Delphi rounds on 51 clinical scenarios with 61 epileptologists (38% of participants), epilepsy neurosurgeons (34%), neurologists (23%), neuropsychiatrists (2%), and neuropsychologists (3%) from 28 countries. Most of clinicians focused on adults (39%) or adults and children (41%) while 20% focused only on pediatric epilepsy.

The physicians involved had a median 22 years of practice and represented all six ILAE regions: 30% from North America, 28% from Europe, 18% from Asia/Oceania, 13% from Latin America, 7% from the Eastern Mediterranean, and 4% from Africa.

The result of these rounds were three key recommendations arising from the consensus of experts consulted. First, every patient up to 70 years old who has drug-resistant epilepsy should be offered the option of a surgical evaluation as soon as it’s apparent that they have drug resistance. The option for surgical evaluation should be provided independent of their sex or socioeconomic status and regardless of how long they have had epilepsy, their seizure type, their epilepsy type, localization, and their comorbidities, ”including severe psychiatric comorbidity like psychogenic nonepileptic seizures (PNES) or substance abuse if patients are cooperative with management,” the authors wrote.

”Resective surgery can improve quality of life and cognitive outcomes and is the only treatment demonstrated to improve survival and reverse excess mortality attributed to drug-resistant epilepsy,” the authors wrote. Evidence supports that surgical evaluation is the most cost-effective approach to treating drug-resistant epilepsy, they added. Yet, it still takes about 20 years with epilepsy before an adult patient might be referred, ”and the neurology community remains ambivalent due to ongoing barriers and misconceptions about epilepsy surgery,” they wrote.

The second recommendation is to consider a surgical referral for older patients with drug-resistant epilepsy who have no surgical contraindication. Physicians can also consider a referral for patients of any age who are seizure free while taking one to two antiseizure drugs but who have a brain lesion in the noneloquent cortex.

The third recommendation is not to offer surgery if a patient has an active substance dependency and is not cooperative with management.

“Although there is some evidence that seizure outcomes are no different in individuals with active substance use disorder who have epilepsy surgery, the literature suggests increased perioperative surgical and anesthetic risk in this cohort,” the authors wrote. ”Patients with active substance abuse are more likely to be nonadherent with their seizure medications, and to leave the hospital against medical advice.”

One area where the participants did not reach consensus was regarding whether to refer patients who did not become seizure-free after trying just one “tolerated and appropriately chosen” antiseizure medication. Half (49%) said they would be unlikely to refer or would never refer that patient while 44% said they would likely or always refer them, and 7% weren’t sure.
 

The ‘next level’ of epilepsy care

“Similar recommendations have been published before, by the National Association of Epilepsy Centers, more than once, and have not changed the referral patterns,” Dr. Benbadis said. “They are not implemented by the average general neurologist.” While there are many reasons for this, one with a relativity simple fix is to adjust the language doctors use to when talking with patients about getting an evaluation, Dr. Benbadis said. ”The key is to rephrase: Instead of referrals ‘for surgery,’ which can be scary to many neurologists and patients, we should use more general terms, like referrals for the ‘next level of care by epilepsy specialists,’ ” said Dr. Benbadis, who advocated for this change in terminology in a 2019 editorial. Such language is less frightening and can ease patients’ concerns about going to an epilepsy center where they can learn about more options than just surgery.

Further, surgical options have expanded in recent years, including the development of laser interstitial thermal therapy and neuromodulation. “Identifying candidacy for any of these approaches starts with a surgical referral, so a timely evaluation is key,” the authors wrote.
 

Referral delays persist

Despite the strong evidence for timely referrals, delays have persisted for decades, said Dr. Benbadis, echoing what the authors describe. ”Despite the results of two randomized controlled trials showing that surgery for temporal lobe epilepsy in adults, and resective surgery in children, is superior to continued antiseizure medications both in terms of seizure freedom and improved quality of life, the mean epilepsy duration to temporal lobe resection has persisted at over 20 years,” the authors wrote. ”Although drug resistance is reached with a mean latency of 9 years in epilepsy surgery candidates, these patients have experienced a decade of unabating seizures with detrimental effects including cognitive and psychiatric comorbidities, poor psychosocial outcomes, potential injuries, and risk of death.”

Surgery is not a ‘dangerous last resort’

The authors point out a variety of likely reasons for these delays, including patients experiencing temporary remissions with a new drug, lack of adequate health care access, overestimating surgery risks, and underestimating the seriousness and risk of death from ongoing seizures.

Dr. Benbadis agreed, referring to a “combination of lack of knowledge and unrealistic views about surgery outcomes and complications.” Patients and their neurologists think surgery is a “dangerous last resort, fraught with complications, and they don’t know the outcome, so it’s mainly that they are not very well-educated about epilepsy surgery,” he said. Complacency about a patient’s infrequent seizures plays a role as well, he added. “Their patient is having one seizure every 2 months, and they might say, ‘well, that’s okay, that’s not that bad,’ but it is when we can cure it.”

Similar factors are barriers to epilepsy surgery: “lack of knowledge or misconceptions about surgical risks, negative behaviors, or cultural issues and access issues.”

Another major barrier, both within neurology and throughout medicine in general, is that large academic centers that accept referrals, including epilepsy centers, have poor communication, follow-up, and scheduling, Dr. Benbadis said.

The authors provided a table with suggestions on potential solutions to those barriers, including identifying online resources to help doctors identify possible surgery candidates, such as www.toolsforepilepsy.com, and a range of educational resources. Ways to improve access and cost include mobile clinics, telehealth, coordinating with an epilepsy organization, and employing a multidisciplinary team that includes a social worker to help with support such as transportation and health insurance.

Most patients with drug-resistant epilepsy should receive a referral for a surgical evaluation as soon as it’s clear their disease is drug resistant, according to expert consensus recommendations from the International League Against Epilepsy (ILAE) published in the journal Epilepsia.

Comprehensive epilepsy care

Such a referral is not ”a commitment to undergo brain surgery,” wrote the authors of the new recommendations study, but surgical evaluations offer patients an opportunity to learn about the range of therapies available to them and to have their diagnosis verified, as well as learning about the cause and type of epilepsy they have, even if they ultimately do not pursue surgery.

”In fact, most patients with drug-resistant epilepsy do not end up undergoing surgery after referral, but still benefit from comprehensive epilepsy care improving quality of life and lowering mortality,” wrote lead author Lara Jehi, MD, professor of neurology and epilepsy specialist at Cleveland Clinic, and her colleagues. “A better characterization of the epilepsy can also help optimize medical therapy and address somatic, cognitive, behavioral, and psychiatric comorbidities.”
 

Is the diagnosis correct?

They noted that about one-third of patients referred to epilepsy centers with an apparent diagnosis of drug-resistant epilepsy actually have psychogenic nonepileptic seizures (PNES) – not epilepsy – and an early, accurate diagnosis of PNES can ensure they receive psychotherapy, stop taking antiseizure medications, and have better outcomes.

“These recommendations are necessary, as the delay to surgery and the overall underutilization of surgery have not improved much over the last 20 years,” said Selim R. Benbadis, MD, professor of neurology and director of the comprehensive epilepsy program at the University of South Florida and Tampa General Hospital. “Comprehensive epilepsy centers offer more than surgery, including correct and precise diagnosis, drug options, three [Food and Drug Administration]–approved neurostimulation options, and more,” said Dr. Benbadis, who was not involved in the development of these recommendations.
 

Consensus recommendations

On behalf of the the ILAE’s Surgical Therapies Commission, the authors used the Delphi consensus process to develop expert consensus recommendations on when to refer patients with epilepsy to surgery. They conducted three Delphi rounds on 51 clinical scenarios with 61 epileptologists (38% of participants), epilepsy neurosurgeons (34%), neurologists (23%), neuropsychiatrists (2%), and neuropsychologists (3%) from 28 countries. Most of clinicians focused on adults (39%) or adults and children (41%) while 20% focused only on pediatric epilepsy.

The physicians involved had a median 22 years of practice and represented all six ILAE regions: 30% from North America, 28% from Europe, 18% from Asia/Oceania, 13% from Latin America, 7% from the Eastern Mediterranean, and 4% from Africa.

The result of these rounds were three key recommendations arising from the consensus of experts consulted. First, every patient up to 70 years old who has drug-resistant epilepsy should be offered the option of a surgical evaluation as soon as it’s apparent that they have drug resistance. The option for surgical evaluation should be provided independent of their sex or socioeconomic status and regardless of how long they have had epilepsy, their seizure type, their epilepsy type, localization, and their comorbidities, ”including severe psychiatric comorbidity like psychogenic nonepileptic seizures (PNES) or substance abuse if patients are cooperative with management,” the authors wrote.

”Resective surgery can improve quality of life and cognitive outcomes and is the only treatment demonstrated to improve survival and reverse excess mortality attributed to drug-resistant epilepsy,” the authors wrote. Evidence supports that surgical evaluation is the most cost-effective approach to treating drug-resistant epilepsy, they added. Yet, it still takes about 20 years with epilepsy before an adult patient might be referred, ”and the neurology community remains ambivalent due to ongoing barriers and misconceptions about epilepsy surgery,” they wrote.

The second recommendation is to consider a surgical referral for older patients with drug-resistant epilepsy who have no surgical contraindication. Physicians can also consider a referral for patients of any age who are seizure free while taking one to two antiseizure drugs but who have a brain lesion in the noneloquent cortex.

The third recommendation is not to offer surgery if a patient has an active substance dependency and is not cooperative with management.

“Although there is some evidence that seizure outcomes are no different in individuals with active substance use disorder who have epilepsy surgery, the literature suggests increased perioperative surgical and anesthetic risk in this cohort,” the authors wrote. ”Patients with active substance abuse are more likely to be nonadherent with their seizure medications, and to leave the hospital against medical advice.”

One area where the participants did not reach consensus was regarding whether to refer patients who did not become seizure-free after trying just one “tolerated and appropriately chosen” antiseizure medication. Half (49%) said they would be unlikely to refer or would never refer that patient while 44% said they would likely or always refer them, and 7% weren’t sure.
 

The ‘next level’ of epilepsy care

“Similar recommendations have been published before, by the National Association of Epilepsy Centers, more than once, and have not changed the referral patterns,” Dr. Benbadis said. “They are not implemented by the average general neurologist.” While there are many reasons for this, one with a relativity simple fix is to adjust the language doctors use to when talking with patients about getting an evaluation, Dr. Benbadis said. ”The key is to rephrase: Instead of referrals ‘for surgery,’ which can be scary to many neurologists and patients, we should use more general terms, like referrals for the ‘next level of care by epilepsy specialists,’ ” said Dr. Benbadis, who advocated for this change in terminology in a 2019 editorial. Such language is less frightening and can ease patients’ concerns about going to an epilepsy center where they can learn about more options than just surgery.

Further, surgical options have expanded in recent years, including the development of laser interstitial thermal therapy and neuromodulation. “Identifying candidacy for any of these approaches starts with a surgical referral, so a timely evaluation is key,” the authors wrote.
 

Referral delays persist

Despite the strong evidence for timely referrals, delays have persisted for decades, said Dr. Benbadis, echoing what the authors describe. ”Despite the results of two randomized controlled trials showing that surgery for temporal lobe epilepsy in adults, and resective surgery in children, is superior to continued antiseizure medications both in terms of seizure freedom and improved quality of life, the mean epilepsy duration to temporal lobe resection has persisted at over 20 years,” the authors wrote. ”Although drug resistance is reached with a mean latency of 9 years in epilepsy surgery candidates, these patients have experienced a decade of unabating seizures with detrimental effects including cognitive and psychiatric comorbidities, poor psychosocial outcomes, potential injuries, and risk of death.”

Surgery is not a ‘dangerous last resort’

The authors point out a variety of likely reasons for these delays, including patients experiencing temporary remissions with a new drug, lack of adequate health care access, overestimating surgery risks, and underestimating the seriousness and risk of death from ongoing seizures.

Dr. Benbadis agreed, referring to a “combination of lack of knowledge and unrealistic views about surgery outcomes and complications.” Patients and their neurologists think surgery is a “dangerous last resort, fraught with complications, and they don’t know the outcome, so it’s mainly that they are not very well-educated about epilepsy surgery,” he said. Complacency about a patient’s infrequent seizures plays a role as well, he added. “Their patient is having one seizure every 2 months, and they might say, ‘well, that’s okay, that’s not that bad,’ but it is when we can cure it.”

Similar factors are barriers to epilepsy surgery: “lack of knowledge or misconceptions about surgical risks, negative behaviors, or cultural issues and access issues.”

Another major barrier, both within neurology and throughout medicine in general, is that large academic centers that accept referrals, including epilepsy centers, have poor communication, follow-up, and scheduling, Dr. Benbadis said.

The authors provided a table with suggestions on potential solutions to those barriers, including identifying online resources to help doctors identify possible surgery candidates, such as www.toolsforepilepsy.com, and a range of educational resources. Ways to improve access and cost include mobile clinics, telehealth, coordinating with an epilepsy organization, and employing a multidisciplinary team that includes a social worker to help with support such as transportation and health insurance.

Most patients with drug-resistant epilepsy should receive a referral for a surgical evaluation as soon as it’s clear their disease is drug resistant, according to expert consensus recommendations from the International League Against Epilepsy (ILAE) published in the journal Epilepsia.

Comprehensive epilepsy care

Such a referral is not ”a commitment to undergo brain surgery,” wrote the authors of the new recommendations study, but surgical evaluations offer patients an opportunity to learn about the range of therapies available to them and to have their diagnosis verified, as well as learning about the cause and type of epilepsy they have, even if they ultimately do not pursue surgery.

”In fact, most patients with drug-resistant epilepsy do not end up undergoing surgery after referral, but still benefit from comprehensive epilepsy care improving quality of life and lowering mortality,” wrote lead author Lara Jehi, MD, professor of neurology and epilepsy specialist at Cleveland Clinic, and her colleagues. “A better characterization of the epilepsy can also help optimize medical therapy and address somatic, cognitive, behavioral, and psychiatric comorbidities.”
 

Is the diagnosis correct?

They noted that about one-third of patients referred to epilepsy centers with an apparent diagnosis of drug-resistant epilepsy actually have psychogenic nonepileptic seizures (PNES) – not epilepsy – and an early, accurate diagnosis of PNES can ensure they receive psychotherapy, stop taking antiseizure medications, and have better outcomes.

“These recommendations are necessary, as the delay to surgery and the overall underutilization of surgery have not improved much over the last 20 years,” said Selim R. Benbadis, MD, professor of neurology and director of the comprehensive epilepsy program at the University of South Florida and Tampa General Hospital. “Comprehensive epilepsy centers offer more than surgery, including correct and precise diagnosis, drug options, three [Food and Drug Administration]–approved neurostimulation options, and more,” said Dr. Benbadis, who was not involved in the development of these recommendations.
 

Consensus recommendations

On behalf of the the ILAE’s Surgical Therapies Commission, the authors used the Delphi consensus process to develop expert consensus recommendations on when to refer patients with epilepsy to surgery. They conducted three Delphi rounds on 51 clinical scenarios with 61 epileptologists (38% of participants), epilepsy neurosurgeons (34%), neurologists (23%), neuropsychiatrists (2%), and neuropsychologists (3%) from 28 countries. Most of clinicians focused on adults (39%) or adults and children (41%) while 20% focused only on pediatric epilepsy.

The physicians involved had a median 22 years of practice and represented all six ILAE regions: 30% from North America, 28% from Europe, 18% from Asia/Oceania, 13% from Latin America, 7% from the Eastern Mediterranean, and 4% from Africa.

The result of these rounds were three key recommendations arising from the consensus of experts consulted. First, every patient up to 70 years old who has drug-resistant epilepsy should be offered the option of a surgical evaluation as soon as it’s apparent that they have drug resistance. The option for surgical evaluation should be provided independent of their sex or socioeconomic status and regardless of how long they have had epilepsy, their seizure type, their epilepsy type, localization, and their comorbidities, ”including severe psychiatric comorbidity like psychogenic nonepileptic seizures (PNES) or substance abuse if patients are cooperative with management,” the authors wrote.

”Resective surgery can improve quality of life and cognitive outcomes and is the only treatment demonstrated to improve survival and reverse excess mortality attributed to drug-resistant epilepsy,” the authors wrote. Evidence supports that surgical evaluation is the most cost-effective approach to treating drug-resistant epilepsy, they added. Yet, it still takes about 20 years with epilepsy before an adult patient might be referred, ”and the neurology community remains ambivalent due to ongoing barriers and misconceptions about epilepsy surgery,” they wrote.

The second recommendation is to consider a surgical referral for older patients with drug-resistant epilepsy who have no surgical contraindication. Physicians can also consider a referral for patients of any age who are seizure free while taking one to two antiseizure drugs but who have a brain lesion in the noneloquent cortex.

The third recommendation is not to offer surgery if a patient has an active substance dependency and is not cooperative with management.

“Although there is some evidence that seizure outcomes are no different in individuals with active substance use disorder who have epilepsy surgery, the literature suggests increased perioperative surgical and anesthetic risk in this cohort,” the authors wrote. ”Patients with active substance abuse are more likely to be nonadherent with their seizure medications, and to leave the hospital against medical advice.”

One area where the participants did not reach consensus was regarding whether to refer patients who did not become seizure-free after trying just one “tolerated and appropriately chosen” antiseizure medication. Half (49%) said they would be unlikely to refer or would never refer that patient while 44% said they would likely or always refer them, and 7% weren’t sure.
 

The ‘next level’ of epilepsy care

“Similar recommendations have been published before, by the National Association of Epilepsy Centers, more than once, and have not changed the referral patterns,” Dr. Benbadis said. “They are not implemented by the average general neurologist.” While there are many reasons for this, one with a relativity simple fix is to adjust the language doctors use to when talking with patients about getting an evaluation, Dr. Benbadis said. ”The key is to rephrase: Instead of referrals ‘for surgery,’ which can be scary to many neurologists and patients, we should use more general terms, like referrals for the ‘next level of care by epilepsy specialists,’ ” said Dr. Benbadis, who advocated for this change in terminology in a 2019 editorial. Such language is less frightening and can ease patients’ concerns about going to an epilepsy center where they can learn about more options than just surgery.

Further, surgical options have expanded in recent years, including the development of laser interstitial thermal therapy and neuromodulation. “Identifying candidacy for any of these approaches starts with a surgical referral, so a timely evaluation is key,” the authors wrote.
 

Referral delays persist

Despite the strong evidence for timely referrals, delays have persisted for decades, said Dr. Benbadis, echoing what the authors describe. ”Despite the results of two randomized controlled trials showing that surgery for temporal lobe epilepsy in adults, and resective surgery in children, is superior to continued antiseizure medications both in terms of seizure freedom and improved quality of life, the mean epilepsy duration to temporal lobe resection has persisted at over 20 years,” the authors wrote. ”Although drug resistance is reached with a mean latency of 9 years in epilepsy surgery candidates, these patients have experienced a decade of unabating seizures with detrimental effects including cognitive and psychiatric comorbidities, poor psychosocial outcomes, potential injuries, and risk of death.”

Surgery is not a ‘dangerous last resort’

The authors point out a variety of likely reasons for these delays, including patients experiencing temporary remissions with a new drug, lack of adequate health care access, overestimating surgery risks, and underestimating the seriousness and risk of death from ongoing seizures.

Dr. Benbadis agreed, referring to a “combination of lack of knowledge and unrealistic views about surgery outcomes and complications.” Patients and their neurologists think surgery is a “dangerous last resort, fraught with complications, and they don’t know the outcome, so it’s mainly that they are not very well-educated about epilepsy surgery,” he said. Complacency about a patient’s infrequent seizures plays a role as well, he added. “Their patient is having one seizure every 2 months, and they might say, ‘well, that’s okay, that’s not that bad,’ but it is when we can cure it.”

Similar factors are barriers to epilepsy surgery: “lack of knowledge or misconceptions about surgical risks, negative behaviors, or cultural issues and access issues.”

Another major barrier, both within neurology and throughout medicine in general, is that large academic centers that accept referrals, including epilepsy centers, have poor communication, follow-up, and scheduling, Dr. Benbadis said.

The authors provided a table with suggestions on potential solutions to those barriers, including identifying online resources to help doctors identify possible surgery candidates, such as www.toolsforepilepsy.com, and a range of educational resources. Ways to improve access and cost include mobile clinics, telehealth, coordinating with an epilepsy organization, and employing a multidisciplinary team that includes a social worker to help with support such as transportation and health insurance.

In the United States, the cost of brand-name medications for treating epilepsy soared during the period 2010-2018, while the cost of generic antiseizure medications (ASMs) decreased, a new analysis shows.

After adjustment for inflation, the cost of a 1-year supply of brand-name ASMs grew 277%, while generics became 42% less expensive.

“Our study makes transparent striking trends in brand name prescribing patterns,” the study team wrote.

Since 2010, the costs for brand-name ASMs have “consistently” increased. Costs were particularly boosted by increases in prescriptions for lacosamide (Vimpat), in addition to a “steep increase in the cost per pill, with brand-name drugs costing 10 times more than their generic counterparts,” first author Samuel Waller Terman, MD, of the University of Michigan, Ann Arbor, added in a news release.

The study was published online  in Neurology.
 

Is a 10-fold increase in cost worth it?

To evaluate trends in ASM prescriptions and costs, the researchers used a random sample of 20% of Medicare beneficiaries with coverage from 2008 to 2018. There were 77,000 to 133,000 patients with epilepsy each year.

Over time, likely because of increasing availability of generics, brand-name ASMs made up a smaller proportion of pills prescribed, from 56% in 2008 to 14% in 2018, but still made up 79% of prescription drug costs in 2018.

The annual cost of brand-name ASMs rose from $2,800 in 2008 to $10,700 in 2018, while the cost of generic drugs decreased from $800 to $460 during that time.

An increased number of prescriptions for lacosamide was responsible for 45% of the total increase in brand-name costs.

As of 2018, lacosamide comprised 30% of all brand-name pill supply (followed by pregabalin, at 15%) and 30% of all brand-name costs (followed by clobazam and pregabalin, both at 9%), the investigators reported.

Brand-name antiepileptic drug costs decreased from 2008 to 2010, but after the introduction of lacosamide, total brand-name costs steadily rose from $72 million in 2010 (in 2018 dollars) to $256 million in 2018, they noted.

Because the dataset consists of a 20% random Medicare sample, total Medicare costs for brand-name ASMs for beneficiaries with epilepsy alone likely rose from roughly $360 million in 2010 to $1.3 billion in 2018, they added.

“Clinicians must remain cognizant of this societal cost magnitude when judging whether the 10-fold increased expense per pill for brand name medications is worth the possible benefits,” they wrote.

“While newer-generation drugs have potential advantages such as limited drug interactions and different side effect profiles, there have been conflicting studies on whether they are cost effective,” Dr. Terman noted in a news release.
 

A barrier to treatment

The authors of an accompanying editorial propose that the problem of prescription drug costs could be solved through a combination of competition and government regulation of prices. Patients and physicians are the most important stakeholders in this issue.

“When something represents 14% of the total use, but contributes 79% of the cost, it would be wise to consider alternatives, assuming that these alternatives are not of lower quality,” wrote Wyatt Bensken, with Case Western Reserve University, Cleveland, and Iván Sánchez Fernández, MD, with Boston Medical Center.

“When there are several ASMs with a similar mechanism of action, similar efficacy, similar safety and tolerability profile, and different costs, it would be unwise to choose the more expensive alternative just because it is newer,” they said.

This study, they added, provides data to “understand, and begin to act, on the challenging problem of the cost of prescription ASMs. After all, what is the point of having a large number of ASMs if their cost severely limits their use?”

A limitation of the study is that only Medicare prescription claims were included, so the results may not apply to younger patients with private insurance.

The study received no direct funding. The authors and editorialists have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In the United States, the cost of brand-name medications for treating epilepsy soared during the period 2010-2018, while the cost of generic antiseizure medications (ASMs) decreased, a new analysis shows.

After adjustment for inflation, the cost of a 1-year supply of brand-name ASMs grew 277%, while generics became 42% less expensive.

“Our study makes transparent striking trends in brand name prescribing patterns,” the study team wrote.

Since 2010, the costs for brand-name ASMs have “consistently” increased. Costs were particularly boosted by increases in prescriptions for lacosamide (Vimpat), in addition to a “steep increase in the cost per pill, with brand-name drugs costing 10 times more than their generic counterparts,” first author Samuel Waller Terman, MD, of the University of Michigan, Ann Arbor, added in a news release.

The study was published online  in Neurology.
 

Is a 10-fold increase in cost worth it?

To evaluate trends in ASM prescriptions and costs, the researchers used a random sample of 20% of Medicare beneficiaries with coverage from 2008 to 2018. There were 77,000 to 133,000 patients with epilepsy each year.

Over time, likely because of increasing availability of generics, brand-name ASMs made up a smaller proportion of pills prescribed, from 56% in 2008 to 14% in 2018, but still made up 79% of prescription drug costs in 2018.

The annual cost of brand-name ASMs rose from $2,800 in 2008 to $10,700 in 2018, while the cost of generic drugs decreased from $800 to $460 during that time.

An increased number of prescriptions for lacosamide was responsible for 45% of the total increase in brand-name costs.

As of 2018, lacosamide comprised 30% of all brand-name pill supply (followed by pregabalin, at 15%) and 30% of all brand-name costs (followed by clobazam and pregabalin, both at 9%), the investigators reported.

Brand-name antiepileptic drug costs decreased from 2008 to 2010, but after the introduction of lacosamide, total brand-name costs steadily rose from $72 million in 2010 (in 2018 dollars) to $256 million in 2018, they noted.

Because the dataset consists of a 20% random Medicare sample, total Medicare costs for brand-name ASMs for beneficiaries with epilepsy alone likely rose from roughly $360 million in 2010 to $1.3 billion in 2018, they added.

“Clinicians must remain cognizant of this societal cost magnitude when judging whether the 10-fold increased expense per pill for brand name medications is worth the possible benefits,” they wrote.

“While newer-generation drugs have potential advantages such as limited drug interactions and different side effect profiles, there have been conflicting studies on whether they are cost effective,” Dr. Terman noted in a news release.
 

A barrier to treatment

The authors of an accompanying editorial propose that the problem of prescription drug costs could be solved through a combination of competition and government regulation of prices. Patients and physicians are the most important stakeholders in this issue.

“When something represents 14% of the total use, but contributes 79% of the cost, it would be wise to consider alternatives, assuming that these alternatives are not of lower quality,” wrote Wyatt Bensken, with Case Western Reserve University, Cleveland, and Iván Sánchez Fernández, MD, with Boston Medical Center.

“When there are several ASMs with a similar mechanism of action, similar efficacy, similar safety and tolerability profile, and different costs, it would be unwise to choose the more expensive alternative just because it is newer,” they said.

This study, they added, provides data to “understand, and begin to act, on the challenging problem of the cost of prescription ASMs. After all, what is the point of having a large number of ASMs if their cost severely limits their use?”

A limitation of the study is that only Medicare prescription claims were included, so the results may not apply to younger patients with private insurance.

The study received no direct funding. The authors and editorialists have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In the United States, the cost of brand-name medications for treating epilepsy soared during the period 2010-2018, while the cost of generic antiseizure medications (ASMs) decreased, a new analysis shows.

After adjustment for inflation, the cost of a 1-year supply of brand-name ASMs grew 277%, while generics became 42% less expensive.

“Our study makes transparent striking trends in brand name prescribing patterns,” the study team wrote.

Since 2010, the costs for brand-name ASMs have “consistently” increased. Costs were particularly boosted by increases in prescriptions for lacosamide (Vimpat), in addition to a “steep increase in the cost per pill, with brand-name drugs costing 10 times more than their generic counterparts,” first author Samuel Waller Terman, MD, of the University of Michigan, Ann Arbor, added in a news release.

The study was published online  in Neurology.
 

Is a 10-fold increase in cost worth it?

To evaluate trends in ASM prescriptions and costs, the researchers used a random sample of 20% of Medicare beneficiaries with coverage from 2008 to 2018. There were 77,000 to 133,000 patients with epilepsy each year.

Over time, likely because of increasing availability of generics, brand-name ASMs made up a smaller proportion of pills prescribed, from 56% in 2008 to 14% in 2018, but still made up 79% of prescription drug costs in 2018.

The annual cost of brand-name ASMs rose from $2,800 in 2008 to $10,700 in 2018, while the cost of generic drugs decreased from $800 to $460 during that time.

An increased number of prescriptions for lacosamide was responsible for 45% of the total increase in brand-name costs.

As of 2018, lacosamide comprised 30% of all brand-name pill supply (followed by pregabalin, at 15%) and 30% of all brand-name costs (followed by clobazam and pregabalin, both at 9%), the investigators reported.

Brand-name antiepileptic drug costs decreased from 2008 to 2010, but after the introduction of lacosamide, total brand-name costs steadily rose from $72 million in 2010 (in 2018 dollars) to $256 million in 2018, they noted.

Because the dataset consists of a 20% random Medicare sample, total Medicare costs for brand-name ASMs for beneficiaries with epilepsy alone likely rose from roughly $360 million in 2010 to $1.3 billion in 2018, they added.

“Clinicians must remain cognizant of this societal cost magnitude when judging whether the 10-fold increased expense per pill for brand name medications is worth the possible benefits,” they wrote.

“While newer-generation drugs have potential advantages such as limited drug interactions and different side effect profiles, there have been conflicting studies on whether they are cost effective,” Dr. Terman noted in a news release.
 

A barrier to treatment

The authors of an accompanying editorial propose that the problem of prescription drug costs could be solved through a combination of competition and government regulation of prices. Patients and physicians are the most important stakeholders in this issue.

“When something represents 14% of the total use, but contributes 79% of the cost, it would be wise to consider alternatives, assuming that these alternatives are not of lower quality,” wrote Wyatt Bensken, with Case Western Reserve University, Cleveland, and Iván Sánchez Fernández, MD, with Boston Medical Center.

“When there are several ASMs with a similar mechanism of action, similar efficacy, similar safety and tolerability profile, and different costs, it would be unwise to choose the more expensive alternative just because it is newer,” they said.

This study, they added, provides data to “understand, and begin to act, on the challenging problem of the cost of prescription ASMs. After all, what is the point of having a large number of ASMs if their cost severely limits their use?”

A limitation of the study is that only Medicare prescription claims were included, so the results may not apply to younger patients with private insurance.

The study received no direct funding. The authors and editorialists have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Elevated concentrations of carbon monoxide (CO) due to air pollution increases the risk of epileptic seizures, a unique new study suggests.

The link between daily outdoor CO exposure and seizure risk was particularly evident for subclinical seizures – those in patients with abnormal electroencephalography (EEG) signals but no clinical symptoms.

“Our findings suggest that people with epilepsy should avoid high CO exposure to reduce potential seizure risk,” said study investigator Zhuying Chen, PhD candidate, department of biomedical engineering, University of Melbourne.

The study was published online in Epilepsia.
 

Pollution’s impact on brain health

Emerging evidence indicates air pollution affects brain health and may increase the risk of hospitalization or outpatient visits for epilepsy. However, little is known about the effect of pollution on the occurrence of epileptic seizures.

The study used two independent long-term seizure datasets – the NeuroVista (NV) study and the Seer App seizure diary (SD). In the NeuroVista study, researchers recorded continuous intracranial iEEG from patients with refractory focal epilepsy who had been implanted with a personal seizure advisory device that wirelessly recorded seizures on an external device.

The SD dataset included diaries documenting self-reported seizures, seizure cycles, and medication adherence.

Researchers collected data on hourly concentrations of outdoor CO, nitrogen dioxide (NO₂), particulate matter of 10 μm or less in diameter (PM₁₀), ozone (O₃), and sulfur dioxide (SO₂). The levels were measured at air quality monitoring stations in Australia.

Investigators aggregated hourly observations into daily mean data. All daily concentrations of CO and SO₂ and at least 95% of daily concentrations of NO₂, O₃, and PM₁₀ were within Australian air quality standards, said Mr. Chen.

The study included 49 participants, with epilepsy data on 15 patients in the NeuroVista study and on 34 from the SD dataset.

Overall, 6,692 epileptic seizures on 3,639 seizure days were recorded during 23,349 follow-up days from 2010 to 2012 (NV dataset) and 2018 to 2021 (SD dataset).

The investigators found a significant positive association between CO concentrations and epileptic seizure risks. The relative risk (RR) was 1.04 (95% confidence interval, 1.01–1.07; P < .01) for an interquartile range (IQR) increase of CO (0.13 parts per million).
 

Sex differences

There were no significant relationships for the other four air pollutants. However, Mr. Chen noted that Australia has very low air pollution levels; most usually are within World Health Organization air quality guidelines.

“Our findings may not be generalized to other countries with high air pollution levels,” said Mr. Chen. He noted that the relatively small number of patients in the study may limit the statistical power to detect some associations.

The study showed that females had a significantly increased risk of epileptic seizures when exposed to elevated CO (RR, 1.05; 95% CI, 1.01–1.08; P < .05) and NO₂ (RR, 1.09; 95% CI, 1.01–1.16; P < .05) concentrations. There were no significant associations in males for any air pollutants.

Differences in outdoor activities and behaviors such as smoking and exercise may lead to variations in environmental exposure and help explain the sex differences, said Mr. Chen. These differences may also be due to the study’s limited sample size.

Analyzing the two datasets separately, the researchers found there was a significant association between CO concentration and epileptic seizure risk in the NV dataset (RR, 1.10; 95% CI, 1.03–1.17; P < .01).

There were no significant associations in the SD dataset for any air pollutants. This may be because only clinical seizures – those associated with evident symptoms – are self-reported, said Mr. Chen. He also noted that seizure diaries may be unreliable.

In the NV dataset, the epileptic seizure risk was significantly increased when only subclinical seizures were considered (RR, 1.20; 95% CI, 1.12–1.28; P < .001) for an IQR increase of CO concentration.

The risk was significantly decreased by 13% for subclinical seizures with an IQR increase of PM₁₀ and by 9% for subclinical seizures with an IQR increase of SO₂ concentrations.

These negative associations should be interpreted with caution, inasmuch as the associations were not robust in subsequent subgroup and sensitivity analyses, said Mr. Chen.

There were no significant associations when considering clinical seizures for any air pollutants.

The positive association for subclinical but not clinical seizures suggests that low-level CO exposure may not be strong enough to directly trigger clinical seizures, said Mr. Chen.

Although previous research has demonstrated adverse neurologic effects of exposure to air pollutants, most studies were based on hospital databases or registers. Thus, they may have missed seizures that did not lead to hospital admission.
 

Unclear mechanism

The exact mechanisms linking air pollution to seizures are unclear but probably involve the synergistic interaction of multiple pathways, said Mr. Chen. “Air pollution may affect brain metabolism, alter the immune response of the brain, and induce oxidative stress and neuroinflammation, causing the brain to be more susceptible to seizures,” he noted.

This is the first study to investigate seizure rates through intracranial EEG signals and self-reported seizure diaries. It’s also the first to look into the impact of pollutants at low concentration levels on subclinical seizures.

However, the study has some limitations. Self-reported seizures in the SD dataset might underestimate the influence of air pollution on seizures. The study used postal codes as proxies for exposure to pollution, which could introduce measurement errors and underestimate associations.

In addition, Mr. Chen noted that seizures from the NeuroVista dataset were recorded from patients with drug-resistant focal epilepsy. “Whether our findings can be generalized to other epilepsy types needs further investigation.”

The study could have important clinical and public health implications. For example, said Mr. Chen, it’s possible that seizure risk could be reduced through behavioral interventions, such as avoiding being outside or using an air filtration system when pollutant levels are high.

“Clinicians could counsel their patients to avoid the potential risk of high carbon monoxide exposure,” he said.

CO exposure could be a new factor for seizure risk forecasting, which could reduce the uncertainty of seizures and help guide epilepsy management, Mr. Chen added.

The study was supported by the Melbourne Monash Consciousness Research Seed Funding and an Australian National Health and Medical Research Council Ideas grant. Mr. Chen has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Elevated concentrations of carbon monoxide (CO) due to air pollution increases the risk of epileptic seizures, a unique new study suggests.

The link between daily outdoor CO exposure and seizure risk was particularly evident for subclinical seizures – those in patients with abnormal electroencephalography (EEG) signals but no clinical symptoms.

“Our findings suggest that people with epilepsy should avoid high CO exposure to reduce potential seizure risk,” said study investigator Zhuying Chen, PhD candidate, department of biomedical engineering, University of Melbourne.

The study was published online in Epilepsia.
 

Pollution’s impact on brain health

Emerging evidence indicates air pollution affects brain health and may increase the risk of hospitalization or outpatient visits for epilepsy. However, little is known about the effect of pollution on the occurrence of epileptic seizures.

The study used two independent long-term seizure datasets – the NeuroVista (NV) study and the Seer App seizure diary (SD). In the NeuroVista study, researchers recorded continuous intracranial iEEG from patients with refractory focal epilepsy who had been implanted with a personal seizure advisory device that wirelessly recorded seizures on an external device.

The SD dataset included diaries documenting self-reported seizures, seizure cycles, and medication adherence.

Researchers collected data on hourly concentrations of outdoor CO, nitrogen dioxide (NO₂), particulate matter of 10 μm or less in diameter (PM₁₀), ozone (O₃), and sulfur dioxide (SO₂). The levels were measured at air quality monitoring stations in Australia.

Investigators aggregated hourly observations into daily mean data. All daily concentrations of CO and SO₂ and at least 95% of daily concentrations of NO₂, O₃, and PM₁₀ were within Australian air quality standards, said Mr. Chen.

The study included 49 participants, with epilepsy data on 15 patients in the NeuroVista study and on 34 from the SD dataset.

Overall, 6,692 epileptic seizures on 3,639 seizure days were recorded during 23,349 follow-up days from 2010 to 2012 (NV dataset) and 2018 to 2021 (SD dataset).

The investigators found a significant positive association between CO concentrations and epileptic seizure risks. The relative risk (RR) was 1.04 (95% confidence interval, 1.01–1.07; P < .01) for an interquartile range (IQR) increase of CO (0.13 parts per million).
 

Sex differences

There were no significant relationships for the other four air pollutants. However, Mr. Chen noted that Australia has very low air pollution levels; most usually are within World Health Organization air quality guidelines.

“Our findings may not be generalized to other countries with high air pollution levels,” said Mr. Chen. He noted that the relatively small number of patients in the study may limit the statistical power to detect some associations.

The study showed that females had a significantly increased risk of epileptic seizures when exposed to elevated CO (RR, 1.05; 95% CI, 1.01–1.08; P < .05) and NO₂ (RR, 1.09; 95% CI, 1.01–1.16; P < .05) concentrations. There were no significant associations in males for any air pollutants.

Differences in outdoor activities and behaviors such as smoking and exercise may lead to variations in environmental exposure and help explain the sex differences, said Mr. Chen. These differences may also be due to the study’s limited sample size.

Analyzing the two datasets separately, the researchers found there was a significant association between CO concentration and epileptic seizure risk in the NV dataset (RR, 1.10; 95% CI, 1.03–1.17; P < .01).

There were no significant associations in the SD dataset for any air pollutants. This may be because only clinical seizures – those associated with evident symptoms – are self-reported, said Mr. Chen. He also noted that seizure diaries may be unreliable.

In the NV dataset, the epileptic seizure risk was significantly increased when only subclinical seizures were considered (RR, 1.20; 95% CI, 1.12–1.28; P < .001) for an IQR increase of CO concentration.

The risk was significantly decreased by 13% for subclinical seizures with an IQR increase of PM₁₀ and by 9% for subclinical seizures with an IQR increase of SO₂ concentrations.

These negative associations should be interpreted with caution, inasmuch as the associations were not robust in subsequent subgroup and sensitivity analyses, said Mr. Chen.

There were no significant associations when considering clinical seizures for any air pollutants.

The positive association for subclinical but not clinical seizures suggests that low-level CO exposure may not be strong enough to directly trigger clinical seizures, said Mr. Chen.

Although previous research has demonstrated adverse neurologic effects of exposure to air pollutants, most studies were based on hospital databases or registers. Thus, they may have missed seizures that did not lead to hospital admission.
 

Unclear mechanism

The exact mechanisms linking air pollution to seizures are unclear but probably involve the synergistic interaction of multiple pathways, said Mr. Chen. “Air pollution may affect brain metabolism, alter the immune response of the brain, and induce oxidative stress and neuroinflammation, causing the brain to be more susceptible to seizures,” he noted.

This is the first study to investigate seizure rates through intracranial EEG signals and self-reported seizure diaries. It’s also the first to look into the impact of pollutants at low concentration levels on subclinical seizures.

However, the study has some limitations. Self-reported seizures in the SD dataset might underestimate the influence of air pollution on seizures. The study used postal codes as proxies for exposure to pollution, which could introduce measurement errors and underestimate associations.

In addition, Mr. Chen noted that seizures from the NeuroVista dataset were recorded from patients with drug-resistant focal epilepsy. “Whether our findings can be generalized to other epilepsy types needs further investigation.”

The study could have important clinical and public health implications. For example, said Mr. Chen, it’s possible that seizure risk could be reduced through behavioral interventions, such as avoiding being outside or using an air filtration system when pollutant levels are high.

“Clinicians could counsel their patients to avoid the potential risk of high carbon monoxide exposure,” he said.

CO exposure could be a new factor for seizure risk forecasting, which could reduce the uncertainty of seizures and help guide epilepsy management, Mr. Chen added.

The study was supported by the Melbourne Monash Consciousness Research Seed Funding and an Australian National Health and Medical Research Council Ideas grant. Mr. Chen has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Elevated concentrations of carbon monoxide (CO) due to air pollution increases the risk of epileptic seizures, a unique new study suggests.

The link between daily outdoor CO exposure and seizure risk was particularly evident for subclinical seizures – those in patients with abnormal electroencephalography (EEG) signals but no clinical symptoms.

“Our findings suggest that people with epilepsy should avoid high CO exposure to reduce potential seizure risk,” said study investigator Zhuying Chen, PhD candidate, department of biomedical engineering, University of Melbourne.

The study was published online in Epilepsia.
 

Pollution’s impact on brain health

Emerging evidence indicates air pollution affects brain health and may increase the risk of hospitalization or outpatient visits for epilepsy. However, little is known about the effect of pollution on the occurrence of epileptic seizures.

The study used two independent long-term seizure datasets – the NeuroVista (NV) study and the Seer App seizure diary (SD). In the NeuroVista study, researchers recorded continuous intracranial iEEG from patients with refractory focal epilepsy who had been implanted with a personal seizure advisory device that wirelessly recorded seizures on an external device.

The SD dataset included diaries documenting self-reported seizures, seizure cycles, and medication adherence.

Researchers collected data on hourly concentrations of outdoor CO, nitrogen dioxide (NO₂), particulate matter of 10 μm or less in diameter (PM₁₀), ozone (O₃), and sulfur dioxide (SO₂). The levels were measured at air quality monitoring stations in Australia.

Investigators aggregated hourly observations into daily mean data. All daily concentrations of CO and SO₂ and at least 95% of daily concentrations of NO₂, O₃, and PM₁₀ were within Australian air quality standards, said Mr. Chen.

The study included 49 participants, with epilepsy data on 15 patients in the NeuroVista study and on 34 from the SD dataset.

Overall, 6,692 epileptic seizures on 3,639 seizure days were recorded during 23,349 follow-up days from 2010 to 2012 (NV dataset) and 2018 to 2021 (SD dataset).

The investigators found a significant positive association between CO concentrations and epileptic seizure risks. The relative risk (RR) was 1.04 (95% confidence interval, 1.01–1.07; P < .01) for an interquartile range (IQR) increase of CO (0.13 parts per million).
 

Sex differences

There were no significant relationships for the other four air pollutants. However, Mr. Chen noted that Australia has very low air pollution levels; most usually are within World Health Organization air quality guidelines.

“Our findings may not be generalized to other countries with high air pollution levels,” said Mr. Chen. He noted that the relatively small number of patients in the study may limit the statistical power to detect some associations.

The study showed that females had a significantly increased risk of epileptic seizures when exposed to elevated CO (RR, 1.05; 95% CI, 1.01–1.08; P < .05) and NO₂ (RR, 1.09; 95% CI, 1.01–1.16; P < .05) concentrations. There were no significant associations in males for any air pollutants.

Differences in outdoor activities and behaviors such as smoking and exercise may lead to variations in environmental exposure and help explain the sex differences, said Mr. Chen. These differences may also be due to the study’s limited sample size.

Analyzing the two datasets separately, the researchers found there was a significant association between CO concentration and epileptic seizure risk in the NV dataset (RR, 1.10; 95% CI, 1.03–1.17; P < .01).

There were no significant associations in the SD dataset for any air pollutants. This may be because only clinical seizures – those associated with evident symptoms – are self-reported, said Mr. Chen. He also noted that seizure diaries may be unreliable.

In the NV dataset, the epileptic seizure risk was significantly increased when only subclinical seizures were considered (RR, 1.20; 95% CI, 1.12–1.28; P < .001) for an IQR increase of CO concentration.

The risk was significantly decreased by 13% for subclinical seizures with an IQR increase of PM₁₀ and by 9% for subclinical seizures with an IQR increase of SO₂ concentrations.

These negative associations should be interpreted with caution, inasmuch as the associations were not robust in subsequent subgroup and sensitivity analyses, said Mr. Chen.

There were no significant associations when considering clinical seizures for any air pollutants.

The positive association for subclinical but not clinical seizures suggests that low-level CO exposure may not be strong enough to directly trigger clinical seizures, said Mr. Chen.

Although previous research has demonstrated adverse neurologic effects of exposure to air pollutants, most studies were based on hospital databases or registers. Thus, they may have missed seizures that did not lead to hospital admission.
 

Unclear mechanism

The exact mechanisms linking air pollution to seizures are unclear but probably involve the synergistic interaction of multiple pathways, said Mr. Chen. “Air pollution may affect brain metabolism, alter the immune response of the brain, and induce oxidative stress and neuroinflammation, causing the brain to be more susceptible to seizures,” he noted.

This is the first study to investigate seizure rates through intracranial EEG signals and self-reported seizure diaries. It’s also the first to look into the impact of pollutants at low concentration levels on subclinical seizures.

However, the study has some limitations. Self-reported seizures in the SD dataset might underestimate the influence of air pollution on seizures. The study used postal codes as proxies for exposure to pollution, which could introduce measurement errors and underestimate associations.

In addition, Mr. Chen noted that seizures from the NeuroVista dataset were recorded from patients with drug-resistant focal epilepsy. “Whether our findings can be generalized to other epilepsy types needs further investigation.”

The study could have important clinical and public health implications. For example, said Mr. Chen, it’s possible that seizure risk could be reduced through behavioral interventions, such as avoiding being outside or using an air filtration system when pollutant levels are high.

“Clinicians could counsel their patients to avoid the potential risk of high carbon monoxide exposure,” he said.

CO exposure could be a new factor for seizure risk forecasting, which could reduce the uncertainty of seizures and help guide epilepsy management, Mr. Chen added.

The study was supported by the Melbourne Monash Consciousness Research Seed Funding and an Australian National Health and Medical Research Council Ideas grant. Mr. Chen has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

SEATTLE – Use of antiseizure medications while breastfeeding is not associated with differences in child cognitive outcomes at age 3, according to new results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

The study follows results from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, which found no evidence of cognitive harm in children who were exposed in utero to antiepileptic drugs. “[In the NEAD study] we followed our cohort to age 6 and found them to have actually an improvement in cognition by about 4 IQ points by the time they got to age 6,” Kimford J. Meador, MD, said during a presentation of the results of the MONEAD study at the 2022 annual meeting of the American Academy of Neurology.

Breastfeeding has health benefits for both mothers and children, including reduced risk of respiratory tract infections, atopic dermatitis, asthma, and diabetes in children, and reduced risk of diabetes, breast cancer, ovarian cancer, and postpartum depression in mothers. Despite those benefits, concerns about harms from exposure to antiepileptic drugs may prompt some women to avoid breastfeeding.

The results of NEAD and MONEAD should reassure patients, according to Dr. Meador, professor of neurology at Stanford (Calif.) University. “Given the known multiple benefits of breastfeeding … women with epilepsy should be encouraged to breastfeed,” he said.
 

A responsibility to ‘engage and educate’ patients

Jennifer Hopp, MD, who served as a discussant for the presentation, underscored the need for neurologists to address pregnancy with female patients of childbearing agents. “The issues may include fertility, peripartum management, and outcomes that really go through the lifespan to also include issues of menopause,” Dr. Hopp, associate professor of neurology at the University of Maryland, Baltimore, said during her presentation.

Dr. Hopp noted one study showing lower rates of breastfeeding among mothers with epilepsy. “Breastfeeding rates in women with epilepsy are strikingly lower than in women who do not have epilepsy,” said Dr. Hopp. Another study showed that women with epilepsy were less likely to sustain breastfeeding after 6 weeks.

Dr. Hopp implored neurologists to address this. “It’s our responsibility to engage and educate our patients. These data provide us messaging to our patients that the newer drugs do not adversely affect outcome independently of their other exposure, and really support well-informed choices in breastfeeding,” said Dr. Hopp.
 

Outdated attitudes still persist

Dr. Meador referred to the stigma that surrounds epilepsy, including some state laws that called for sterilization of women with epilepsy that lasted until the 1960s. One might think that such attitudes are gone, “but it’s still there,” said Dr. Meador, who recounted a story a colleague told him about a woman on antiseizure medication. In the hospital, the nurse told her not to breastfeed. The neurological consult told her not to breastfeed. She breastfed anyway. “Then they reported her for child neglect, and that was just a few years ago. So I think the message needs to be loud and clear that we encourage [women with epilepsy] to breastfeed because we have the known benefits, and now several studies showing clearly no adverse effects of breastfeeding while taking antiseizure medications,” said Dr. Meador.

MONEAD findings

The MONEAD study included women from 20 different sites, with 145 participating investigators. The researchers compared outcomes in 284 women with epilepsy and 87 healthy women. The maternal mean IQ was 98 among women with epilepsy (95% confidence interval [CI], 96-99), and 105 (95% CI, 102-107) among healthy women. Seventy-six percent of women with epilepsy breastfed, versus 89% of controls.

Among the study cohort, 79% of women with epilepsy were on monotherapy, and 21% were on polytherapy. Thirty-five percent received lamotrigine, 28% levetiracetam, 16% were on another monotherapy, 10% received a combination of lamotrigine and levetiracetam, and 11% received a different combination.

At age 3, there was no association between the verbal index score of the child and whether the mother had epilepsy or not (difference, 0.4; P = .770). The researchers did find associations with the mother’s IQ (0.3; P < .001), male versus female child sex (–4.9; P < .001), Hispanic or Latino ethnicity (vs. Non-Hispanic, –5.5; P < .001), mother without college degree (–7.0; P < .001), average Beck Anxiety Inventory score after birth (–0.4; P < .001), and weeks of gestational age at enrollment.

The researchers found no association between third trimester antiseizure medication blood levels and verbal index score after adjustment (–2.9; P = .149), with the exception of levetiracetam (–9.0; P = .033). “This is interesting (but) not to be overblown, because overall the children on levetiracetam did well. But it must be remembered that teratogens act in an exposure dependent manner, so we’re constantly in this balancing act of trying to make sure you get enough medication on board to stop the seizures and protect the mother and the child, and at the same time, not too much on board where we increase the risk of teratogenicity in the child,” said Dr. Meador.

The study was funded by the National Institutes of Health. Dr. Meador and Dr. Hopp have no relevant financial disclosures.

SEATTLE – Use of antiseizure medications while breastfeeding is not associated with differences in child cognitive outcomes at age 3, according to new results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

The study follows results from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, which found no evidence of cognitive harm in children who were exposed in utero to antiepileptic drugs. “[In the NEAD study] we followed our cohort to age 6 and found them to have actually an improvement in cognition by about 4 IQ points by the time they got to age 6,” Kimford J. Meador, MD, said during a presentation of the results of the MONEAD study at the 2022 annual meeting of the American Academy of Neurology.

Breastfeeding has health benefits for both mothers and children, including reduced risk of respiratory tract infections, atopic dermatitis, asthma, and diabetes in children, and reduced risk of diabetes, breast cancer, ovarian cancer, and postpartum depression in mothers. Despite those benefits, concerns about harms from exposure to antiepileptic drugs may prompt some women to avoid breastfeeding.

The results of NEAD and MONEAD should reassure patients, according to Dr. Meador, professor of neurology at Stanford (Calif.) University. “Given the known multiple benefits of breastfeeding … women with epilepsy should be encouraged to breastfeed,” he said.
 

A responsibility to ‘engage and educate’ patients

Jennifer Hopp, MD, who served as a discussant for the presentation, underscored the need for neurologists to address pregnancy with female patients of childbearing agents. “The issues may include fertility, peripartum management, and outcomes that really go through the lifespan to also include issues of menopause,” Dr. Hopp, associate professor of neurology at the University of Maryland, Baltimore, said during her presentation.

Dr. Hopp noted one study showing lower rates of breastfeeding among mothers with epilepsy. “Breastfeeding rates in women with epilepsy are strikingly lower than in women who do not have epilepsy,” said Dr. Hopp. Another study showed that women with epilepsy were less likely to sustain breastfeeding after 6 weeks.

Dr. Hopp implored neurologists to address this. “It’s our responsibility to engage and educate our patients. These data provide us messaging to our patients that the newer drugs do not adversely affect outcome independently of their other exposure, and really support well-informed choices in breastfeeding,” said Dr. Hopp.
 

Outdated attitudes still persist

Dr. Meador referred to the stigma that surrounds epilepsy, including some state laws that called for sterilization of women with epilepsy that lasted until the 1960s. One might think that such attitudes are gone, “but it’s still there,” said Dr. Meador, who recounted a story a colleague told him about a woman on antiseizure medication. In the hospital, the nurse told her not to breastfeed. The neurological consult told her not to breastfeed. She breastfed anyway. “Then they reported her for child neglect, and that was just a few years ago. So I think the message needs to be loud and clear that we encourage [women with epilepsy] to breastfeed because we have the known benefits, and now several studies showing clearly no adverse effects of breastfeeding while taking antiseizure medications,” said Dr. Meador.

MONEAD findings

The MONEAD study included women from 20 different sites, with 145 participating investigators. The researchers compared outcomes in 284 women with epilepsy and 87 healthy women. The maternal mean IQ was 98 among women with epilepsy (95% confidence interval [CI], 96-99), and 105 (95% CI, 102-107) among healthy women. Seventy-six percent of women with epilepsy breastfed, versus 89% of controls.

Among the study cohort, 79% of women with epilepsy were on monotherapy, and 21% were on polytherapy. Thirty-five percent received lamotrigine, 28% levetiracetam, 16% were on another monotherapy, 10% received a combination of lamotrigine and levetiracetam, and 11% received a different combination.

At age 3, there was no association between the verbal index score of the child and whether the mother had epilepsy or not (difference, 0.4; P = .770). The researchers did find associations with the mother’s IQ (0.3; P < .001), male versus female child sex (–4.9; P < .001), Hispanic or Latino ethnicity (vs. Non-Hispanic, –5.5; P < .001), mother without college degree (–7.0; P < .001), average Beck Anxiety Inventory score after birth (–0.4; P < .001), and weeks of gestational age at enrollment.

The researchers found no association between third trimester antiseizure medication blood levels and verbal index score after adjustment (–2.9; P = .149), with the exception of levetiracetam (–9.0; P = .033). “This is interesting (but) not to be overblown, because overall the children on levetiracetam did well. But it must be remembered that teratogens act in an exposure dependent manner, so we’re constantly in this balancing act of trying to make sure you get enough medication on board to stop the seizures and protect the mother and the child, and at the same time, not too much on board where we increase the risk of teratogenicity in the child,” said Dr. Meador.

The study was funded by the National Institutes of Health. Dr. Meador and Dr. Hopp have no relevant financial disclosures.

SEATTLE – Use of antiseizure medications while breastfeeding is not associated with differences in child cognitive outcomes at age 3, according to new results from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

The study follows results from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, which found no evidence of cognitive harm in children who were exposed in utero to antiepileptic drugs. “[In the NEAD study] we followed our cohort to age 6 and found them to have actually an improvement in cognition by about 4 IQ points by the time they got to age 6,” Kimford J. Meador, MD, said during a presentation of the results of the MONEAD study at the 2022 annual meeting of the American Academy of Neurology.

Breastfeeding has health benefits for both mothers and children, including reduced risk of respiratory tract infections, atopic dermatitis, asthma, and diabetes in children, and reduced risk of diabetes, breast cancer, ovarian cancer, and postpartum depression in mothers. Despite those benefits, concerns about harms from exposure to antiepileptic drugs may prompt some women to avoid breastfeeding.

The results of NEAD and MONEAD should reassure patients, according to Dr. Meador, professor of neurology at Stanford (Calif.) University. “Given the known multiple benefits of breastfeeding … women with epilepsy should be encouraged to breastfeed,” he said.
 

A responsibility to ‘engage and educate’ patients

Jennifer Hopp, MD, who served as a discussant for the presentation, underscored the need for neurologists to address pregnancy with female patients of childbearing agents. “The issues may include fertility, peripartum management, and outcomes that really go through the lifespan to also include issues of menopause,” Dr. Hopp, associate professor of neurology at the University of Maryland, Baltimore, said during her presentation.

Dr. Hopp noted one study showing lower rates of breastfeeding among mothers with epilepsy. “Breastfeeding rates in women with epilepsy are strikingly lower than in women who do not have epilepsy,” said Dr. Hopp. Another study showed that women with epilepsy were less likely to sustain breastfeeding after 6 weeks.

Dr. Hopp implored neurologists to address this. “It’s our responsibility to engage and educate our patients. These data provide us messaging to our patients that the newer drugs do not adversely affect outcome independently of their other exposure, and really support well-informed choices in breastfeeding,” said Dr. Hopp.
 

Outdated attitudes still persist

Dr. Meador referred to the stigma that surrounds epilepsy, including some state laws that called for sterilization of women with epilepsy that lasted until the 1960s. One might think that such attitudes are gone, “but it’s still there,” said Dr. Meador, who recounted a story a colleague told him about a woman on antiseizure medication. In the hospital, the nurse told her not to breastfeed. The neurological consult told her not to breastfeed. She breastfed anyway. “Then they reported her for child neglect, and that was just a few years ago. So I think the message needs to be loud and clear that we encourage [women with epilepsy] to breastfeed because we have the known benefits, and now several studies showing clearly no adverse effects of breastfeeding while taking antiseizure medications,” said Dr. Meador.

MONEAD findings

The MONEAD study included women from 20 different sites, with 145 participating investigators. The researchers compared outcomes in 284 women with epilepsy and 87 healthy women. The maternal mean IQ was 98 among women with epilepsy (95% confidence interval [CI], 96-99), and 105 (95% CI, 102-107) among healthy women. Seventy-six percent of women with epilepsy breastfed, versus 89% of controls.

Among the study cohort, 79% of women with epilepsy were on monotherapy, and 21% were on polytherapy. Thirty-five percent received lamotrigine, 28% levetiracetam, 16% were on another monotherapy, 10% received a combination of lamotrigine and levetiracetam, and 11% received a different combination.

At age 3, there was no association between the verbal index score of the child and whether the mother had epilepsy or not (difference, 0.4; P = .770). The researchers did find associations with the mother’s IQ (0.3; P < .001), male versus female child sex (–4.9; P < .001), Hispanic or Latino ethnicity (vs. Non-Hispanic, –5.5; P < .001), mother without college degree (–7.0; P < .001), average Beck Anxiety Inventory score after birth (–0.4; P < .001), and weeks of gestational age at enrollment.

The researchers found no association between third trimester antiseizure medication blood levels and verbal index score after adjustment (–2.9; P = .149), with the exception of levetiracetam (–9.0; P = .033). “This is interesting (but) not to be overblown, because overall the children on levetiracetam did well. But it must be remembered that teratogens act in an exposure dependent manner, so we’re constantly in this balancing act of trying to make sure you get enough medication on board to stop the seizures and protect the mother and the child, and at the same time, not too much on board where we increase the risk of teratogenicity in the child,” said Dr. Meador.

The study was funded by the National Institutes of Health. Dr. Meador and Dr. Hopp have no relevant financial disclosures.

Differing state regulations and a paucity of research has made it difficult to develop consensus guidelines for the use of cannabinoids in treating drug-resistant epilepsy. A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.

The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.

“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.

“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
 

Appropriate patient populations

Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.

Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.

“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”

Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.

No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.

The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.

The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
 

Considerations for unapproved cannabinoids

The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.

The guidance document notes several reasons to use a regulated medication instead of an unregulated product:

• Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
• Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
• More scientific evidence is available for regulated products.
• Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
• Nonregulated products are rarely covered by insurance or other reimbursement.

Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.

The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.

Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”

“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
 

Dosing and adverse effects

Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.

“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.

The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.

Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.

“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”

Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.

“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”

Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.

Differing state regulations and a paucity of research has made it difficult to develop consensus guidelines for the use of cannabinoids in treating drug-resistant epilepsy. A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.

The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.

“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.

“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
 

Appropriate patient populations

Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.

Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.

“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”

Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.

No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.

The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.

The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
 

Considerations for unapproved cannabinoids

The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.

The guidance document notes several reasons to use a regulated medication instead of an unregulated product:

• Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
• Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
• More scientific evidence is available for regulated products.
• Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
• Nonregulated products are rarely covered by insurance or other reimbursement.

Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.

The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.

Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”

“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
 

Dosing and adverse effects

Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.

“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.

The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.

Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.

“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”

Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.

“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”

Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.

Differing state regulations and a paucity of research has made it difficult to develop consensus guidelines for the use of cannabinoids in treating drug-resistant epilepsy. A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.

The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.

“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.

“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
 

Appropriate patient populations

Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.

Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.

“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”

Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.

No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.

The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.

The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
 

Considerations for unapproved cannabinoids

The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.

The guidance document notes several reasons to use a regulated medication instead of an unregulated product:

• Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
• Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
• More scientific evidence is available for regulated products.
• Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
• Nonregulated products are rarely covered by insurance or other reimbursement.

Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.

The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.

Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”

“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
 

Dosing and adverse effects

Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.

“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.

The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.

Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.

“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”

Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.

“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”

Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.

The International League Against Epilepsy (ILAE) has issued recommendations for treating depression in patients with epilepsy.

The new guidance highlights the high prevalence of depression among patients with epilepsy while offering the first systematic approach to treatment, reported lead author Marco Mula, MD, PhD, of Atkinson Morley Regional Neuroscience Centre at St George’s University Hospital, London, and colleagues.

“Despite evidence that depression represents a frequently encountered comorbidity [among patients with epilepsy], data on the treatment of depression in epilepsy [are] still limited and recommendations rely mostly on individual clinical experience and expertise,” the investigators wrote in Epilepsia.

Recommendations cover first-line treatment of unipolar depression in epilepsy without other psychiatric disorders.

For patients with mild depression, the guidance supports psychological intervention without pharmacologic therapy; however, if the patient wishes to use medication, has had a positive response to medication in the past, or nonpharmacologic treatments have previously failed or are unavailable, then SSRIs should be considered first-choice therapy. For moderate to severe depression, SSRIs are the first choice, according to Dr. Mula and colleagues.

“It has to be acknowledged that there is considerable debate in the psychiatric literature about the treatment of mild depression in adults,” the investigators noted. “A patient-level meta-analysis pointed out that the magnitude of benefit of antidepressant medications compared with placebo increases with severity of depression symptoms and it may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.”

If a patient does not respond to first-line therapy, then venlafaxine should be considered, according to the guidance. When a patient does respond to therapy, treatment should be continued for at least 6 months, and when residual symptoms persist, treatment should be continued until resolution.

“In people with depression it is established that around two-thirds of patients do not achieve full remission with first-line treatment,” Dr. Mula and colleagues wrote. “In people with epilepsy, current data show that up to 50% of patients do not achieve full remission from depression. For this reason, augmentation strategies are often needed. They should be adopted by psychiatrists, neuropsychiatrists, or mental health professionals familiar with such therapeutic strategies.”

Beyond these key recommendations, the guidance covers a range of additional topics, including other pharmacologic options, medication discontinuation strategies, electroconvulsive therapy, light therapy, exercise training, vagus nerve stimulation, and repetitive transcranial magnetic stimulation.
 

Useful advice that counters common misconceptions

According to Jacqueline A. French, MD, a professor at NYU Langone Medical Center, Dr. Mula and colleagues are “top notch,” and their recommendations “hit every nail on the head.”

Dr. French, chief medical officer of The Epilepsy Foundation, emphasized the importance of the publication, which addresses two common misconceptions within the medical community: First, that standard antidepressants are insufficient to treat depression in patients with epilepsy, and second, that antidepressants may trigger seizures.

“The first purpose [of the publication] is to say, yes, these antidepressants do work,” Dr. French said, “and no, they don’t worsen seizures, and you can use them safely, and they are appropriate to use.”

Dr. French explained that managing depression remains a practice gap among epileptologists and neurologists because it is a diagnosis that doesn’t traditionally fall into their purview, yet many patients with epilepsy forgo visiting their primary care providers, who more frequently diagnose and manage depression. Dr. French agreed with the guidance that epilepsy specialists should fill this gap.

“We need to at least be able to take people through their first antidepressant, even though we were not trained to be psychiatrists,” Dr. French said. “That’s part of the best care of our patients.”

Imad Najm, MD, director of the Charles Shor Epilepsy Center, Cleveland Clinic, said the recommendations are a step forward in the field, as they are supported by clinical data, instead of just clinical experience and expertise.

Still, Dr. Najm noted that more work is needed to stratify risk of depression in epilepsy and evaluate a possible causal relationship between epilepsy therapies and depression.

He went on to emphasizes the scale of issue at hand, and the stakes involved.

“Depression, anxiety, and psychosis affect a large number of patients with epilepsy,” Dr. Najm said. “Clinical screening and recognition of these comorbidities leads to the institution of treatment options and significant improvement in quality of life. Mental health professionals should be an integral part of any comprehensive epilepsy center.”

The investigators disclosed relationships with Esai, UCB, Elsevier, and others. Dr. French is indirectly involved with multiple pharmaceutical companies developing epilepsy drugs through her role as director of The Epilepsy Study Consortium, a nonprofit organization. Dr. Najm reported no conflicts of interest.

The International League Against Epilepsy (ILAE) has issued recommendations for treating depression in patients with epilepsy.

The new guidance highlights the high prevalence of depression among patients with epilepsy while offering the first systematic approach to treatment, reported lead author Marco Mula, MD, PhD, of Atkinson Morley Regional Neuroscience Centre at St George’s University Hospital, London, and colleagues.

“Despite evidence that depression represents a frequently encountered comorbidity [among patients with epilepsy], data on the treatment of depression in epilepsy [are] still limited and recommendations rely mostly on individual clinical experience and expertise,” the investigators wrote in Epilepsia.

Recommendations cover first-line treatment of unipolar depression in epilepsy without other psychiatric disorders.

For patients with mild depression, the guidance supports psychological intervention without pharmacologic therapy; however, if the patient wishes to use medication, has had a positive response to medication in the past, or nonpharmacologic treatments have previously failed or are unavailable, then SSRIs should be considered first-choice therapy. For moderate to severe depression, SSRIs are the first choice, according to Dr. Mula and colleagues.

“It has to be acknowledged that there is considerable debate in the psychiatric literature about the treatment of mild depression in adults,” the investigators noted. “A patient-level meta-analysis pointed out that the magnitude of benefit of antidepressant medications compared with placebo increases with severity of depression symptoms and it may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.”

If a patient does not respond to first-line therapy, then venlafaxine should be considered, according to the guidance. When a patient does respond to therapy, treatment should be continued for at least 6 months, and when residual symptoms persist, treatment should be continued until resolution.

“In people with depression it is established that around two-thirds of patients do not achieve full remission with first-line treatment,” Dr. Mula and colleagues wrote. “In people with epilepsy, current data show that up to 50% of patients do not achieve full remission from depression. For this reason, augmentation strategies are often needed. They should be adopted by psychiatrists, neuropsychiatrists, or mental health professionals familiar with such therapeutic strategies.”

Beyond these key recommendations, the guidance covers a range of additional topics, including other pharmacologic options, medication discontinuation strategies, electroconvulsive therapy, light therapy, exercise training, vagus nerve stimulation, and repetitive transcranial magnetic stimulation.
 

Useful advice that counters common misconceptions

According to Jacqueline A. French, MD, a professor at NYU Langone Medical Center, Dr. Mula and colleagues are “top notch,” and their recommendations “hit every nail on the head.”

Dr. French, chief medical officer of The Epilepsy Foundation, emphasized the importance of the publication, which addresses two common misconceptions within the medical community: First, that standard antidepressants are insufficient to treat depression in patients with epilepsy, and second, that antidepressants may trigger seizures.

“The first purpose [of the publication] is to say, yes, these antidepressants do work,” Dr. French said, “and no, they don’t worsen seizures, and you can use them safely, and they are appropriate to use.”

Dr. French explained that managing depression remains a practice gap among epileptologists and neurologists because it is a diagnosis that doesn’t traditionally fall into their purview, yet many patients with epilepsy forgo visiting their primary care providers, who more frequently diagnose and manage depression. Dr. French agreed with the guidance that epilepsy specialists should fill this gap.

“We need to at least be able to take people through their first antidepressant, even though we were not trained to be psychiatrists,” Dr. French said. “That’s part of the best care of our patients.”

Imad Najm, MD, director of the Charles Shor Epilepsy Center, Cleveland Clinic, said the recommendations are a step forward in the field, as they are supported by clinical data, instead of just clinical experience and expertise.

Still, Dr. Najm noted that more work is needed to stratify risk of depression in epilepsy and evaluate a possible causal relationship between epilepsy therapies and depression.

He went on to emphasizes the scale of issue at hand, and the stakes involved.

“Depression, anxiety, and psychosis affect a large number of patients with epilepsy,” Dr. Najm said. “Clinical screening and recognition of these comorbidities leads to the institution of treatment options and significant improvement in quality of life. Mental health professionals should be an integral part of any comprehensive epilepsy center.”

The investigators disclosed relationships with Esai, UCB, Elsevier, and others. Dr. French is indirectly involved with multiple pharmaceutical companies developing epilepsy drugs through her role as director of The Epilepsy Study Consortium, a nonprofit organization. Dr. Najm reported no conflicts of interest.

The International League Against Epilepsy (ILAE) has issued recommendations for treating depression in patients with epilepsy.

The new guidance highlights the high prevalence of depression among patients with epilepsy while offering the first systematic approach to treatment, reported lead author Marco Mula, MD, PhD, of Atkinson Morley Regional Neuroscience Centre at St George’s University Hospital, London, and colleagues.

“Despite evidence that depression represents a frequently encountered comorbidity [among patients with epilepsy], data on the treatment of depression in epilepsy [are] still limited and recommendations rely mostly on individual clinical experience and expertise,” the investigators wrote in Epilepsia.

Recommendations cover first-line treatment of unipolar depression in epilepsy without other psychiatric disorders.

For patients with mild depression, the guidance supports psychological intervention without pharmacologic therapy; however, if the patient wishes to use medication, has had a positive response to medication in the past, or nonpharmacologic treatments have previously failed or are unavailable, then SSRIs should be considered first-choice therapy. For moderate to severe depression, SSRIs are the first choice, according to Dr. Mula and colleagues.

“It has to be acknowledged that there is considerable debate in the psychiatric literature about the treatment of mild depression in adults,” the investigators noted. “A patient-level meta-analysis pointed out that the magnitude of benefit of antidepressant medications compared with placebo increases with severity of depression symptoms and it may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.”

If a patient does not respond to first-line therapy, then venlafaxine should be considered, according to the guidance. When a patient does respond to therapy, treatment should be continued for at least 6 months, and when residual symptoms persist, treatment should be continued until resolution.

“In people with depression it is established that around two-thirds of patients do not achieve full remission with first-line treatment,” Dr. Mula and colleagues wrote. “In people with epilepsy, current data show that up to 50% of patients do not achieve full remission from depression. For this reason, augmentation strategies are often needed. They should be adopted by psychiatrists, neuropsychiatrists, or mental health professionals familiar with such therapeutic strategies.”

Beyond these key recommendations, the guidance covers a range of additional topics, including other pharmacologic options, medication discontinuation strategies, electroconvulsive therapy, light therapy, exercise training, vagus nerve stimulation, and repetitive transcranial magnetic stimulation.
 

Useful advice that counters common misconceptions

According to Jacqueline A. French, MD, a professor at NYU Langone Medical Center, Dr. Mula and colleagues are “top notch,” and their recommendations “hit every nail on the head.”

Dr. French, chief medical officer of The Epilepsy Foundation, emphasized the importance of the publication, which addresses two common misconceptions within the medical community: First, that standard antidepressants are insufficient to treat depression in patients with epilepsy, and second, that antidepressants may trigger seizures.

“The first purpose [of the publication] is to say, yes, these antidepressants do work,” Dr. French said, “and no, they don’t worsen seizures, and you can use them safely, and they are appropriate to use.”

Dr. French explained that managing depression remains a practice gap among epileptologists and neurologists because it is a diagnosis that doesn’t traditionally fall into their purview, yet many patients with epilepsy forgo visiting their primary care providers, who more frequently diagnose and manage depression. Dr. French agreed with the guidance that epilepsy specialists should fill this gap.

“We need to at least be able to take people through their first antidepressant, even though we were not trained to be psychiatrists,” Dr. French said. “That’s part of the best care of our patients.”

Imad Najm, MD, director of the Charles Shor Epilepsy Center, Cleveland Clinic, said the recommendations are a step forward in the field, as they are supported by clinical data, instead of just clinical experience and expertise.

Still, Dr. Najm noted that more work is needed to stratify risk of depression in epilepsy and evaluate a possible causal relationship between epilepsy therapies and depression.

He went on to emphasizes the scale of issue at hand, and the stakes involved.

“Depression, anxiety, and psychosis affect a large number of patients with epilepsy,” Dr. Najm said. “Clinical screening and recognition of these comorbidities leads to the institution of treatment options and significant improvement in quality of life. Mental health professionals should be an integral part of any comprehensive epilepsy center.”

The investigators disclosed relationships with Esai, UCB, Elsevier, and others. Dr. French is indirectly involved with multiple pharmaceutical companies developing epilepsy drugs through her role as director of The Epilepsy Study Consortium, a nonprofit organization. Dr. Najm reported no conflicts of interest.