Epilepsy Resource Center

WASHINGTON, DC—The Drug Enforcement Administration (DEA) has reclassified Epidiolex, an oral cannabidiol (CBD) solution, from Schedule I to Schedule V, the lowest category of scheduled substances. The FDA approved Epidiolex earlier this year for the adjunctive treatment of seizures in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome aged 2 and older. The DEA’s action paves the way for the manufacturer, GW Pharmaceuticals, to begin marketing Epidiolex, which is expected to be available in the United States this fall.

The DEA’s final rescheduling order is limited to drugs approved by the FDA that contain cannabis-derived CBD and no more than 0.1% tetrahydrocannabinol (THC). In practice, this means that the rescheduling currently applies only to Epidiolex, since this is the only formulation of CBD that has received FDA approval.

A Low Potential for Abuse

“We are pleased that the DEA has placed Epidiolex in the lowest restriction schedule, because it will help ensure that patients with LGS and Dravet syndrome, two of the most debilitating forms of epilepsy, can access this important new treatment option through their physicians,” said GW Pharmaceutical’s Chief Executive Officer Justin Gover in a statement.

During the FDA advisory committee meeting for the approval of Epidiolex to treat LGS and Dravet syndrome, the FDA and GW Pharmaceuticals concluded that the potential to abuse CBD was low, since it does not contain THC, the primary psychoactive component of cannabis.

All other marijuana products are currently classified as Schedule I, along with illegal substances such as heroin and cocaine.

An Established Medical Use

Epidiolex had received fast track and rare pediatric designations from the FDA for LGS and Dravet syndrome; the approval was based on three pivotal randomized, double-blind, placebo-controlled clinical trials. The drug met its primary end point of reduced seizure frequency in all trials when added to standard of care for patients with drug-resistant LGS and those with Dravet syndrome.

Safety evaluations assessed data from 1,756 patients and found that the 20 deaths seen during the study period were not clearly linked to Epidiolex and may be expected for children with severe seizure disorders.

In supplementary information accompanying the order, the DEA’s Acting Administrator Uttam Dhillon noted that the FDA’s approval of Epidiolex means that “it has a currently accepted medical use in treatment for purposes of the Controlled Substances Act [CSA]. Accordingly, Epidiolex no longer meets the criteria for placement in Schedule I of the CSA.” Schedule I drugs do not have a currently accepted medical use.

Schedule V drugs, according to the DEA, are defined as “drugs with lower potential for abuse than Schedule IV and [that] consist of preparations containing limited quantities of certain narcotics.” Other Schedule V drugs include cough medicine with less than 200 mg of codeine or per 100 mL, antidiarrheal medications, pregabalin, and the antiepileptic drugs brivaracetam and lacosamide. “Schedule V drugs represent the least potential for abuse,” according to the DEA.

Initial dosing recommendations for Epidiolex are to titrate to a dose of 10 mg/kg/day. Dose adjustments to 20 mg/kg/day are permissible, depending on clinical response and tolerability. The manufacturer has submitted a marketing agreement to the European Medicines Agency and has received orphan drug designation for Epidiolex in the treatment of tuberous sclerosis complex.

—Kari Oakes

WASHINGTON, DC—The Drug Enforcement Administration (DEA) has reclassified Epidiolex, an oral cannabidiol (CBD) solution, from Schedule I to Schedule V, the lowest category of scheduled substances. The FDA approved Epidiolex earlier this year for the adjunctive treatment of seizures in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome aged 2 and older. The DEA’s action paves the way for the manufacturer, GW Pharmaceuticals, to begin marketing Epidiolex, which is expected to be available in the United States this fall.

The DEA’s final rescheduling order is limited to drugs approved by the FDA that contain cannabis-derived CBD and no more than 0.1% tetrahydrocannabinol (THC). In practice, this means that the rescheduling currently applies only to Epidiolex, since this is the only formulation of CBD that has received FDA approval.

A Low Potential for Abuse

“We are pleased that the DEA has placed Epidiolex in the lowest restriction schedule, because it will help ensure that patients with LGS and Dravet syndrome, two of the most debilitating forms of epilepsy, can access this important new treatment option through their physicians,” said GW Pharmaceutical’s Chief Executive Officer Justin Gover in a statement.

During the FDA advisory committee meeting for the approval of Epidiolex to treat LGS and Dravet syndrome, the FDA and GW Pharmaceuticals concluded that the potential to abuse CBD was low, since it does not contain THC, the primary psychoactive component of cannabis.

All other marijuana products are currently classified as Schedule I, along with illegal substances such as heroin and cocaine.

An Established Medical Use

Epidiolex had received fast track and rare pediatric designations from the FDA for LGS and Dravet syndrome; the approval was based on three pivotal randomized, double-blind, placebo-controlled clinical trials. The drug met its primary end point of reduced seizure frequency in all trials when added to standard of care for patients with drug-resistant LGS and those with Dravet syndrome.

Safety evaluations assessed data from 1,756 patients and found that the 20 deaths seen during the study period were not clearly linked to Epidiolex and may be expected for children with severe seizure disorders.

In supplementary information accompanying the order, the DEA’s Acting Administrator Uttam Dhillon noted that the FDA’s approval of Epidiolex means that “it has a currently accepted medical use in treatment for purposes of the Controlled Substances Act [CSA]. Accordingly, Epidiolex no longer meets the criteria for placement in Schedule I of the CSA.” Schedule I drugs do not have a currently accepted medical use.

Schedule V drugs, according to the DEA, are defined as “drugs with lower potential for abuse than Schedule IV and [that] consist of preparations containing limited quantities of certain narcotics.” Other Schedule V drugs include cough medicine with less than 200 mg of codeine or per 100 mL, antidiarrheal medications, pregabalin, and the antiepileptic drugs brivaracetam and lacosamide. “Schedule V drugs represent the least potential for abuse,” according to the DEA.

Initial dosing recommendations for Epidiolex are to titrate to a dose of 10 mg/kg/day. Dose adjustments to 20 mg/kg/day are permissible, depending on clinical response and tolerability. The manufacturer has submitted a marketing agreement to the European Medicines Agency and has received orphan drug designation for Epidiolex in the treatment of tuberous sclerosis complex.

—Kari Oakes

WASHINGTON, DC—The Drug Enforcement Administration (DEA) has reclassified Epidiolex, an oral cannabidiol (CBD) solution, from Schedule I to Schedule V, the lowest category of scheduled substances. The FDA approved Epidiolex earlier this year for the adjunctive treatment of seizures in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome aged 2 and older. The DEA’s action paves the way for the manufacturer, GW Pharmaceuticals, to begin marketing Epidiolex, which is expected to be available in the United States this fall.

The DEA’s final rescheduling order is limited to drugs approved by the FDA that contain cannabis-derived CBD and no more than 0.1% tetrahydrocannabinol (THC). In practice, this means that the rescheduling currently applies only to Epidiolex, since this is the only formulation of CBD that has received FDA approval.

A Low Potential for Abuse

“We are pleased that the DEA has placed Epidiolex in the lowest restriction schedule, because it will help ensure that patients with LGS and Dravet syndrome, two of the most debilitating forms of epilepsy, can access this important new treatment option through their physicians,” said GW Pharmaceutical’s Chief Executive Officer Justin Gover in a statement.

During the FDA advisory committee meeting for the approval of Epidiolex to treat LGS and Dravet syndrome, the FDA and GW Pharmaceuticals concluded that the potential to abuse CBD was low, since it does not contain THC, the primary psychoactive component of cannabis.

All other marijuana products are currently classified as Schedule I, along with illegal substances such as heroin and cocaine.

An Established Medical Use

Epidiolex had received fast track and rare pediatric designations from the FDA for LGS and Dravet syndrome; the approval was based on three pivotal randomized, double-blind, placebo-controlled clinical trials. The drug met its primary end point of reduced seizure frequency in all trials when added to standard of care for patients with drug-resistant LGS and those with Dravet syndrome.

Safety evaluations assessed data from 1,756 patients and found that the 20 deaths seen during the study period were not clearly linked to Epidiolex and may be expected for children with severe seizure disorders.

In supplementary information accompanying the order, the DEA’s Acting Administrator Uttam Dhillon noted that the FDA’s approval of Epidiolex means that “it has a currently accepted medical use in treatment for purposes of the Controlled Substances Act [CSA]. Accordingly, Epidiolex no longer meets the criteria for placement in Schedule I of the CSA.” Schedule I drugs do not have a currently accepted medical use.

Schedule V drugs, according to the DEA, are defined as “drugs with lower potential for abuse than Schedule IV and [that] consist of preparations containing limited quantities of certain narcotics.” Other Schedule V drugs include cough medicine with less than 200 mg of codeine or per 100 mL, antidiarrheal medications, pregabalin, and the antiepileptic drugs brivaracetam and lacosamide. “Schedule V drugs represent the least potential for abuse,” according to the DEA.

Initial dosing recommendations for Epidiolex are to titrate to a dose of 10 mg/kg/day. Dose adjustments to 20 mg/kg/day are permissible, depending on clinical response and tolerability. The manufacturer has submitted a marketing agreement to the European Medicines Agency and has received orphan drug designation for Epidiolex in the treatment of tuberous sclerosis complex.

—Kari Oakes

CHICAGO—Use of rapid sequence MRI in the evaluation of neonates with seizures and no hypoxic-ischemic encephalopathy (HIE) is associated with reduced number of CT and MRI scans and similar length of hospital stay and cost, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. “The potential reduction in radiation and sedation exposure associated with CTs and regular MRIs makes rapid sequence MRI an attractive imaging modality in this population,” said Theresa M. Czech, MD, and Andrea C. Pardo, MD, attending physicians at Ann & Robert H. Lurie Children’s Hospital of Chicago. Dr. Czech is an Instructor in Pediatrics, and Dr. Pardo is an Assistant Professor of Pediatrics, both at Northwestern University Feinberg School of Medicine in Chicago.

Neurologists routinely use brain imaging to identify the etiologies of neonatal seizures. Rapid sequence MRI “can reduce the risk of radiation associated with CT or the need for procedural sedation associated with regular MRIs,” said Drs. Czech and Pardo. “Our goal was to determine whether the implementation of a protocol recommending the use of rapid sequence MRI was associated with increased efficiency in the evaluation of neonates with seizures.” Rapid sequence MRI consisted of three plane ultrafast T2 sequences with gradient echo and diffusion weighted sequences.

The researchers compared outcomes before and after the implementation of a protocol recommending the use of rapid sequence MRI. The primary outcome was hospital length of stay. Secondary outcomes included the use of other imaging modalities (ie, head ultrasound, CT, and MRI), cost of imaging, and cost of hospitalization. They excluded neonates with clinical evidence of HIE. Continuous variables were compared using the Mann-Whitney U test, and categorical variables were compared using the chi-squared test.

In all, 95 patients (gestational age, 39 weeks; 63% male) met inclusion criteria—47 in the preintervention group and 48 in the postintervention group. The groups had similar demographics and severity of illness. Implementation of the protocol-guided rapid sequence MRI was associated with decreased use of CT (34% vs 10%) and full MRI (85% vs 62%). Use of head ultrasound (28% vs 12%), length of hospital stay, and costs were not significantly different between groups.

CHICAGO—Use of rapid sequence MRI in the evaluation of neonates with seizures and no hypoxic-ischemic encephalopathy (HIE) is associated with reduced number of CT and MRI scans and similar length of hospital stay and cost, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. “The potential reduction in radiation and sedation exposure associated with CTs and regular MRIs makes rapid sequence MRI an attractive imaging modality in this population,” said Theresa M. Czech, MD, and Andrea C. Pardo, MD, attending physicians at Ann & Robert H. Lurie Children’s Hospital of Chicago. Dr. Czech is an Instructor in Pediatrics, and Dr. Pardo is an Assistant Professor of Pediatrics, both at Northwestern University Feinberg School of Medicine in Chicago.

Neurologists routinely use brain imaging to identify the etiologies of neonatal seizures. Rapid sequence MRI “can reduce the risk of radiation associated with CT or the need for procedural sedation associated with regular MRIs,” said Drs. Czech and Pardo. “Our goal was to determine whether the implementation of a protocol recommending the use of rapid sequence MRI was associated with increased efficiency in the evaluation of neonates with seizures.” Rapid sequence MRI consisted of three plane ultrafast T2 sequences with gradient echo and diffusion weighted sequences.

The researchers compared outcomes before and after the implementation of a protocol recommending the use of rapid sequence MRI. The primary outcome was hospital length of stay. Secondary outcomes included the use of other imaging modalities (ie, head ultrasound, CT, and MRI), cost of imaging, and cost of hospitalization. They excluded neonates with clinical evidence of HIE. Continuous variables were compared using the Mann-Whitney U test, and categorical variables were compared using the chi-squared test.

In all, 95 patients (gestational age, 39 weeks; 63% male) met inclusion criteria—47 in the preintervention group and 48 in the postintervention group. The groups had similar demographics and severity of illness. Implementation of the protocol-guided rapid sequence MRI was associated with decreased use of CT (34% vs 10%) and full MRI (85% vs 62%). Use of head ultrasound (28% vs 12%), length of hospital stay, and costs were not significantly different between groups.

CHICAGO—Use of rapid sequence MRI in the evaluation of neonates with seizures and no hypoxic-ischemic encephalopathy (HIE) is associated with reduced number of CT and MRI scans and similar length of hospital stay and cost, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. “The potential reduction in radiation and sedation exposure associated with CTs and regular MRIs makes rapid sequence MRI an attractive imaging modality in this population,” said Theresa M. Czech, MD, and Andrea C. Pardo, MD, attending physicians at Ann & Robert H. Lurie Children’s Hospital of Chicago. Dr. Czech is an Instructor in Pediatrics, and Dr. Pardo is an Assistant Professor of Pediatrics, both at Northwestern University Feinberg School of Medicine in Chicago.

Neurologists routinely use brain imaging to identify the etiologies of neonatal seizures. Rapid sequence MRI “can reduce the risk of radiation associated with CT or the need for procedural sedation associated with regular MRIs,” said Drs. Czech and Pardo. “Our goal was to determine whether the implementation of a protocol recommending the use of rapid sequence MRI was associated with increased efficiency in the evaluation of neonates with seizures.” Rapid sequence MRI consisted of three plane ultrafast T2 sequences with gradient echo and diffusion weighted sequences.

The researchers compared outcomes before and after the implementation of a protocol recommending the use of rapid sequence MRI. The primary outcome was hospital length of stay. Secondary outcomes included the use of other imaging modalities (ie, head ultrasound, CT, and MRI), cost of imaging, and cost of hospitalization. They excluded neonates with clinical evidence of HIE. Continuous variables were compared using the Mann-Whitney U test, and categorical variables were compared using the chi-squared test.

In all, 95 patients (gestational age, 39 weeks; 63% male) met inclusion criteria—47 in the preintervention group and 48 in the postintervention group. The groups had similar demographics and severity of illness. Implementation of the protocol-guided rapid sequence MRI was associated with decreased use of CT (34% vs 10%) and full MRI (85% vs 62%). Use of head ultrasound (28% vs 12%), length of hospital stay, and costs were not significantly different between groups.

Immediate treatment of a first unprovoked seizure may be preferable to delayed treatment over a wide range of patients, including those who are at low risk of recurrent seizures, results of a decision analysis suggest.

Taking into account quality of life, seizure risk, and antiepileptic drug (AED) side effects, a model favored treatment of a patient with a single unprovoked seizure who did not meet the International League Against Epilepsy (ILAE) definition of epilepsy, investigators reported.

The model also favored treatment of patients who did meet ILAE criteria, namely, a 10-year recurrence risk greater than 60% in a patient with a single unprovoked seizure, according to the analysis, which was published in the October 9 issue of Neurology.

Together, these findings suggest that the current ILAE epilepsy definition is “too simplistic” for deciding whether to start or withhold AED treatment after a first unprovoked seizure, said M. Brandon Westover, MD, PhD, Associate Professor of Neurology at Massachusetts General Hospital in Boston, and his coauthors.

“A more precise and patient-personalized definition of epilepsy should encompass not only seizure recurrence probability but also a multitude of other risks and benefits associated with AED treatment,” they said.

Weighing Risks and Benefits

To determine which patients with a first unprovoked seizure might benefit from immediate AED treatment, Dr. Westover and his colleagues used a decision model with measures constructed from retrospective clinical trial data.

The goal of the simulation was to determine which treatment strategy—immediate or delayed AED treatment—would maximize the patient’s expected quality-adjusted life years (QALYs). Toward that end, Dr. Westover and his coinvestigators considered three base cases, which represented various degrees of seizure-recurrence risk.

The first case was a 30-year-old man with no risk factors for recurrent seizure other than having had a first seizure. In that case, immediate and deferred AED treatment resulted in 19.04 and 18.65 QALYs, respectively.

“In dollar values, using the conservative approximation of $50,000/QALY gained, this difference in treatment outcomes would amount to $19,500 gained per individual,” Dr. Westover and his coauthors wrote in their report.

The second case was a 30-year-old woman who presented with a first unprovoked seizure and had positive MRI results that establish a high risk of recurrence. As expected, because of the high recurrence risk, this scenario also favored immediate treatment, with 15.23 and 14.75 QALYs, respectively, for the immediate and deferred strategies.

The final case was a wheelchair-bound 60-year-old woman with a first unprovoked seizure and high risk of recurrence, but also a high risk of AED adverse effects and a smaller expected quality of life reduction from further seizures. In this scenario, in which treatment might be “intuitively discouraged” because of the AED side-effect risk, the cohort simulation favored deferred AED treatment by a small margin, the investigators said.

“A high baseline risk for recurrent seizures does not by itself always favor immediate AED treatment,” they said.

Findings May Shift Discussions About Therapy

The conclusion of this decision analysis by Dr. Westover and colleagues is “likely correct” that early treatment of a first unprovoked seizure could be favorable in a wide range of clinical scenarios, according to the authors of an accompanying editorial.

The decision analysis is based on a reasonable, though not comprehensive, set of parameters to simulate base cases representative of common first-ever seizure clinical scenarios, said editorialists Claire S. Jacobs, MD, PhD, and Jong Woo Lee, MD, PhD, both with the Department of Neurology at Brigham and Women’s Hospital in Boston.

Potentially the most controversial scenario addressed in the decision model, they noted, is the patient with low seizure recurrence risk but substantial quality of life decline upon recurrence. While that patient would not meet the commonly accepted 60% recurrence risk threshold that would indicate that treatment is warranted, this model favors immediate treatment because of the potentially disruptive effect of recurrence.

This study does not address important issues such as the cost of medication and patient preferences, they pointed out, and furthermore, QALYs can be difficult to integrate into clinical decision making.

Nonetheless, the findings are worth considering in clinical practice, the authors suggested. “At the very least, this study should, however subtly, shift the starting point of discussion with the patient toward a default of immediate, rather than deferred, treatment after a first unprovoked seizure and apparent absence of disease,” said Drs. Jacob and Lee.

The study was supported by NINDS.

—Andrew D. Bowser

Suggested Reading

Bao EL, Chao LY, Ni P, et al. Antiepileptic drug treatment after an unprovoked first seizure: a decision analysis. Neurology. 2018;91(15):e1429-e1439.

Jacobs CS, Lee JW. Immediate vs delayed treatment of first unprovoked seizure: to treat, or not to treat? Neurology. 2018;91(15):684-685.

Immediate treatment of a first unprovoked seizure may be preferable to delayed treatment over a wide range of patients, including those who are at low risk of recurrent seizures, results of a decision analysis suggest.

Taking into account quality of life, seizure risk, and antiepileptic drug (AED) side effects, a model favored treatment of a patient with a single unprovoked seizure who did not meet the International League Against Epilepsy (ILAE) definition of epilepsy, investigators reported.

The model also favored treatment of patients who did meet ILAE criteria, namely, a 10-year recurrence risk greater than 60% in a patient with a single unprovoked seizure, according to the analysis, which was published in the October 9 issue of Neurology.

Together, these findings suggest that the current ILAE epilepsy definition is “too simplistic” for deciding whether to start or withhold AED treatment after a first unprovoked seizure, said M. Brandon Westover, MD, PhD, Associate Professor of Neurology at Massachusetts General Hospital in Boston, and his coauthors.

“A more precise and patient-personalized definition of epilepsy should encompass not only seizure recurrence probability but also a multitude of other risks and benefits associated with AED treatment,” they said.

Weighing Risks and Benefits

To determine which patients with a first unprovoked seizure might benefit from immediate AED treatment, Dr. Westover and his colleagues used a decision model with measures constructed from retrospective clinical trial data.

The goal of the simulation was to determine which treatment strategy—immediate or delayed AED treatment—would maximize the patient’s expected quality-adjusted life years (QALYs). Toward that end, Dr. Westover and his coinvestigators considered three base cases, which represented various degrees of seizure-recurrence risk.

The first case was a 30-year-old man with no risk factors for recurrent seizure other than having had a first seizure. In that case, immediate and deferred AED treatment resulted in 19.04 and 18.65 QALYs, respectively.

“In dollar values, using the conservative approximation of $50,000/QALY gained, this difference in treatment outcomes would amount to $19,500 gained per individual,” Dr. Westover and his coauthors wrote in their report.

The second case was a 30-year-old woman who presented with a first unprovoked seizure and had positive MRI results that establish a high risk of recurrence. As expected, because of the high recurrence risk, this scenario also favored immediate treatment, with 15.23 and 14.75 QALYs, respectively, for the immediate and deferred strategies.

The final case was a wheelchair-bound 60-year-old woman with a first unprovoked seizure and high risk of recurrence, but also a high risk of AED adverse effects and a smaller expected quality of life reduction from further seizures. In this scenario, in which treatment might be “intuitively discouraged” because of the AED side-effect risk, the cohort simulation favored deferred AED treatment by a small margin, the investigators said.

“A high baseline risk for recurrent seizures does not by itself always favor immediate AED treatment,” they said.

Findings May Shift Discussions About Therapy

The conclusion of this decision analysis by Dr. Westover and colleagues is “likely correct” that early treatment of a first unprovoked seizure could be favorable in a wide range of clinical scenarios, according to the authors of an accompanying editorial.

The decision analysis is based on a reasonable, though not comprehensive, set of parameters to simulate base cases representative of common first-ever seizure clinical scenarios, said editorialists Claire S. Jacobs, MD, PhD, and Jong Woo Lee, MD, PhD, both with the Department of Neurology at Brigham and Women’s Hospital in Boston.

Potentially the most controversial scenario addressed in the decision model, they noted, is the patient with low seizure recurrence risk but substantial quality of life decline upon recurrence. While that patient would not meet the commonly accepted 60% recurrence risk threshold that would indicate that treatment is warranted, this model favors immediate treatment because of the potentially disruptive effect of recurrence.

This study does not address important issues such as the cost of medication and patient preferences, they pointed out, and furthermore, QALYs can be difficult to integrate into clinical decision making.

Nonetheless, the findings are worth considering in clinical practice, the authors suggested. “At the very least, this study should, however subtly, shift the starting point of discussion with the patient toward a default of immediate, rather than deferred, treatment after a first unprovoked seizure and apparent absence of disease,” said Drs. Jacob and Lee.

The study was supported by NINDS.

—Andrew D. Bowser

Suggested Reading

Bao EL, Chao LY, Ni P, et al. Antiepileptic drug treatment after an unprovoked first seizure: a decision analysis. Neurology. 2018;91(15):e1429-e1439.

Jacobs CS, Lee JW. Immediate vs delayed treatment of first unprovoked seizure: to treat, or not to treat? Neurology. 2018;91(15):684-685.

Immediate treatment of a first unprovoked seizure may be preferable to delayed treatment over a wide range of patients, including those who are at low risk of recurrent seizures, results of a decision analysis suggest.

Taking into account quality of life, seizure risk, and antiepileptic drug (AED) side effects, a model favored treatment of a patient with a single unprovoked seizure who did not meet the International League Against Epilepsy (ILAE) definition of epilepsy, investigators reported.

The model also favored treatment of patients who did meet ILAE criteria, namely, a 10-year recurrence risk greater than 60% in a patient with a single unprovoked seizure, according to the analysis, which was published in the October 9 issue of Neurology.

Together, these findings suggest that the current ILAE epilepsy definition is “too simplistic” for deciding whether to start or withhold AED treatment after a first unprovoked seizure, said M. Brandon Westover, MD, PhD, Associate Professor of Neurology at Massachusetts General Hospital in Boston, and his coauthors.

“A more precise and patient-personalized definition of epilepsy should encompass not only seizure recurrence probability but also a multitude of other risks and benefits associated with AED treatment,” they said.

Weighing Risks and Benefits

To determine which patients with a first unprovoked seizure might benefit from immediate AED treatment, Dr. Westover and his colleagues used a decision model with measures constructed from retrospective clinical trial data.

The goal of the simulation was to determine which treatment strategy—immediate or delayed AED treatment—would maximize the patient’s expected quality-adjusted life years (QALYs). Toward that end, Dr. Westover and his coinvestigators considered three base cases, which represented various degrees of seizure-recurrence risk.

The first case was a 30-year-old man with no risk factors for recurrent seizure other than having had a first seizure. In that case, immediate and deferred AED treatment resulted in 19.04 and 18.65 QALYs, respectively.

“In dollar values, using the conservative approximation of $50,000/QALY gained, this difference in treatment outcomes would amount to $19,500 gained per individual,” Dr. Westover and his coauthors wrote in their report.

The second case was a 30-year-old woman who presented with a first unprovoked seizure and had positive MRI results that establish a high risk of recurrence. As expected, because of the high recurrence risk, this scenario also favored immediate treatment, with 15.23 and 14.75 QALYs, respectively, for the immediate and deferred strategies.

The final case was a wheelchair-bound 60-year-old woman with a first unprovoked seizure and high risk of recurrence, but also a high risk of AED adverse effects and a smaller expected quality of life reduction from further seizures. In this scenario, in which treatment might be “intuitively discouraged” because of the AED side-effect risk, the cohort simulation favored deferred AED treatment by a small margin, the investigators said.

“A high baseline risk for recurrent seizures does not by itself always favor immediate AED treatment,” they said.

Findings May Shift Discussions About Therapy

The conclusion of this decision analysis by Dr. Westover and colleagues is “likely correct” that early treatment of a first unprovoked seizure could be favorable in a wide range of clinical scenarios, according to the authors of an accompanying editorial.

The decision analysis is based on a reasonable, though not comprehensive, set of parameters to simulate base cases representative of common first-ever seizure clinical scenarios, said editorialists Claire S. Jacobs, MD, PhD, and Jong Woo Lee, MD, PhD, both with the Department of Neurology at Brigham and Women’s Hospital in Boston.

Potentially the most controversial scenario addressed in the decision model, they noted, is the patient with low seizure recurrence risk but substantial quality of life decline upon recurrence. While that patient would not meet the commonly accepted 60% recurrence risk threshold that would indicate that treatment is warranted, this model favors immediate treatment because of the potentially disruptive effect of recurrence.

This study does not address important issues such as the cost of medication and patient preferences, they pointed out, and furthermore, QALYs can be difficult to integrate into clinical decision making.

Nonetheless, the findings are worth considering in clinical practice, the authors suggested. “At the very least, this study should, however subtly, shift the starting point of discussion with the patient toward a default of immediate, rather than deferred, treatment after a first unprovoked seizure and apparent absence of disease,” said Drs. Jacob and Lee.

The study was supported by NINDS.

—Andrew D. Bowser

Suggested Reading

Bao EL, Chao LY, Ni P, et al. Antiepileptic drug treatment after an unprovoked first seizure: a decision analysis. Neurology. 2018;91(15):e1429-e1439.

Jacobs CS, Lee JW. Immediate vs delayed treatment of first unprovoked seizure: to treat, or not to treat? Neurology. 2018;91(15):684-685.

Pediatric patients who have been initially diagnosed with epilepsy with myoclonic-atonic seizures (EMAS) are likely to be switched to another diagnosis over time, according to a retrospective chart analysis of 77 children at Children’s Hospital of Colorado.

• Over 50% of patients in this study were switched from suspected EMAS to another epilepsy diagnosis.
• Among the 77 patients, 30 had an initial diagnosis of EMAS and 57 had a final diagnosis of EMAS.
• Among 65% of patients who had more than one diagnosis over time, the first, second, and third diagnoses were provided within 1 year, 3 years, and 10 years after the onset of the disease.
• Signs of Lennox-Gastaut syndrome (LGS), including paroxysmal fast activity, slow spike-and-wave, and tonic seizure, were detected in 50% of the 77 patients but only a minority received a final diagnosis of LGS.

Eschbach K., Moss A, Joshi C, et al. Diagnosis switching and outcomes in a cohort of patients with potential epilepsy with myoclonic-atonic seizures. Epilepsy Res. 2018; 147:95-101. https://doi.org/10.1016/j.eplepsyres.2018.09.011

Pediatric patients who have been initially diagnosed with epilepsy with myoclonic-atonic seizures (EMAS) are likely to be switched to another diagnosis over time, according to a retrospective chart analysis of 77 children at Children’s Hospital of Colorado.

• Over 50% of patients in this study were switched from suspected EMAS to another epilepsy diagnosis.
• Among the 77 patients, 30 had an initial diagnosis of EMAS and 57 had a final diagnosis of EMAS.
• Among 65% of patients who had more than one diagnosis over time, the first, second, and third diagnoses were provided within 1 year, 3 years, and 10 years after the onset of the disease.
• Signs of Lennox-Gastaut syndrome (LGS), including paroxysmal fast activity, slow spike-and-wave, and tonic seizure, were detected in 50% of the 77 patients but only a minority received a final diagnosis of LGS.

Eschbach K., Moss A, Joshi C, et al. Diagnosis switching and outcomes in a cohort of patients with potential epilepsy with myoclonic-atonic seizures. Epilepsy Res. 2018; 147:95-101. https://doi.org/10.1016/j.eplepsyres.2018.09.011

Pediatric patients who have been initially diagnosed with epilepsy with myoclonic-atonic seizures (EMAS) are likely to be switched to another diagnosis over time, according to a retrospective chart analysis of 77 children at Children’s Hospital of Colorado.

• Over 50% of patients in this study were switched from suspected EMAS to another epilepsy diagnosis.
• Among the 77 patients, 30 had an initial diagnosis of EMAS and 57 had a final diagnosis of EMAS.
• Among 65% of patients who had more than one diagnosis over time, the first, second, and third diagnoses were provided within 1 year, 3 years, and 10 years after the onset of the disease.
• Signs of Lennox-Gastaut syndrome (LGS), including paroxysmal fast activity, slow spike-and-wave, and tonic seizure, were detected in 50% of the 77 patients but only a minority received a final diagnosis of LGS.

Eschbach K., Moss A, Joshi C, et al. Diagnosis switching and outcomes in a cohort of patients with potential epilepsy with myoclonic-atonic seizures. Epilepsy Res. 2018; 147:95-101. https://doi.org/10.1016/j.eplepsyres.2018.09.011

Researchers have found that using 256-channel high-density EEG and high-resolution head models of individual patients can help establish precise electrical source imaging of oscillatory features of the onset of a seizure, which in turn improves presurgical planning. Precisely localizing the seizure onset zone in the cortex is important for the best surgical outcomes.

• Using noninvasive electrical source imaging to plan surgery has proven problematic to date because of the interference of noise artifacts and non-seizure activity, which can be superimposed over the seizure signal.
• In this study, high density EEG was combined with exact sensor positioning and individual electrical head models, which were derived from T1 MRI results.
• Among 84 seizures, investigators were able to localize the onset of 56.
• High density EEG with interictal spikes was more accurate than international 10-20 EEG for interictal spikes and ictal onset.

Kuo C-C, Tucker DM, Luu P, et al. EEG source imaging of epileptic activity at seizure onset. Epilepsy Res. 2018;146:160-171. https://doi.org/10.1016/j.eplepsyres.2018.07.006

Researchers have found that using 256-channel high-density EEG and high-resolution head models of individual patients can help establish precise electrical source imaging of oscillatory features of the onset of a seizure, which in turn improves presurgical planning. Precisely localizing the seizure onset zone in the cortex is important for the best surgical outcomes.

• Using noninvasive electrical source imaging to plan surgery has proven problematic to date because of the interference of noise artifacts and non-seizure activity, which can be superimposed over the seizure signal.
• In this study, high density EEG was combined with exact sensor positioning and individual electrical head models, which were derived from T1 MRI results.
• Among 84 seizures, investigators were able to localize the onset of 56.
• High density EEG with interictal spikes was more accurate than international 10-20 EEG for interictal spikes and ictal onset.

Kuo C-C, Tucker DM, Luu P, et al. EEG source imaging of epileptic activity at seizure onset. Epilepsy Res. 2018;146:160-171. https://doi.org/10.1016/j.eplepsyres.2018.07.006

Researchers have found that using 256-channel high-density EEG and high-resolution head models of individual patients can help establish precise electrical source imaging of oscillatory features of the onset of a seizure, which in turn improves presurgical planning. Precisely localizing the seizure onset zone in the cortex is important for the best surgical outcomes.

• Using noninvasive electrical source imaging to plan surgery has proven problematic to date because of the interference of noise artifacts and non-seizure activity, which can be superimposed over the seizure signal.
• In this study, high density EEG was combined with exact sensor positioning and individual electrical head models, which were derived from T1 MRI results.
• Among 84 seizures, investigators were able to localize the onset of 56.
• High density EEG with interictal spikes was more accurate than international 10-20 EEG for interictal spikes and ictal onset.

Kuo C-C, Tucker DM, Luu P, et al. EEG source imaging of epileptic activity at seizure onset. Epilepsy Res. 2018;146:160-171. https://doi.org/10.1016/j.eplepsyres.2018.07.006

The cortical regions of the brains of patients with juvenile myoclonic epilepsy (JME) are more likely to be disassociated from subcortical structures, according to a recent study that compared the MRI readings of JME patients to those of normal children. 

• Investigators from the University of Wisconsin School of Medicine compared 21 children with JME to 22 healthy controls over a 2 year period.
• Normal children had modular cortical development and network integration between cortical and subcortical regions.
• Patients with epilepsy had a less modular cortical network that was disassociated from subcortical structures.
• Children with JME were also found to have weaker modules or communities, as indicated by higher clustering and lower modularity indices.

Garcia-Ramos C, Dabbs K, Lin JJ, et al. Progressive dissociation of cortical and subcortical network development in children with new‐onset juvenile myoclonic epilepsy [Published online ahead of print Oct 3, 2018]. Epilepsia.  https://doi.org/10.1111/epi.14560

The cortical regions of the brains of patients with juvenile myoclonic epilepsy (JME) are more likely to be disassociated from subcortical structures, according to a recent study that compared the MRI readings of JME patients to those of normal children. 

• Investigators from the University of Wisconsin School of Medicine compared 21 children with JME to 22 healthy controls over a 2 year period.
• Normal children had modular cortical development and network integration between cortical and subcortical regions.
• Patients with epilepsy had a less modular cortical network that was disassociated from subcortical structures.
• Children with JME were also found to have weaker modules or communities, as indicated by higher clustering and lower modularity indices.

Garcia-Ramos C, Dabbs K, Lin JJ, et al. Progressive dissociation of cortical and subcortical network development in children with new‐onset juvenile myoclonic epilepsy [Published online ahead of print Oct 3, 2018]. Epilepsia.  https://doi.org/10.1111/epi.14560

The cortical regions of the brains of patients with juvenile myoclonic epilepsy (JME) are more likely to be disassociated from subcortical structures, according to a recent study that compared the MRI readings of JME patients to those of normal children. 

• Investigators from the University of Wisconsin School of Medicine compared 21 children with JME to 22 healthy controls over a 2 year period.
• Normal children had modular cortical development and network integration between cortical and subcortical regions.
• Patients with epilepsy had a less modular cortical network that was disassociated from subcortical structures.
• Children with JME were also found to have weaker modules or communities, as indicated by higher clustering and lower modularity indices.

Garcia-Ramos C, Dabbs K, Lin JJ, et al. Progressive dissociation of cortical and subcortical network development in children with new‐onset juvenile myoclonic epilepsy [Published online ahead of print Oct 3, 2018]. Epilepsia.  https://doi.org/10.1111/epi.14560

Pediatric status epilepticus (SE) is an expensive disorder and is not uncommon in this patient population, according to a recent review of the medical literature.

• Gurcharran et al note that pediatric SE occurs in about 20per 100,000 children each year.
• The disorder carries a mortality of 3%.
• The most common risk factor for morbidity and death is symptomatic etiology, with acute presentation more common than remote.
• A single episode of status epilepticus costs more than $10,000 to manage and can reach more than $100,000 in children with refractory disease.
• The most common cause of the condition is febrile SE, which usually occurs in early childhood.

Gurcharran K, Grinspan ZM. The burden of pediatric status epilepticus: epidemiology, morbidity, and mortality. [Published online ahead of print August 29, 2018] Seizure. https://doi.org/10.1016/j.seizure.2018.08.021.

Pediatric status epilepticus (SE) is an expensive disorder and is not uncommon in this patient population, according to a recent review of the medical literature.

• Gurcharran et al note that pediatric SE occurs in about 20per 100,000 children each year.
• The disorder carries a mortality of 3%.
• The most common risk factor for morbidity and death is symptomatic etiology, with acute presentation more common than remote.
• A single episode of status epilepticus costs more than $10,000 to manage and can reach more than $100,000 in children with refractory disease.
• The most common cause of the condition is febrile SE, which usually occurs in early childhood.

Gurcharran K, Grinspan ZM. The burden of pediatric status epilepticus: epidemiology, morbidity, and mortality. [Published online ahead of print August 29, 2018] Seizure. https://doi.org/10.1016/j.seizure.2018.08.021.

Pediatric status epilepticus (SE) is an expensive disorder and is not uncommon in this patient population, according to a recent review of the medical literature.

• Gurcharran et al note that pediatric SE occurs in about 20per 100,000 children each year.
• The disorder carries a mortality of 3%.
• The most common risk factor for morbidity and death is symptomatic etiology, with acute presentation more common than remote.
• A single episode of status epilepticus costs more than $10,000 to manage and can reach more than $100,000 in children with refractory disease.
• The most common cause of the condition is febrile SE, which usually occurs in early childhood.

Gurcharran K, Grinspan ZM. The burden of pediatric status epilepticus: epidemiology, morbidity, and mortality. [Published online ahead of print August 29, 2018] Seizure. https://doi.org/10.1016/j.seizure.2018.08.021.

While several emerging treatments have been recommended for children with refractory status epilepticus, most of the research supporting these modalities are anecdotal in nature, according to a review published in Seizure.

• Randomized controlled trials have evaluated hypothermia and found it is no more effective than placebo for refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE).
• Case series have suggested that a ketogenic diet may benefit children with RSE.
• A few case reports involving the ketogenic diet found seizures were stopped within a week in 20-90% of children.
• One double blind trial concluded that brexanolone was no more effective than placebo for weaning patients off 3^rd line anesthetic agents and freedom from RSE after 24 hours.

Arya R, Rotenberg A.  Dietary, immunological, surgical, and other emerging treatments for pediatric refractory status epilepticus.  [Published online ahead of print Sept 14, 2018]. Seizure. https://doi.org/10.1016/j.seizure.2018.09.002.

While several emerging treatments have been recommended for children with refractory status epilepticus, most of the research supporting these modalities are anecdotal in nature, according to a review published in Seizure.

• Randomized controlled trials have evaluated hypothermia and found it is no more effective than placebo for refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE).
• Case series have suggested that a ketogenic diet may benefit children with RSE.
• A few case reports involving the ketogenic diet found seizures were stopped within a week in 20-90% of children.
• One double blind trial concluded that brexanolone was no more effective than placebo for weaning patients off 3^rd line anesthetic agents and freedom from RSE after 24 hours.

Arya R, Rotenberg A.  Dietary, immunological, surgical, and other emerging treatments for pediatric refractory status epilepticus.  [Published online ahead of print Sept 14, 2018]. Seizure. https://doi.org/10.1016/j.seizure.2018.09.002.

While several emerging treatments have been recommended for children with refractory status epilepticus, most of the research supporting these modalities are anecdotal in nature, according to a review published in Seizure.

• Randomized controlled trials have evaluated hypothermia and found it is no more effective than placebo for refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE).
• Case series have suggested that a ketogenic diet may benefit children with RSE.
• A few case reports involving the ketogenic diet found seizures were stopped within a week in 20-90% of children.
• One double blind trial concluded that brexanolone was no more effective than placebo for weaning patients off 3^rd line anesthetic agents and freedom from RSE after 24 hours.

Arya R, Rotenberg A.  Dietary, immunological, surgical, and other emerging treatments for pediatric refractory status epilepticus.  [Published online ahead of print Sept 14, 2018]. Seizure. https://doi.org/10.1016/j.seizure.2018.09.002.

Patients will likely develop intolerable psychiatric and behavioral side effects (IPBSE) to an antiepileptic drug if they are already sensitive to another one, according to researchers from Yale and Columbia University.

• A review of the records of over 2,000 patients found that about 20% were taking at least two antiepileptic drug and had at IPBSE to at least one of the drugs.
• Cross sensitivity was detected between zonisamide and levetiracetam.
• The odds of developing said side effects from levetiracetam or from zonisamide were significantly higher in a patient that had had a side effect to another antiepileptic drug than in patients who had no IPBSE to other antiepileptic drugs (20.5% versus 7.5%.)
•  A history of depression and psychosis increase the risk of IPBSE among patients taking antiepileptic medication.

Chen B, Choi H, Hirsch LJ, et al. Cross-sensitivity of psychiatric and behavioral side effects with antiepileptic drug use. [Published online ahead of print Sept 22, 2018]. Seizure. https://doi.org/10.1016/j.seizure.2018.09.014.

Patients will likely develop intolerable psychiatric and behavioral side effects (IPBSE) to an antiepileptic drug if they are already sensitive to another one, according to researchers from Yale and Columbia University.

• A review of the records of over 2,000 patients found that about 20% were taking at least two antiepileptic drug and had at IPBSE to at least one of the drugs.
• Cross sensitivity was detected between zonisamide and levetiracetam.
• The odds of developing said side effects from levetiracetam or from zonisamide were significantly higher in a patient that had had a side effect to another antiepileptic drug than in patients who had no IPBSE to other antiepileptic drugs (20.5% versus 7.5%.)
•  A history of depression and psychosis increase the risk of IPBSE among patients taking antiepileptic medication.

Chen B, Choi H, Hirsch LJ, et al. Cross-sensitivity of psychiatric and behavioral side effects with antiepileptic drug use. [Published online ahead of print Sept 22, 2018]. Seizure. https://doi.org/10.1016/j.seizure.2018.09.014.

Patients will likely develop intolerable psychiatric and behavioral side effects (IPBSE) to an antiepileptic drug if they are already sensitive to another one, according to researchers from Yale and Columbia University.

• A review of the records of over 2,000 patients found that about 20% were taking at least two antiepileptic drug and had at IPBSE to at least one of the drugs.
• Cross sensitivity was detected between zonisamide and levetiracetam.
• The odds of developing said side effects from levetiracetam or from zonisamide were significantly higher in a patient that had had a side effect to another antiepileptic drug than in patients who had no IPBSE to other antiepileptic drugs (20.5% versus 7.5%.)
•  A history of depression and psychosis increase the risk of IPBSE among patients taking antiepileptic medication.

Chen B, Choi H, Hirsch LJ, et al. Cross-sensitivity of psychiatric and behavioral side effects with antiepileptic drug use. [Published online ahead of print Sept 22, 2018]. Seizure. https://doi.org/10.1016/j.seizure.2018.09.014.

Periictal cardiorespiratory dysfunction, sleep-disordered breathing, and endocrine dysfunction have all been linked to sudden unexpected death from epilepsy (SUDEP).

• Investigators conducted a prospective observational study on 30 patients in the Columbia University Medical Center’s adult epilepsy monitoring unit.
• Their analysis found that patients who were at high risk for SUDEP were more likely to experience cardiorespiratory dysfunction (60% vs 27%).
• Sleep-disordered breathing was found in 88% of patients with inpatient or outpatient polysomnography results that were fully scorable.
• The researchers also found endocrine dysfunction in 35% of patients, with men more likely to experience the problem.
• The analysis did not detect a significant relationship between cardiorespiratory dysfunction, sleep-disordered breathing, and neuroendocrine status.

Billakota S, Odom N, Westwood AJ, et al. Sleep-disordered breathing, neuroendocrine function, and clinical SUDEP risk in patients with epilepsy. Epilepsy Behav. 2018;87:78-82.

Periictal cardiorespiratory dysfunction, sleep-disordered breathing, and endocrine dysfunction have all been linked to sudden unexpected death from epilepsy (SUDEP).

• Investigators conducted a prospective observational study on 30 patients in the Columbia University Medical Center’s adult epilepsy monitoring unit.
• Their analysis found that patients who were at high risk for SUDEP were more likely to experience cardiorespiratory dysfunction (60% vs 27%).
• Sleep-disordered breathing was found in 88% of patients with inpatient or outpatient polysomnography results that were fully scorable.
• The researchers also found endocrine dysfunction in 35% of patients, with men more likely to experience the problem.
• The analysis did not detect a significant relationship between cardiorespiratory dysfunction, sleep-disordered breathing, and neuroendocrine status.

Billakota S, Odom N, Westwood AJ, et al. Sleep-disordered breathing, neuroendocrine function, and clinical SUDEP risk in patients with epilepsy. Epilepsy Behav. 2018;87:78-82.

Periictal cardiorespiratory dysfunction, sleep-disordered breathing, and endocrine dysfunction have all been linked to sudden unexpected death from epilepsy (SUDEP).

• Investigators conducted a prospective observational study on 30 patients in the Columbia University Medical Center’s adult epilepsy monitoring unit.
• Their analysis found that patients who were at high risk for SUDEP were more likely to experience cardiorespiratory dysfunction (60% vs 27%).
• Sleep-disordered breathing was found in 88% of patients with inpatient or outpatient polysomnography results that were fully scorable.
• The researchers also found endocrine dysfunction in 35% of patients, with men more likely to experience the problem.
• The analysis did not detect a significant relationship between cardiorespiratory dysfunction, sleep-disordered breathing, and neuroendocrine status.

Billakota S, Odom N, Westwood AJ, et al. Sleep-disordered breathing, neuroendocrine function, and clinical SUDEP risk in patients with epilepsy. Epilepsy Behav. 2018;87:78-82.