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Cerliponase alfa continues to impress for CLN2 disease
BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.
Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.
When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.
Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.
At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.
Side effects included several cases of device failure, infection, and hypersensitivity reactions.
In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).
The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.
SOURCE: Trivisano M et al. IEC 2019, Abstract P333.
BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.
Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.
When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.
Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.
At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.
Side effects included several cases of device failure, infection, and hypersensitivity reactions.
In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).
The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.
SOURCE: Trivisano M et al. IEC 2019, Abstract P333.
BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.
Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.
When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.
Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.
At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.
Side effects included several cases of device failure, infection, and hypersensitivity reactions.
In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).
The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.
SOURCE: Trivisano M et al. IEC 2019, Abstract P333.
REPORTING FROM IEC 2019
Combo therapy outcomes for West syndrome prove no better than monotherapy
BANGKOK – Hiroki Nariai, MD, declared at the International Epilepsy Congress.
West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).
However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.
“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.
The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).
The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.
Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.
“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.
The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.
BANGKOK – Hiroki Nariai, MD, declared at the International Epilepsy Congress.
West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).
However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.
“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.
The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).
The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.
Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.
“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.
The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.
BANGKOK – Hiroki Nariai, MD, declared at the International Epilepsy Congress.
West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).
However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.
“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.
The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).
The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.
Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.
“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.
The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.
EXPERT ANALYSIS FROM IEC 2019
A new beverage aims to make ketogenic diets more palatable
BANGKOK –
Chief among those shortcomings is the notoriously poor compliance with these highly restrictive diets, which, as defining features, emphasize high fat intake and scrupulous restriction of carbohydrates in an effort to mimic the metabolic effects of starvation, J. Helen Cross, MD, explained at the International Epilepsy Congress.
She was a coauthor of a study led by Natasha E. Schoeler, PhD, a research dietician at the University College London Great Ormond Street Institute of Child Health, which demonstrated that children and adults with epilepsy who experience a significant antiseizure effect in response to ketogenic diet therapies have higher baseline blood levels of acetyl carnitine (Epilepsia. 2017 May;58(5):893-900).
The importance of this novel observation is twofold: It indicates a potential role for baseline acetyl carnitine level as a predictor of differential response to ketogenic diet therapies, a predictor for which there is an unmet need, and it is consistent with the hypothesis that an important potential mechanism of ketogenic diet effectiveness in epilepsy involves altered mitochondrial energy metabolism. That is because acetyl carnitine plays an essential role in mitochondrial uptake of long-chain fatty acids, noted Dr. Cross, professor of pediatric neurology and head of the developmental neurosciences program at the University College London Great Ormond Street Institute of Child Health.
At the congress sponsored by the International League Against Epilepsy, Dr. Cross and Dr. Schoeler presented the results of the initial 12-week tolerability study of Betashot, a ready-to-use, palatable blend of specific medium-chain triglycerides designed to be consumed three to four times daily with normal meals, limiting only intake of foods high in refined sugar. The Betashot beverage was developed in conjunction with Vitaflo International, a nutritional products company.
“It actually tastes good. It tastes like a strawberry shake,” according to Dr. Schoeler.
The 12-week study included 35 children with genetically caused forms of epilepsy and 26 adults with drug-resistant epilepsy. This was primarily a tolerability and compliance study, and the main finding was that two-thirds of the children and 69% of adults who started the study were still using Betashot at the 12-week mark. Moreover, 91% of the children and 56% of adults who completed the study elected to stay on Betashot afterwards. By week 12, after titrating their daily dose of Betashot upward as tolerated, the pediatric patients averaged 18% of their total daily energy intake from Betashot, the adults 24%.
The most common reasons for discontinuation among both children and adults were gastrointestinal side effects: abdominal discomfort, diarrhea, and/or vomiting.
“What’s exciting is that, even though the study is not powered to look at seizure response – it’s a tolerability study – we can report that there was a statistically significant reduction in the number of seizures in the group overall after 3 months of treatment,” Dr. Cross said.
She declined to provide specific data on seizure frequency because the study was underpowered for that endpoint. However, she added that further larger studies looking at a possible antiseizure effect of Betashot are ongoing.
The Betashot study was funded by Vitaflo International.
BANGKOK –
Chief among those shortcomings is the notoriously poor compliance with these highly restrictive diets, which, as defining features, emphasize high fat intake and scrupulous restriction of carbohydrates in an effort to mimic the metabolic effects of starvation, J. Helen Cross, MD, explained at the International Epilepsy Congress.
She was a coauthor of a study led by Natasha E. Schoeler, PhD, a research dietician at the University College London Great Ormond Street Institute of Child Health, which demonstrated that children and adults with epilepsy who experience a significant antiseizure effect in response to ketogenic diet therapies have higher baseline blood levels of acetyl carnitine (Epilepsia. 2017 May;58(5):893-900).
The importance of this novel observation is twofold: It indicates a potential role for baseline acetyl carnitine level as a predictor of differential response to ketogenic diet therapies, a predictor for which there is an unmet need, and it is consistent with the hypothesis that an important potential mechanism of ketogenic diet effectiveness in epilepsy involves altered mitochondrial energy metabolism. That is because acetyl carnitine plays an essential role in mitochondrial uptake of long-chain fatty acids, noted Dr. Cross, professor of pediatric neurology and head of the developmental neurosciences program at the University College London Great Ormond Street Institute of Child Health.
At the congress sponsored by the International League Against Epilepsy, Dr. Cross and Dr. Schoeler presented the results of the initial 12-week tolerability study of Betashot, a ready-to-use, palatable blend of specific medium-chain triglycerides designed to be consumed three to four times daily with normal meals, limiting only intake of foods high in refined sugar. The Betashot beverage was developed in conjunction with Vitaflo International, a nutritional products company.
“It actually tastes good. It tastes like a strawberry shake,” according to Dr. Schoeler.
The 12-week study included 35 children with genetically caused forms of epilepsy and 26 adults with drug-resistant epilepsy. This was primarily a tolerability and compliance study, and the main finding was that two-thirds of the children and 69% of adults who started the study were still using Betashot at the 12-week mark. Moreover, 91% of the children and 56% of adults who completed the study elected to stay on Betashot afterwards. By week 12, after titrating their daily dose of Betashot upward as tolerated, the pediatric patients averaged 18% of their total daily energy intake from Betashot, the adults 24%.
The most common reasons for discontinuation among both children and adults were gastrointestinal side effects: abdominal discomfort, diarrhea, and/or vomiting.
“What’s exciting is that, even though the study is not powered to look at seizure response – it’s a tolerability study – we can report that there was a statistically significant reduction in the number of seizures in the group overall after 3 months of treatment,” Dr. Cross said.
She declined to provide specific data on seizure frequency because the study was underpowered for that endpoint. However, she added that further larger studies looking at a possible antiseizure effect of Betashot are ongoing.
The Betashot study was funded by Vitaflo International.
BANGKOK –
Chief among those shortcomings is the notoriously poor compliance with these highly restrictive diets, which, as defining features, emphasize high fat intake and scrupulous restriction of carbohydrates in an effort to mimic the metabolic effects of starvation, J. Helen Cross, MD, explained at the International Epilepsy Congress.
She was a coauthor of a study led by Natasha E. Schoeler, PhD, a research dietician at the University College London Great Ormond Street Institute of Child Health, which demonstrated that children and adults with epilepsy who experience a significant antiseizure effect in response to ketogenic diet therapies have higher baseline blood levels of acetyl carnitine (Epilepsia. 2017 May;58(5):893-900).
The importance of this novel observation is twofold: It indicates a potential role for baseline acetyl carnitine level as a predictor of differential response to ketogenic diet therapies, a predictor for which there is an unmet need, and it is consistent with the hypothesis that an important potential mechanism of ketogenic diet effectiveness in epilepsy involves altered mitochondrial energy metabolism. That is because acetyl carnitine plays an essential role in mitochondrial uptake of long-chain fatty acids, noted Dr. Cross, professor of pediatric neurology and head of the developmental neurosciences program at the University College London Great Ormond Street Institute of Child Health.
At the congress sponsored by the International League Against Epilepsy, Dr. Cross and Dr. Schoeler presented the results of the initial 12-week tolerability study of Betashot, a ready-to-use, palatable blend of specific medium-chain triglycerides designed to be consumed three to four times daily with normal meals, limiting only intake of foods high in refined sugar. The Betashot beverage was developed in conjunction with Vitaflo International, a nutritional products company.
“It actually tastes good. It tastes like a strawberry shake,” according to Dr. Schoeler.
The 12-week study included 35 children with genetically caused forms of epilepsy and 26 adults with drug-resistant epilepsy. This was primarily a tolerability and compliance study, and the main finding was that two-thirds of the children and 69% of adults who started the study were still using Betashot at the 12-week mark. Moreover, 91% of the children and 56% of adults who completed the study elected to stay on Betashot afterwards. By week 12, after titrating their daily dose of Betashot upward as tolerated, the pediatric patients averaged 18% of their total daily energy intake from Betashot, the adults 24%.
The most common reasons for discontinuation among both children and adults were gastrointestinal side effects: abdominal discomfort, diarrhea, and/or vomiting.
“What’s exciting is that, even though the study is not powered to look at seizure response – it’s a tolerability study – we can report that there was a statistically significant reduction in the number of seizures in the group overall after 3 months of treatment,” Dr. Cross said.
She declined to provide specific data on seizure frequency because the study was underpowered for that endpoint. However, she added that further larger studies looking at a possible antiseizure effect of Betashot are ongoing.
The Betashot study was funded by Vitaflo International.
REPORTING FROM IEC 2019
Intranasal midazolam as first line for status epilepticus
BANGKOK – Lara Kay, MD, said at the International Epilepsy Congress.
Why? Because status epilepticus is a major medical emergency. It’s associated with substantial morbidity and mortality. And of the various factors that influence outcome in status epilepticus – including age, underlying etiology, and level of consciousness – only one is potentially within physician control: time to treatment, she noted at the congress sponsored by the International League Against Epilepsy.
“Time is brain,” observed Dr. Kay, a neurologist at the epilepsy center at University Hospital Frankfurt.
While intravenous benzodiazepines – for example, lorazepam at 2-4 mg – are widely accepted as the time-honored first-line treatment for status epilepticus, trying to place a line in a patient experiencing this emergency can be a tricky, time-consuming business. Multiple studies have demonstrated that various nonintravenous formulations of benzodiazepines, such as rectal diazepam or buccal or intramuscular midazolam, can be administered much faster and are as effective as intravenous benzodiazepines. But buccal midazolam is quite expensive in Germany, and the ready-to-use intramuscular midazolam applicator that’s available in the United States isn’t marketed in Germany. So several years ago Dr. Kay and her fellow neurologists started having their university hospital pharmacy manufacture intranasal midazolam.
Dr. Kay presented an observational study of 42 consecutive patients with status epilepticus who received intranasal midazolam as first-line treatment. The patients had a mean age of nearly 53 years and 23 were women. The starting dose was 2.5 mg per nostril, moving up to 5 mg per nostril after waiting 5 minutes in initial nonresponders.
Status epilepticus ceased both clinically and by EEG in 24 of the 42 patients, or 57%, in an average of 5 minutes after administration of the intranasal medication at a mean dose of 5.6 mg. Nonresponders received a mean dose of 7.5 mg. There were no significant differences between responders and nonresponders in terms of the proportion presenting with preexisting epilepsy or the epilepsy etiology. However, responders presented at a mean of 54 minutes in status epilepticus, while nonresponders had been in status for 17 minutes.
The 57% response rate with intranasal midazolam is comparable with other investigators’ reported success rates using other benzodiazepines and routes of administration, she noted.
Session cochair Gregory Krauss, MD, commented that he thought the Frankfurt neurologists may have been too cautious in their dosing of intranasal midazolam for status epilepticus.
“Often in the U.S. 5 mg is initially used in each nostril,” according to Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Kay reported having no financial conflicts of interest regarding her study.
SOURCE: Kay L et al. IEC 2019, Abstract P029.
BANGKOK – Lara Kay, MD, said at the International Epilepsy Congress.
Why? Because status epilepticus is a major medical emergency. It’s associated with substantial morbidity and mortality. And of the various factors that influence outcome in status epilepticus – including age, underlying etiology, and level of consciousness – only one is potentially within physician control: time to treatment, she noted at the congress sponsored by the International League Against Epilepsy.
“Time is brain,” observed Dr. Kay, a neurologist at the epilepsy center at University Hospital Frankfurt.
While intravenous benzodiazepines – for example, lorazepam at 2-4 mg – are widely accepted as the time-honored first-line treatment for status epilepticus, trying to place a line in a patient experiencing this emergency can be a tricky, time-consuming business. Multiple studies have demonstrated that various nonintravenous formulations of benzodiazepines, such as rectal diazepam or buccal or intramuscular midazolam, can be administered much faster and are as effective as intravenous benzodiazepines. But buccal midazolam is quite expensive in Germany, and the ready-to-use intramuscular midazolam applicator that’s available in the United States isn’t marketed in Germany. So several years ago Dr. Kay and her fellow neurologists started having their university hospital pharmacy manufacture intranasal midazolam.
Dr. Kay presented an observational study of 42 consecutive patients with status epilepticus who received intranasal midazolam as first-line treatment. The patients had a mean age of nearly 53 years and 23 were women. The starting dose was 2.5 mg per nostril, moving up to 5 mg per nostril after waiting 5 minutes in initial nonresponders.
Status epilepticus ceased both clinically and by EEG in 24 of the 42 patients, or 57%, in an average of 5 minutes after administration of the intranasal medication at a mean dose of 5.6 mg. Nonresponders received a mean dose of 7.5 mg. There were no significant differences between responders and nonresponders in terms of the proportion presenting with preexisting epilepsy or the epilepsy etiology. However, responders presented at a mean of 54 minutes in status epilepticus, while nonresponders had been in status for 17 minutes.
The 57% response rate with intranasal midazolam is comparable with other investigators’ reported success rates using other benzodiazepines and routes of administration, she noted.
Session cochair Gregory Krauss, MD, commented that he thought the Frankfurt neurologists may have been too cautious in their dosing of intranasal midazolam for status epilepticus.
“Often in the U.S. 5 mg is initially used in each nostril,” according to Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Kay reported having no financial conflicts of interest regarding her study.
SOURCE: Kay L et al. IEC 2019, Abstract P029.
BANGKOK – Lara Kay, MD, said at the International Epilepsy Congress.
Why? Because status epilepticus is a major medical emergency. It’s associated with substantial morbidity and mortality. And of the various factors that influence outcome in status epilepticus – including age, underlying etiology, and level of consciousness – only one is potentially within physician control: time to treatment, she noted at the congress sponsored by the International League Against Epilepsy.
“Time is brain,” observed Dr. Kay, a neurologist at the epilepsy center at University Hospital Frankfurt.
While intravenous benzodiazepines – for example, lorazepam at 2-4 mg – are widely accepted as the time-honored first-line treatment for status epilepticus, trying to place a line in a patient experiencing this emergency can be a tricky, time-consuming business. Multiple studies have demonstrated that various nonintravenous formulations of benzodiazepines, such as rectal diazepam or buccal or intramuscular midazolam, can be administered much faster and are as effective as intravenous benzodiazepines. But buccal midazolam is quite expensive in Germany, and the ready-to-use intramuscular midazolam applicator that’s available in the United States isn’t marketed in Germany. So several years ago Dr. Kay and her fellow neurologists started having their university hospital pharmacy manufacture intranasal midazolam.
Dr. Kay presented an observational study of 42 consecutive patients with status epilepticus who received intranasal midazolam as first-line treatment. The patients had a mean age of nearly 53 years and 23 were women. The starting dose was 2.5 mg per nostril, moving up to 5 mg per nostril after waiting 5 minutes in initial nonresponders.
Status epilepticus ceased both clinically and by EEG in 24 of the 42 patients, or 57%, in an average of 5 minutes after administration of the intranasal medication at a mean dose of 5.6 mg. Nonresponders received a mean dose of 7.5 mg. There were no significant differences between responders and nonresponders in terms of the proportion presenting with preexisting epilepsy or the epilepsy etiology. However, responders presented at a mean of 54 minutes in status epilepticus, while nonresponders had been in status for 17 minutes.
The 57% response rate with intranasal midazolam is comparable with other investigators’ reported success rates using other benzodiazepines and routes of administration, she noted.
Session cochair Gregory Krauss, MD, commented that he thought the Frankfurt neurologists may have been too cautious in their dosing of intranasal midazolam for status epilepticus.
“Often in the U.S. 5 mg is initially used in each nostril,” according to Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Kay reported having no financial conflicts of interest regarding her study.
SOURCE: Kay L et al. IEC 2019, Abstract P029.
REPORTING FROM IEC 2019
A practical tool predicts childhood epilepsy diagnosis
BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.
This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.
The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.
Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.
The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.
The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.
The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
Future predictive refinements are under study
Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).
In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).
A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).
Dr. Braun reported having no financial conflicts regarding his presentation.
BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.
This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.
The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.
Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.
The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.
The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.
The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
Future predictive refinements are under study
Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).
In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).
A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).
Dr. Braun reported having no financial conflicts regarding his presentation.
BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.
This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.
The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.
Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.
The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.
The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.
The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
Future predictive refinements are under study
Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).
In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).
A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).
Dr. Braun reported having no financial conflicts regarding his presentation.
REPORTING FROM IEC 2019
‘Pot’ is still hot for Dravet, Lennox-Gastaut
BANGKOK – Interim results of long-term, open-label extension trials of add-on prescription cannabidiol in patients with Dravet syndrome or Lennox-Gastaut syndrome show sustained, clinically meaningful seizure reductions with no new safety concerns, Anup D. Patel, MD, reported at the International Epilepsy Congress.
“Overall, this is a very promising and sustainable result that we were happy to see,” said Dr. Patel, chief of child neurology at Nationwide Children’s Hospital in Columbus, Ohio.
Epidiolex is the brand name for the plant-derived, highly purified cannabidiol (CBD) in an oil-based oral solution at 100 mg/mL. Dr. Patel has been involved in the medication’s development program since the earliest open-label compassionate use study, which was followed by rigorous phase 3, double-blind, placebo-controlled randomized trials, eventually leading to Food and Drug Administration marketing approval for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years of age or older.
“On June 25th, 2018, history was made: for the first time in United States history, a plant-based derivative of marijuana was approved for use as a medication, and it was also the first FDA-approved treatment for Dravet syndrome,” Dr. Patel noted at the congress sponsored by the International League Against Epilepsy.
A total of 96% of the 289 children with Dravet syndrome who completed the 14-week, double-blind, controlled randomized trials enrolled in the open-label, long-term extension study, during which they were on a median of three concurrent antiepileptic drugs along with a mean modal dose of CBD at 22 mg/kg/day. Although the target maintenance dose of CBD was 20 mg/kg/day, as advised in the product labeling, physicians could reduce or increase the dose up to 30 mg/kg/day.
“In the initial compassionate-use study, our site could go up to 50 mg/kg/day,” according to Dr. Patel. “We have plenty of data showing efficacy and continued safety beyond the FDA-recommended dose.”
In the open-label extension study, the median reduction from baseline in monthly seizure frequency assessed in 12-week intervals up to a maximum of week 72 was 44%-57% for convulsive seizures and 49%-67% for total seizures. More than 80% of patients and/or caregivers reported improvement in the patient’s overall condition as assessed on the Subject/Caregiver Global Impression of Change scale.
The pattern of adverse events associated with CBD has been consistent across all of the studies. The most common side effects are diarrhea in about one-third of patients, sleepiness in one-quarter, and decreased appetite in about one-quarter. Seven percent of patients discontinued the long-term extension trial because of adverse events.
Seventy percent of patients remained in the long-term extension study at 1 year.
Twenty-six patients developed liver transaminase levels greater than three times the upper limit of normal, and of note, 23 of the 26 were on concomitant valproic acid. None met criteria for severe drug-induced liver injury, and all recovered either spontaneously or after a reduction in the dose of CBD or valproic acid. But this association between CBD, valproic acid, and increased risk of mild liver injury has been a consistent finding across the clinical trials program.
“This is a very important clinical pearl to take away,” commented Dr. Patel, who is also a pediatric neurologist at Ohio State University.
The interim results of the long-term, open-label extension study of add-on CBD in patients with Lennox-Gastaut syndrome are similar to the Dravet syndrome study. Overall, 99% of the 368 patients with Lennox-Gastaut syndrome who completed the 14-week, double-blind, randomized trials signed up for the open-label extension. During a median follow-up of 61 weeks, the median percent reduction in seizure frequency as assessed in serial 12-week windows was 48%-70% for drop seizures and 48%-63% for total seizures. Twenty-four percent of patients withdrew from the study. Eighty-eight percent of patients or caregivers reported an improvement in overall condition when assessed at weeks 24 and 48. Forty-seven patients developed elevated transaminase levels – typically within the first 2 months on CBD – and 35 of them were on concomitant valproic acid.
More on drug-drug interactions
Elsewhere at IEC 2019, Gilmour Morrison of GW Pharmaceuticals, the Cambridge, England, company that markets Epidiolex, presented the findings of a series of drug-drug interaction studies involving coadministration of their CBD with clobazam (Sympazan and Onfi), valproate, stiripentol (Diacomit), or midazolam (Versed) in adult epilepsy patients and healthy volunteers. The researchers reported a bidirectional drug-drug interaction between Epidiolex and clobazam resulting in increased levels of the active metabolites of both drugs. The mechanism is believed to involve inhibition of cytochrome P450 2C19. However, there were no interactions with midazolam or valproate, and the slight bump in stiripentol levels when given with CBD didn’t reach the level of a clinically meaningful drug-drug interaction, according to the investigators.
On the horizon, Canadian researchers are investigating the possibility that since both the tetrahydrocannabinol (THC) and CBD components of marijuana have been shown to have anticonvulsant effects, adding a bit of THC to CBD will result in even better seizure control than with pure CBD in patients with Dravet syndrome. Investigators at Toronto’s Hospital for Sick Children have conducted a prospective, open-label study of a product containing CBD and THC in a 50:1 ratio as add-on therapy in 20 children with Dravet syndrome. The dose was 2-16 mg/kg/day of CBD and 0.04-0.32 mg/kg/day of THC. The cannabis plant extract used in the study was produced by Tilray, a Canadian pharmaceutical company.
Nineteen of the 20 patients completed the 20-week study. The sole noncompleter died of SUDEP (sudden unexpected death in epilepsy) deemed treatment unrelated. Patients experienced a median 71% reduction in motor seizures, compared with baseline. Sixty-three percent of patients had at least a 50% reduction in seizure frequency. Elevated liver transaminases occurred in patients on concomitant valproic acid, as did platelet abnormalities, which have not been seen in the Epidiolex studies, noted Dr. Patel, who was not involved in the Canadian study (Ann Clin Transl Neurol. 2018 Aug 1;5[9]:1077-88).
Dr. Patel reported serving as a consultant to Greenwich Biosciences, a U.S. offshoot of GW Pharmaceuticals. He receives research grants from that company as well as from the National Institutes of Health and the Pediatric Epilepsy Research Foundation.
BANGKOK – Interim results of long-term, open-label extension trials of add-on prescription cannabidiol in patients with Dravet syndrome or Lennox-Gastaut syndrome show sustained, clinically meaningful seizure reductions with no new safety concerns, Anup D. Patel, MD, reported at the International Epilepsy Congress.
“Overall, this is a very promising and sustainable result that we were happy to see,” said Dr. Patel, chief of child neurology at Nationwide Children’s Hospital in Columbus, Ohio.
Epidiolex is the brand name for the plant-derived, highly purified cannabidiol (CBD) in an oil-based oral solution at 100 mg/mL. Dr. Patel has been involved in the medication’s development program since the earliest open-label compassionate use study, which was followed by rigorous phase 3, double-blind, placebo-controlled randomized trials, eventually leading to Food and Drug Administration marketing approval for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years of age or older.
“On June 25th, 2018, history was made: for the first time in United States history, a plant-based derivative of marijuana was approved for use as a medication, and it was also the first FDA-approved treatment for Dravet syndrome,” Dr. Patel noted at the congress sponsored by the International League Against Epilepsy.
A total of 96% of the 289 children with Dravet syndrome who completed the 14-week, double-blind, controlled randomized trials enrolled in the open-label, long-term extension study, during which they were on a median of three concurrent antiepileptic drugs along with a mean modal dose of CBD at 22 mg/kg/day. Although the target maintenance dose of CBD was 20 mg/kg/day, as advised in the product labeling, physicians could reduce or increase the dose up to 30 mg/kg/day.
“In the initial compassionate-use study, our site could go up to 50 mg/kg/day,” according to Dr. Patel. “We have plenty of data showing efficacy and continued safety beyond the FDA-recommended dose.”
In the open-label extension study, the median reduction from baseline in monthly seizure frequency assessed in 12-week intervals up to a maximum of week 72 was 44%-57% for convulsive seizures and 49%-67% for total seizures. More than 80% of patients and/or caregivers reported improvement in the patient’s overall condition as assessed on the Subject/Caregiver Global Impression of Change scale.
The pattern of adverse events associated with CBD has been consistent across all of the studies. The most common side effects are diarrhea in about one-third of patients, sleepiness in one-quarter, and decreased appetite in about one-quarter. Seven percent of patients discontinued the long-term extension trial because of adverse events.
Seventy percent of patients remained in the long-term extension study at 1 year.
Twenty-six patients developed liver transaminase levels greater than three times the upper limit of normal, and of note, 23 of the 26 were on concomitant valproic acid. None met criteria for severe drug-induced liver injury, and all recovered either spontaneously or after a reduction in the dose of CBD or valproic acid. But this association between CBD, valproic acid, and increased risk of mild liver injury has been a consistent finding across the clinical trials program.
“This is a very important clinical pearl to take away,” commented Dr. Patel, who is also a pediatric neurologist at Ohio State University.
The interim results of the long-term, open-label extension study of add-on CBD in patients with Lennox-Gastaut syndrome are similar to the Dravet syndrome study. Overall, 99% of the 368 patients with Lennox-Gastaut syndrome who completed the 14-week, double-blind, randomized trials signed up for the open-label extension. During a median follow-up of 61 weeks, the median percent reduction in seizure frequency as assessed in serial 12-week windows was 48%-70% for drop seizures and 48%-63% for total seizures. Twenty-four percent of patients withdrew from the study. Eighty-eight percent of patients or caregivers reported an improvement in overall condition when assessed at weeks 24 and 48. Forty-seven patients developed elevated transaminase levels – typically within the first 2 months on CBD – and 35 of them were on concomitant valproic acid.
More on drug-drug interactions
Elsewhere at IEC 2019, Gilmour Morrison of GW Pharmaceuticals, the Cambridge, England, company that markets Epidiolex, presented the findings of a series of drug-drug interaction studies involving coadministration of their CBD with clobazam (Sympazan and Onfi), valproate, stiripentol (Diacomit), or midazolam (Versed) in adult epilepsy patients and healthy volunteers. The researchers reported a bidirectional drug-drug interaction between Epidiolex and clobazam resulting in increased levels of the active metabolites of both drugs. The mechanism is believed to involve inhibition of cytochrome P450 2C19. However, there were no interactions with midazolam or valproate, and the slight bump in stiripentol levels when given with CBD didn’t reach the level of a clinically meaningful drug-drug interaction, according to the investigators.
On the horizon, Canadian researchers are investigating the possibility that since both the tetrahydrocannabinol (THC) and CBD components of marijuana have been shown to have anticonvulsant effects, adding a bit of THC to CBD will result in even better seizure control than with pure CBD in patients with Dravet syndrome. Investigators at Toronto’s Hospital for Sick Children have conducted a prospective, open-label study of a product containing CBD and THC in a 50:1 ratio as add-on therapy in 20 children with Dravet syndrome. The dose was 2-16 mg/kg/day of CBD and 0.04-0.32 mg/kg/day of THC. The cannabis plant extract used in the study was produced by Tilray, a Canadian pharmaceutical company.
Nineteen of the 20 patients completed the 20-week study. The sole noncompleter died of SUDEP (sudden unexpected death in epilepsy) deemed treatment unrelated. Patients experienced a median 71% reduction in motor seizures, compared with baseline. Sixty-three percent of patients had at least a 50% reduction in seizure frequency. Elevated liver transaminases occurred in patients on concomitant valproic acid, as did platelet abnormalities, which have not been seen in the Epidiolex studies, noted Dr. Patel, who was not involved in the Canadian study (Ann Clin Transl Neurol. 2018 Aug 1;5[9]:1077-88).
Dr. Patel reported serving as a consultant to Greenwich Biosciences, a U.S. offshoot of GW Pharmaceuticals. He receives research grants from that company as well as from the National Institutes of Health and the Pediatric Epilepsy Research Foundation.
BANGKOK – Interim results of long-term, open-label extension trials of add-on prescription cannabidiol in patients with Dravet syndrome or Lennox-Gastaut syndrome show sustained, clinically meaningful seizure reductions with no new safety concerns, Anup D. Patel, MD, reported at the International Epilepsy Congress.
“Overall, this is a very promising and sustainable result that we were happy to see,” said Dr. Patel, chief of child neurology at Nationwide Children’s Hospital in Columbus, Ohio.
Epidiolex is the brand name for the plant-derived, highly purified cannabidiol (CBD) in an oil-based oral solution at 100 mg/mL. Dr. Patel has been involved in the medication’s development program since the earliest open-label compassionate use study, which was followed by rigorous phase 3, double-blind, placebo-controlled randomized trials, eventually leading to Food and Drug Administration marketing approval for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years of age or older.
“On June 25th, 2018, history was made: for the first time in United States history, a plant-based derivative of marijuana was approved for use as a medication, and it was also the first FDA-approved treatment for Dravet syndrome,” Dr. Patel noted at the congress sponsored by the International League Against Epilepsy.
A total of 96% of the 289 children with Dravet syndrome who completed the 14-week, double-blind, controlled randomized trials enrolled in the open-label, long-term extension study, during which they were on a median of three concurrent antiepileptic drugs along with a mean modal dose of CBD at 22 mg/kg/day. Although the target maintenance dose of CBD was 20 mg/kg/day, as advised in the product labeling, physicians could reduce or increase the dose up to 30 mg/kg/day.
“In the initial compassionate-use study, our site could go up to 50 mg/kg/day,” according to Dr. Patel. “We have plenty of data showing efficacy and continued safety beyond the FDA-recommended dose.”
In the open-label extension study, the median reduction from baseline in monthly seizure frequency assessed in 12-week intervals up to a maximum of week 72 was 44%-57% for convulsive seizures and 49%-67% for total seizures. More than 80% of patients and/or caregivers reported improvement in the patient’s overall condition as assessed on the Subject/Caregiver Global Impression of Change scale.
The pattern of adverse events associated with CBD has been consistent across all of the studies. The most common side effects are diarrhea in about one-third of patients, sleepiness in one-quarter, and decreased appetite in about one-quarter. Seven percent of patients discontinued the long-term extension trial because of adverse events.
Seventy percent of patients remained in the long-term extension study at 1 year.
Twenty-six patients developed liver transaminase levels greater than three times the upper limit of normal, and of note, 23 of the 26 were on concomitant valproic acid. None met criteria for severe drug-induced liver injury, and all recovered either spontaneously or after a reduction in the dose of CBD or valproic acid. But this association between CBD, valproic acid, and increased risk of mild liver injury has been a consistent finding across the clinical trials program.
“This is a very important clinical pearl to take away,” commented Dr. Patel, who is also a pediatric neurologist at Ohio State University.
The interim results of the long-term, open-label extension study of add-on CBD in patients with Lennox-Gastaut syndrome are similar to the Dravet syndrome study. Overall, 99% of the 368 patients with Lennox-Gastaut syndrome who completed the 14-week, double-blind, randomized trials signed up for the open-label extension. During a median follow-up of 61 weeks, the median percent reduction in seizure frequency as assessed in serial 12-week windows was 48%-70% for drop seizures and 48%-63% for total seizures. Twenty-four percent of patients withdrew from the study. Eighty-eight percent of patients or caregivers reported an improvement in overall condition when assessed at weeks 24 and 48. Forty-seven patients developed elevated transaminase levels – typically within the first 2 months on CBD – and 35 of them were on concomitant valproic acid.
More on drug-drug interactions
Elsewhere at IEC 2019, Gilmour Morrison of GW Pharmaceuticals, the Cambridge, England, company that markets Epidiolex, presented the findings of a series of drug-drug interaction studies involving coadministration of their CBD with clobazam (Sympazan and Onfi), valproate, stiripentol (Diacomit), or midazolam (Versed) in adult epilepsy patients and healthy volunteers. The researchers reported a bidirectional drug-drug interaction between Epidiolex and clobazam resulting in increased levels of the active metabolites of both drugs. The mechanism is believed to involve inhibition of cytochrome P450 2C19. However, there were no interactions with midazolam or valproate, and the slight bump in stiripentol levels when given with CBD didn’t reach the level of a clinically meaningful drug-drug interaction, according to the investigators.
On the horizon, Canadian researchers are investigating the possibility that since both the tetrahydrocannabinol (THC) and CBD components of marijuana have been shown to have anticonvulsant effects, adding a bit of THC to CBD will result in even better seizure control than with pure CBD in patients with Dravet syndrome. Investigators at Toronto’s Hospital for Sick Children have conducted a prospective, open-label study of a product containing CBD and THC in a 50:1 ratio as add-on therapy in 20 children with Dravet syndrome. The dose was 2-16 mg/kg/day of CBD and 0.04-0.32 mg/kg/day of THC. The cannabis plant extract used in the study was produced by Tilray, a Canadian pharmaceutical company.
Nineteen of the 20 patients completed the 20-week study. The sole noncompleter died of SUDEP (sudden unexpected death in epilepsy) deemed treatment unrelated. Patients experienced a median 71% reduction in motor seizures, compared with baseline. Sixty-three percent of patients had at least a 50% reduction in seizure frequency. Elevated liver transaminases occurred in patients on concomitant valproic acid, as did platelet abnormalities, which have not been seen in the Epidiolex studies, noted Dr. Patel, who was not involved in the Canadian study (Ann Clin Transl Neurol. 2018 Aug 1;5[9]:1077-88).
Dr. Patel reported serving as a consultant to Greenwich Biosciences, a U.S. offshoot of GW Pharmaceuticals. He receives research grants from that company as well as from the National Institutes of Health and the Pediatric Epilepsy Research Foundation.
REPORTING FROM IEC 2019
Ketogenic diets are what’s cooking for drug-refractory epilepsy
BANGKOK – For a form of epilepsy treatment that’s been around since the 1920s, ketogenic diet therapy has lately been the focus of a surprising wealth of clinical research and development, Suvasini Sharma, MD, observed at the International Epilepsy Congress.
This high-fat, low-carbohydrate diet is now well established as a valid and effective treatment option for children and adults with drug-refractory epilepsy who aren’t candidates for surgery. That’s about a third of all epilepsy patients. And as the recently overhauled pediatric ketogenic diet therapy (KDT) best practice consensus guidelines emphasize, KDT should be strongly considered after two antiepileptic drugs have failed, and even earlier for several epilepsy syndromes, noted Dr. Sharma, a pediatric neurologist at Lady Hardinge Medical College and Kalawati Saran Children’s Hospital in New Delhi, and a coauthor of the updated guidelines.
“The consensus guidelines recommend that you start thinking about the diet early, without waiting for every drug to fail,” she said at the congress, sponsored by the International League Against Epilepsy.
Among the KDT-related topics she highlighted were the recently revised best practice consensus guidelines; an expanding role for KDT in infants, critical care settings, and in epileptic encephalopathies; mounting evidence that KDT provides additional benefits beyond seizure control; and promising new alternative diet therapies. She also described the challenges of using KDT in a low-resource nation such as India, where most of the 1.3 billion people shop in markets where food isn’t packaged with the nutritional content labels essential to traditional KDTs, and low literacy is common.
KDT best practice guidelines
The latest guidelines, which include the details of standardized KDT protocols as well as a summary of recent translational research into mechanisms of action, replace the previous 10-year-old version. Flexibility is now the watchword. While the classic KDT was started as an inpatient intervention involving several days of fasting followed by multiday gradual reintroduction of calories, that approach is now deemed optional (Epilepsia Open. 2018 May 21;3[2]:175-92).
“By and large, the trend now is going to nonfasting initiation on an outpatient basis, but with more stringent monitoring,” according to Dr. Sharma.
The guidelines note that while the research literature shows that, on average, KDT results in about a 50% chance of at least a 50% reduction in seizure frequency in patients with drug-refractory epilepsy, there are a dozen specific conditions with 70% or greater responder rates: infantile spasms, tuberous sclerosis, epilepsy with myoclonic-atonic seizures, Dravet syndrome, glucose transporter 1 deficiency syndrome (Glut 1DS), pyruvate dehydrogenase deficiency (PDHD), febrile infection-related epilepsy syndrome (FIRES), super-refractory status epilepticus (SRSE), Ohtahara syndrome, complex I mitochondrial disorders, Angelman syndrome, and children with gastrostomy tubes. For Glut1DS and PDHD, KDTs should be considered the treatment of first choice.
Traditionally, KDTs weren’t recommended for children younger than age 2 years. There were concerns that maintaining ketosis and meeting growth requirements were contradictory goals. That’s no longer believed to be so. Indeed, current evidence shows that KDT is highly effective and well tolerated in infants with refractory epilepsy. European guidelines address patient selection, pre-KDT counseling, preferred methods of initiation and KDT discontinuation, and other key issues (Eur J Paediatr Neurol. 2016 Nov;20[6]:798-809).
The guidelines recognize four major, well-studied types of KDT: the classic long-chain triglyceride-centric diet; the medium-chain triglyceride diet; the more user-friendly modified Atkins diet; and low glycemic index therapy. Except in children younger than 2 years old, who should be started on the classic KDT, the consensus panel recommended that the specific KDT selected should be based on the family and child situation and the expertise at the local KDT center. Perceived differences in efficacy between the diets aren’t supported by persuasive evidence.
KDT benefits beyond seizure control
“Most of us who work in the diet scene are aware that patients often report increased alertness, and sometimes improved cognition,” said Dr. Sharma.
That subjective experience is now supported by evidence from a randomized, controlled trial. Dutch investigators who randomized 50 drug-refractory pediatric epilepsy patients to KDT or usual care documented a positive impact of the diet therapy on cognitive activation, mood, and anxious behavior (Epilepsy Behav. 2016 Jul;60:153-7).
More recently, a systematic review showed that while subjective assessments support claims of improved alertness, attention, and global cognition in patients on KDT for refractory epilepsy, structured neuropsychologic testing confirms the enhanced alertness but without significantly improved global cognition. The investigators reported that the improvements were unrelated to decreases in medication, the type of KDT or age at its introduction, or sleep improvement. Rather, the benefits appeared to be due to a combination of seizure reduction and direct effects of KDT on cognition (Epilepsy Behav. 2018 Oct;87:69-77).
There is also encouraging preliminary evidence of a possible protective effect of KDT against sudden unexpected death in epilepsy (SUDEP) in a mouse model (Epilepsia. 2016 Aug;57[8]:e178-82. doi: 10.1111/epi.13444).
The use of KDT in critical care settings
Investigators from the pediatric Status Epilepticus Research Group (pSERG) reported that 10 of 14 patients with convulsive refractory status epilepticus achieved EEG seizure resolution within 7 days after starting KDT. Moreover, 11 patients were able to be weaned off their continuous infusions within 14 days of starting KDT. Treatment-emergent gastroparesis and hypertriglyceridemia occurred in three patients (Epilepsy Res. 2018 Aug;144:1-6).
“It was reasonably well tolerated, but they started it quite late – a median of 13 days after onset of refractory status epilepticus. It should come much earlier on our list of therapies. We shouldn’t be waiting 2 weeks before going to the ketogenic diet, because we can diagnose refractory status epilepticus within 48 hours after arrival in the ICU most of the time,” Dr. Sharma said.
Austrian investigators have pioneered the use of intravenous KDT as a bridge when oral therapy is temporarily impossible because of status epilepticus, surgery, or other reasons. They reported that parental KDT with fat intake of 3.5-4 g/kg per day was safe and effective in their series of 17 young children with epilepsy (Epilepsia Open. 2017 Nov 16;3[1]:30-9).
The future: nonketogenic diet therapies
KDT in its various forms is just too demanding and restrictive for some patients. Nonketotic alternatives are being explored.
Triheptanoin is a synthetic medium-chain triglyceride in the form of an edible, odorless, tasteless oil. Its mechanism of action is by anaplerosis: that is, energy generation via replenishment of the tricarboxylic acid cycle. After demonstration of neuroprotective and anticonvulsant effects in several mouse models, Australian investigators conducted a pilot study of 30- to 100-mL/day of oral triheptanoin as add-on therapy in 12 children with drug-refractory epilepsy. Eight of the 12 took triheptanoin for longer than 12 weeks, and 5 of those 8 experienced a sustained greater than 50% reduction in seizure frequency, including 1 who remained seizure free for 30 weeks. Seven children had diarrhea or other GI side effects (Eur J Paediatr Neurol. 2018 Nov;22[6]:1074-80).
Parisian investigators have developed a nonketotic, palatable combination of amino acids, carbohydrates, and fatty acids with a low ratio of fat to protein-plus-carbohydrates that provided potent protection against seizures in a mouse model. This suggests that the traditional 4:1 ratio sought in KDT isn’t necessary for robust seizure reduction (Sci Rep. 2017 Jul 14;7[1]:5496).
“This is probably going to be the future of nutritional therapy in epilepsy,” Dr. Sharma predicted.
She reported having no financial conflicts regarding her presentation.
BANGKOK – For a form of epilepsy treatment that’s been around since the 1920s, ketogenic diet therapy has lately been the focus of a surprising wealth of clinical research and development, Suvasini Sharma, MD, observed at the International Epilepsy Congress.
This high-fat, low-carbohydrate diet is now well established as a valid and effective treatment option for children and adults with drug-refractory epilepsy who aren’t candidates for surgery. That’s about a third of all epilepsy patients. And as the recently overhauled pediatric ketogenic diet therapy (KDT) best practice consensus guidelines emphasize, KDT should be strongly considered after two antiepileptic drugs have failed, and even earlier for several epilepsy syndromes, noted Dr. Sharma, a pediatric neurologist at Lady Hardinge Medical College and Kalawati Saran Children’s Hospital in New Delhi, and a coauthor of the updated guidelines.
“The consensus guidelines recommend that you start thinking about the diet early, without waiting for every drug to fail,” she said at the congress, sponsored by the International League Against Epilepsy.
Among the KDT-related topics she highlighted were the recently revised best practice consensus guidelines; an expanding role for KDT in infants, critical care settings, and in epileptic encephalopathies; mounting evidence that KDT provides additional benefits beyond seizure control; and promising new alternative diet therapies. She also described the challenges of using KDT in a low-resource nation such as India, where most of the 1.3 billion people shop in markets where food isn’t packaged with the nutritional content labels essential to traditional KDTs, and low literacy is common.
KDT best practice guidelines
The latest guidelines, which include the details of standardized KDT protocols as well as a summary of recent translational research into mechanisms of action, replace the previous 10-year-old version. Flexibility is now the watchword. While the classic KDT was started as an inpatient intervention involving several days of fasting followed by multiday gradual reintroduction of calories, that approach is now deemed optional (Epilepsia Open. 2018 May 21;3[2]:175-92).
“By and large, the trend now is going to nonfasting initiation on an outpatient basis, but with more stringent monitoring,” according to Dr. Sharma.
The guidelines note that while the research literature shows that, on average, KDT results in about a 50% chance of at least a 50% reduction in seizure frequency in patients with drug-refractory epilepsy, there are a dozen specific conditions with 70% or greater responder rates: infantile spasms, tuberous sclerosis, epilepsy with myoclonic-atonic seizures, Dravet syndrome, glucose transporter 1 deficiency syndrome (Glut 1DS), pyruvate dehydrogenase deficiency (PDHD), febrile infection-related epilepsy syndrome (FIRES), super-refractory status epilepticus (SRSE), Ohtahara syndrome, complex I mitochondrial disorders, Angelman syndrome, and children with gastrostomy tubes. For Glut1DS and PDHD, KDTs should be considered the treatment of first choice.
Traditionally, KDTs weren’t recommended for children younger than age 2 years. There were concerns that maintaining ketosis and meeting growth requirements were contradictory goals. That’s no longer believed to be so. Indeed, current evidence shows that KDT is highly effective and well tolerated in infants with refractory epilepsy. European guidelines address patient selection, pre-KDT counseling, preferred methods of initiation and KDT discontinuation, and other key issues (Eur J Paediatr Neurol. 2016 Nov;20[6]:798-809).
The guidelines recognize four major, well-studied types of KDT: the classic long-chain triglyceride-centric diet; the medium-chain triglyceride diet; the more user-friendly modified Atkins diet; and low glycemic index therapy. Except in children younger than 2 years old, who should be started on the classic KDT, the consensus panel recommended that the specific KDT selected should be based on the family and child situation and the expertise at the local KDT center. Perceived differences in efficacy between the diets aren’t supported by persuasive evidence.
KDT benefits beyond seizure control
“Most of us who work in the diet scene are aware that patients often report increased alertness, and sometimes improved cognition,” said Dr. Sharma.
That subjective experience is now supported by evidence from a randomized, controlled trial. Dutch investigators who randomized 50 drug-refractory pediatric epilepsy patients to KDT or usual care documented a positive impact of the diet therapy on cognitive activation, mood, and anxious behavior (Epilepsy Behav. 2016 Jul;60:153-7).
More recently, a systematic review showed that while subjective assessments support claims of improved alertness, attention, and global cognition in patients on KDT for refractory epilepsy, structured neuropsychologic testing confirms the enhanced alertness but without significantly improved global cognition. The investigators reported that the improvements were unrelated to decreases in medication, the type of KDT or age at its introduction, or sleep improvement. Rather, the benefits appeared to be due to a combination of seizure reduction and direct effects of KDT on cognition (Epilepsy Behav. 2018 Oct;87:69-77).
There is also encouraging preliminary evidence of a possible protective effect of KDT against sudden unexpected death in epilepsy (SUDEP) in a mouse model (Epilepsia. 2016 Aug;57[8]:e178-82. doi: 10.1111/epi.13444).
The use of KDT in critical care settings
Investigators from the pediatric Status Epilepticus Research Group (pSERG) reported that 10 of 14 patients with convulsive refractory status epilepticus achieved EEG seizure resolution within 7 days after starting KDT. Moreover, 11 patients were able to be weaned off their continuous infusions within 14 days of starting KDT. Treatment-emergent gastroparesis and hypertriglyceridemia occurred in three patients (Epilepsy Res. 2018 Aug;144:1-6).
“It was reasonably well tolerated, but they started it quite late – a median of 13 days after onset of refractory status epilepticus. It should come much earlier on our list of therapies. We shouldn’t be waiting 2 weeks before going to the ketogenic diet, because we can diagnose refractory status epilepticus within 48 hours after arrival in the ICU most of the time,” Dr. Sharma said.
Austrian investigators have pioneered the use of intravenous KDT as a bridge when oral therapy is temporarily impossible because of status epilepticus, surgery, or other reasons. They reported that parental KDT with fat intake of 3.5-4 g/kg per day was safe and effective in their series of 17 young children with epilepsy (Epilepsia Open. 2017 Nov 16;3[1]:30-9).
The future: nonketogenic diet therapies
KDT in its various forms is just too demanding and restrictive for some patients. Nonketotic alternatives are being explored.
Triheptanoin is a synthetic medium-chain triglyceride in the form of an edible, odorless, tasteless oil. Its mechanism of action is by anaplerosis: that is, energy generation via replenishment of the tricarboxylic acid cycle. After demonstration of neuroprotective and anticonvulsant effects in several mouse models, Australian investigators conducted a pilot study of 30- to 100-mL/day of oral triheptanoin as add-on therapy in 12 children with drug-refractory epilepsy. Eight of the 12 took triheptanoin for longer than 12 weeks, and 5 of those 8 experienced a sustained greater than 50% reduction in seizure frequency, including 1 who remained seizure free for 30 weeks. Seven children had diarrhea or other GI side effects (Eur J Paediatr Neurol. 2018 Nov;22[6]:1074-80).
Parisian investigators have developed a nonketotic, palatable combination of amino acids, carbohydrates, and fatty acids with a low ratio of fat to protein-plus-carbohydrates that provided potent protection against seizures in a mouse model. This suggests that the traditional 4:1 ratio sought in KDT isn’t necessary for robust seizure reduction (Sci Rep. 2017 Jul 14;7[1]:5496).
“This is probably going to be the future of nutritional therapy in epilepsy,” Dr. Sharma predicted.
She reported having no financial conflicts regarding her presentation.
BANGKOK – For a form of epilepsy treatment that’s been around since the 1920s, ketogenic diet therapy has lately been the focus of a surprising wealth of clinical research and development, Suvasini Sharma, MD, observed at the International Epilepsy Congress.
This high-fat, low-carbohydrate diet is now well established as a valid and effective treatment option for children and adults with drug-refractory epilepsy who aren’t candidates for surgery. That’s about a third of all epilepsy patients. And as the recently overhauled pediatric ketogenic diet therapy (KDT) best practice consensus guidelines emphasize, KDT should be strongly considered after two antiepileptic drugs have failed, and even earlier for several epilepsy syndromes, noted Dr. Sharma, a pediatric neurologist at Lady Hardinge Medical College and Kalawati Saran Children’s Hospital in New Delhi, and a coauthor of the updated guidelines.
“The consensus guidelines recommend that you start thinking about the diet early, without waiting for every drug to fail,” she said at the congress, sponsored by the International League Against Epilepsy.
Among the KDT-related topics she highlighted were the recently revised best practice consensus guidelines; an expanding role for KDT in infants, critical care settings, and in epileptic encephalopathies; mounting evidence that KDT provides additional benefits beyond seizure control; and promising new alternative diet therapies. She also described the challenges of using KDT in a low-resource nation such as India, where most of the 1.3 billion people shop in markets where food isn’t packaged with the nutritional content labels essential to traditional KDTs, and low literacy is common.
KDT best practice guidelines
The latest guidelines, which include the details of standardized KDT protocols as well as a summary of recent translational research into mechanisms of action, replace the previous 10-year-old version. Flexibility is now the watchword. While the classic KDT was started as an inpatient intervention involving several days of fasting followed by multiday gradual reintroduction of calories, that approach is now deemed optional (Epilepsia Open. 2018 May 21;3[2]:175-92).
“By and large, the trend now is going to nonfasting initiation on an outpatient basis, but with more stringent monitoring,” according to Dr. Sharma.
The guidelines note that while the research literature shows that, on average, KDT results in about a 50% chance of at least a 50% reduction in seizure frequency in patients with drug-refractory epilepsy, there are a dozen specific conditions with 70% or greater responder rates: infantile spasms, tuberous sclerosis, epilepsy with myoclonic-atonic seizures, Dravet syndrome, glucose transporter 1 deficiency syndrome (Glut 1DS), pyruvate dehydrogenase deficiency (PDHD), febrile infection-related epilepsy syndrome (FIRES), super-refractory status epilepticus (SRSE), Ohtahara syndrome, complex I mitochondrial disorders, Angelman syndrome, and children with gastrostomy tubes. For Glut1DS and PDHD, KDTs should be considered the treatment of first choice.
Traditionally, KDTs weren’t recommended for children younger than age 2 years. There were concerns that maintaining ketosis and meeting growth requirements were contradictory goals. That’s no longer believed to be so. Indeed, current evidence shows that KDT is highly effective and well tolerated in infants with refractory epilepsy. European guidelines address patient selection, pre-KDT counseling, preferred methods of initiation and KDT discontinuation, and other key issues (Eur J Paediatr Neurol. 2016 Nov;20[6]:798-809).
The guidelines recognize four major, well-studied types of KDT: the classic long-chain triglyceride-centric diet; the medium-chain triglyceride diet; the more user-friendly modified Atkins diet; and low glycemic index therapy. Except in children younger than 2 years old, who should be started on the classic KDT, the consensus panel recommended that the specific KDT selected should be based on the family and child situation and the expertise at the local KDT center. Perceived differences in efficacy between the diets aren’t supported by persuasive evidence.
KDT benefits beyond seizure control
“Most of us who work in the diet scene are aware that patients often report increased alertness, and sometimes improved cognition,” said Dr. Sharma.
That subjective experience is now supported by evidence from a randomized, controlled trial. Dutch investigators who randomized 50 drug-refractory pediatric epilepsy patients to KDT or usual care documented a positive impact of the diet therapy on cognitive activation, mood, and anxious behavior (Epilepsy Behav. 2016 Jul;60:153-7).
More recently, a systematic review showed that while subjective assessments support claims of improved alertness, attention, and global cognition in patients on KDT for refractory epilepsy, structured neuropsychologic testing confirms the enhanced alertness but without significantly improved global cognition. The investigators reported that the improvements were unrelated to decreases in medication, the type of KDT or age at its introduction, or sleep improvement. Rather, the benefits appeared to be due to a combination of seizure reduction and direct effects of KDT on cognition (Epilepsy Behav. 2018 Oct;87:69-77).
There is also encouraging preliminary evidence of a possible protective effect of KDT against sudden unexpected death in epilepsy (SUDEP) in a mouse model (Epilepsia. 2016 Aug;57[8]:e178-82. doi: 10.1111/epi.13444).
The use of KDT in critical care settings
Investigators from the pediatric Status Epilepticus Research Group (pSERG) reported that 10 of 14 patients with convulsive refractory status epilepticus achieved EEG seizure resolution within 7 days after starting KDT. Moreover, 11 patients were able to be weaned off their continuous infusions within 14 days of starting KDT. Treatment-emergent gastroparesis and hypertriglyceridemia occurred in three patients (Epilepsy Res. 2018 Aug;144:1-6).
“It was reasonably well tolerated, but they started it quite late – a median of 13 days after onset of refractory status epilepticus. It should come much earlier on our list of therapies. We shouldn’t be waiting 2 weeks before going to the ketogenic diet, because we can diagnose refractory status epilepticus within 48 hours after arrival in the ICU most of the time,” Dr. Sharma said.
Austrian investigators have pioneered the use of intravenous KDT as a bridge when oral therapy is temporarily impossible because of status epilepticus, surgery, or other reasons. They reported that parental KDT with fat intake of 3.5-4 g/kg per day was safe and effective in their series of 17 young children with epilepsy (Epilepsia Open. 2017 Nov 16;3[1]:30-9).
The future: nonketogenic diet therapies
KDT in its various forms is just too demanding and restrictive for some patients. Nonketotic alternatives are being explored.
Triheptanoin is a synthetic medium-chain triglyceride in the form of an edible, odorless, tasteless oil. Its mechanism of action is by anaplerosis: that is, energy generation via replenishment of the tricarboxylic acid cycle. After demonstration of neuroprotective and anticonvulsant effects in several mouse models, Australian investigators conducted a pilot study of 30- to 100-mL/day of oral triheptanoin as add-on therapy in 12 children with drug-refractory epilepsy. Eight of the 12 took triheptanoin for longer than 12 weeks, and 5 of those 8 experienced a sustained greater than 50% reduction in seizure frequency, including 1 who remained seizure free for 30 weeks. Seven children had diarrhea or other GI side effects (Eur J Paediatr Neurol. 2018 Nov;22[6]:1074-80).
Parisian investigators have developed a nonketotic, palatable combination of amino acids, carbohydrates, and fatty acids with a low ratio of fat to protein-plus-carbohydrates that provided potent protection against seizures in a mouse model. This suggests that the traditional 4:1 ratio sought in KDT isn’t necessary for robust seizure reduction (Sci Rep. 2017 Jul 14;7[1]:5496).
“This is probably going to be the future of nutritional therapy in epilepsy,” Dr. Sharma predicted.
She reported having no financial conflicts regarding her presentation.
REPORTING FROM IEC 2019
ECT breaks super-refractory status epilepticus
BANGKOK –
“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.
Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.
A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).
And realistically, these small case series are as good as the supporting evidence is likely to get.
“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.
Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.
The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm3. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.
ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.
Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.
At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.
Dr. Nguyen’s presentation met with undisguised audience skepticism.
“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.
Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.
“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.
Another audience member said the treatment strategy smacks of homeopathy.
“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.
“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.
“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.
Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.
Dr. Nguyen reported having no financial conflicts.
SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.
BANGKOK –
“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.
Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.
A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).
And realistically, these small case series are as good as the supporting evidence is likely to get.
“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.
Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.
The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm3. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.
ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.
Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.
At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.
Dr. Nguyen’s presentation met with undisguised audience skepticism.
“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.
Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.
“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.
Another audience member said the treatment strategy smacks of homeopathy.
“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.
“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.
“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.
Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.
Dr. Nguyen reported having no financial conflicts.
SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.
BANGKOK –
“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.
Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.
A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).
And realistically, these small case series are as good as the supporting evidence is likely to get.
“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.
Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.
The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm3. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.
ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.
Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.
At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.
Dr. Nguyen’s presentation met with undisguised audience skepticism.
“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.
Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.
“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.
Another audience member said the treatment strategy smacks of homeopathy.
“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.
“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.
“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.
Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.
Dr. Nguyen reported having no financial conflicts.
SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.
REPORTING FROM IEC 2019
Mortality is high in pediatric superrefractory status epilepticus
BANGKOK – presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.
“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.
The study included 15 consecutive patients aged between 1 month and 17 years treated for superrefractory status epilepticus (SRSE) during 2011-2017 at the Chinese University of Hong Kong, where Dr. Yau practices. Seven children died during their index hospital admission, with a median time to death of 8 days. Two more died within several years post discharge.
Morbidity was substantial: At follow-up 1 year after the index episode of SRSE, two patients had a Glasgow Outcome Scale (GOS) score of 3, indicative of severe disability; three patients had moderate disability, with a GOS of 4; and two patients were in a vegetative state, with a GOS of 2, both of whom subsequently died of aspiration pneumonia. Only 1 of the 15 patients had a good recovery. Through 8 years of follow-up, all six survivors had epilepsy. Common nonneurologic deficits included a predisposition to a variety of infections.
By way of background, Dr. Yau noted that convulsive status epilepticus is the most common neurologic emergency in children, with an incidence of about 20 episodes per 100,000. Of affected children, 10%-40% develop refractory status, with reported mortality rates of 16%-43%. SRSE is a term reserved for persistent or recurrent seizures 24 hours or more after onset of general anesthesia for management of refractory status.
The impetus for Dr. Yau’s study was the dearth of data on SRSE in children. The literature consists of a few case series totaling well under 100 patients.
The Hong Kong case series included 15 patients with SRSE who had a median age of 7.9 years, only 1 of whom had preexisting epilepsy, a case of epileptic encephalopathy with severe developmental delay. Of the 15, 12 were boys. The patients were placed on a median of four antiepileptic drugs. Those who survived to discharge spent a median of 17.8 days under general anesthesia and 42.5 days in the pediatric ICU.
The SRSE etiologies included febrile infection–related epilepsy syndrome in two cases, four serious infections, four cases of autoimmune etiology, two cases of epileptic encephalopathy, one patient with hypoxia caused by severe croup, and two of unknown origin despite intensive work-up.
The four in-hospital deaths caused by acute cerebral edema occurred a median 6.5 days after admission. There were also two deaths because of uncontrolled sepsis and one because of intraventricular bleeding secondary to thrombotic thrombocytopenic purpura thought to have occurred as a complication of interactions between the numerous prescribed medications. All six children with an infectious or unknown etiology died in hospital, whereas none of those with an autoimmune etiology, epileptic encephalopathy, or hypoxia did. Duration of anesthesia did not predict mortality.
Other investigators have reported that younger age is associated with higher mortality, but that was not true in the Hong Kong experience. Neither of the two children aged less than 3 years died during their index hospitalization. All 7 deaths occurred in the 13 children age 3 years or older.
When asked whether she thought SRSE or the underlying disorder was the bigger contributor to mortality, Dr. Yau replied that she believes the prolonged refractory seizures may have worsened cerebral edema in some patients and thereby have been the cause of death.
She reported having no financial conflicts regarding her study.
BANGKOK – presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.
“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.
The study included 15 consecutive patients aged between 1 month and 17 years treated for superrefractory status epilepticus (SRSE) during 2011-2017 at the Chinese University of Hong Kong, where Dr. Yau practices. Seven children died during their index hospital admission, with a median time to death of 8 days. Two more died within several years post discharge.
Morbidity was substantial: At follow-up 1 year after the index episode of SRSE, two patients had a Glasgow Outcome Scale (GOS) score of 3, indicative of severe disability; three patients had moderate disability, with a GOS of 4; and two patients were in a vegetative state, with a GOS of 2, both of whom subsequently died of aspiration pneumonia. Only 1 of the 15 patients had a good recovery. Through 8 years of follow-up, all six survivors had epilepsy. Common nonneurologic deficits included a predisposition to a variety of infections.
By way of background, Dr. Yau noted that convulsive status epilepticus is the most common neurologic emergency in children, with an incidence of about 20 episodes per 100,000. Of affected children, 10%-40% develop refractory status, with reported mortality rates of 16%-43%. SRSE is a term reserved for persistent or recurrent seizures 24 hours or more after onset of general anesthesia for management of refractory status.
The impetus for Dr. Yau’s study was the dearth of data on SRSE in children. The literature consists of a few case series totaling well under 100 patients.
The Hong Kong case series included 15 patients with SRSE who had a median age of 7.9 years, only 1 of whom had preexisting epilepsy, a case of epileptic encephalopathy with severe developmental delay. Of the 15, 12 were boys. The patients were placed on a median of four antiepileptic drugs. Those who survived to discharge spent a median of 17.8 days under general anesthesia and 42.5 days in the pediatric ICU.
The SRSE etiologies included febrile infection–related epilepsy syndrome in two cases, four serious infections, four cases of autoimmune etiology, two cases of epileptic encephalopathy, one patient with hypoxia caused by severe croup, and two of unknown origin despite intensive work-up.
The four in-hospital deaths caused by acute cerebral edema occurred a median 6.5 days after admission. There were also two deaths because of uncontrolled sepsis and one because of intraventricular bleeding secondary to thrombotic thrombocytopenic purpura thought to have occurred as a complication of interactions between the numerous prescribed medications. All six children with an infectious or unknown etiology died in hospital, whereas none of those with an autoimmune etiology, epileptic encephalopathy, or hypoxia did. Duration of anesthesia did not predict mortality.
Other investigators have reported that younger age is associated with higher mortality, but that was not true in the Hong Kong experience. Neither of the two children aged less than 3 years died during their index hospitalization. All 7 deaths occurred in the 13 children age 3 years or older.
When asked whether she thought SRSE or the underlying disorder was the bigger contributor to mortality, Dr. Yau replied that she believes the prolonged refractory seizures may have worsened cerebral edema in some patients and thereby have been the cause of death.
She reported having no financial conflicts regarding her study.
BANGKOK – presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.
“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.
The study included 15 consecutive patients aged between 1 month and 17 years treated for superrefractory status epilepticus (SRSE) during 2011-2017 at the Chinese University of Hong Kong, where Dr. Yau practices. Seven children died during their index hospital admission, with a median time to death of 8 days. Two more died within several years post discharge.
Morbidity was substantial: At follow-up 1 year after the index episode of SRSE, two patients had a Glasgow Outcome Scale (GOS) score of 3, indicative of severe disability; three patients had moderate disability, with a GOS of 4; and two patients were in a vegetative state, with a GOS of 2, both of whom subsequently died of aspiration pneumonia. Only 1 of the 15 patients had a good recovery. Through 8 years of follow-up, all six survivors had epilepsy. Common nonneurologic deficits included a predisposition to a variety of infections.
By way of background, Dr. Yau noted that convulsive status epilepticus is the most common neurologic emergency in children, with an incidence of about 20 episodes per 100,000. Of affected children, 10%-40% develop refractory status, with reported mortality rates of 16%-43%. SRSE is a term reserved for persistent or recurrent seizures 24 hours or more after onset of general anesthesia for management of refractory status.
The impetus for Dr. Yau’s study was the dearth of data on SRSE in children. The literature consists of a few case series totaling well under 100 patients.
The Hong Kong case series included 15 patients with SRSE who had a median age of 7.9 years, only 1 of whom had preexisting epilepsy, a case of epileptic encephalopathy with severe developmental delay. Of the 15, 12 were boys. The patients were placed on a median of four antiepileptic drugs. Those who survived to discharge spent a median of 17.8 days under general anesthesia and 42.5 days in the pediatric ICU.
The SRSE etiologies included febrile infection–related epilepsy syndrome in two cases, four serious infections, four cases of autoimmune etiology, two cases of epileptic encephalopathy, one patient with hypoxia caused by severe croup, and two of unknown origin despite intensive work-up.
The four in-hospital deaths caused by acute cerebral edema occurred a median 6.5 days after admission. There were also two deaths because of uncontrolled sepsis and one because of intraventricular bleeding secondary to thrombotic thrombocytopenic purpura thought to have occurred as a complication of interactions between the numerous prescribed medications. All six children with an infectious or unknown etiology died in hospital, whereas none of those with an autoimmune etiology, epileptic encephalopathy, or hypoxia did. Duration of anesthesia did not predict mortality.
Other investigators have reported that younger age is associated with higher mortality, but that was not true in the Hong Kong experience. Neither of the two children aged less than 3 years died during their index hospitalization. All 7 deaths occurred in the 13 children age 3 years or older.
When asked whether she thought SRSE or the underlying disorder was the bigger contributor to mortality, Dr. Yau replied that she believes the prolonged refractory seizures may have worsened cerebral edema in some patients and thereby have been the cause of death.
She reported having no financial conflicts regarding her study.
REPORTING FROM IEC 2019
Neonatal epileptic syndromes are surprisingly common
BANGKOK – Katherine B. Howell, MD, reported at the International Epilepsy Congress.
“This is an important finding. It’s a considerably larger number than might have been expected and likely has two contributing factors. Neonatal seizures were previously not considered epilepsy, so many previous studies excluded neonates and the conditions were underrecognized. And our large number of ictal EEGs allowed identification of ictal activation, which is a feature of EIMFS [epilepsy of infancy with migrating focal seizures]. Without those ictal recordings, the diagnosis of EIMFS may not have been made,” according to Dr. Howell, a neurologist at the Royal Children’s Hospital and University of Melbourne.
She presented a population-based study of all infants born with severe epilepsies of infancy (SEI) during a 2-year period in the Australian state of Victoria, which is considered an ideal environment for epidemiologic studies because government-funded health care is available to all. SEI was defined as seizures beginning before age 18 months, occurring at a rate of at least one per day for 1 week or weekly for 1 month, refractory to adequate trials of at least two antiepileptic drugs, and accompanied by an epileptiform EEG abnormality. Her focus was on the electroclinical phenotypes of the affected children because of the high clinical utility of this information.
“Assigning an epileptic syndrome is highly useful for clinician-to-clinician communication of an infant’s phenotype. It guides investigation of etiology and possibly selection of optimal therapy, such as steroids in West syndrome. And it can inform prognosis,” Dr. Howell said at the congress sponsored by the International League Against Epilepsy.
She and her coinvestigators analyzed the detailed records of all 114 infants with SEI born during the study period. The incidence was 1 in 2,000 live births.
“Among infants with epilepsy, this patient group with SEI is most critical to better understand. Effective treatment is often not available, the seizure and developmental outcomes are frequently devastating, and the health burden massive,” the neurologist observed.
The full spectrum of SEI
With the help of ictal EEGs, home seizure recordings, MRI scans, and genomic testing, the investigators were able to classify more than 85% of the infants. About 64% had a prototypic syndrome at onset, such as West syndrome, which accounted for 33% of all SEI, or Dravet syndrome, which was diagnosed in 3%.
The prevalence of the prototypic neonatal and early infantile epileptic syndromes was notably higher than previously reported by others: EIMFS accounted for 9% of total SEI, early infantile epileptic encephalopathy (EIEE) for 7%, and early myoclonic encephalopathy (EME) for 2%. This translated to an incidence of 1 in 28,000 live births for EIEE, 1 in 111,000 for EME, and 1 in 22,500 for EIMFS.
“While neither EIEE nor EIMFS are common, these incidences are actually not that much lower than the reported incidence of Dravet syndrome,” the neurologist pointed out.
About 36% of SEI didn’t fit into any of the prototypic syndromes. However, more than half of this subgroup, or 19% of total SEI, were prototypic syndrome like, a designation Dr. Howell and her coworkers used for cases that possessed most but not all of the well-recognized features of a particular prototypic syndrome; for example, West syndrome–like seizures but without hypsarrhythmia. Whether these prototypic syndrome-like SEI have etiologies and outcomes similar to or distinct from the prototypic syndromes remains a topic for further study.
SEI etiologies
A total of 14 patients had SEI because of an acquired syndrome attributed to brain injury, 31 were because of brain malformation, 21 involved single gene disorders, 9 were of chromosomal etiology, and 7 had a metabolic cause.
The key finding with regard to etiology was the glaring difference between children with West syndrome, its variants, or unifocal epilepsies as compared with the rest of the SEI patients. Those with West syndrome, a West syndrome–like designation, or unifocal epilepsies most commonly had a structural etiology for their SEI. Indeed, of the 52 children with West syndrome or a variant, 10 had an acquired brain injury as their etiology and 17 had a brain malformation. And of the 12 patients with unifocal SEI, 1 had a brain injury and 9 had brain malformations.
In contrast, children with neonatal or early infantile epileptic syndromes had predominantly genetic rather than structural etiologies. Of the 20 children with EIEE, EIMFS, or EME, none had brain injury as the etiology, only 1 had a brain malformation, but 9 had a single gene or chromosomal etiology.
Outcomes
“The outcome data highlight the extreme severity of SEI and the imperative for novel treatments: 16% mortality overall, so one in six was deceased by age 2 years. The infants who died after the neonatal period all had profound delays, and almost all had ongoing seizures until their death. Most survivors also had developmental delay, with severity ranging from mild to moderate in 49% to severe/profound in 41%. Just 10 of 114 children had normal development,” Dr. Howell reported.
However, there was a notable difference in outcomes between the various syndromes, and this information is highly relevant prognostically. Of the 20 children with neonatal and early infantile epileptic syndromes, 11 died and the other 9 had profound developmental delay. In contrast, the outlook was far better for children with West syndrome, West syndrome–like variants, or focal epilepsies: Among 64 affected patients, there were just 2 deaths, normal development in 9 patients, mild to moderate developmental delay in 34, and severe/profound delay in 19.
Dr. Howell reported having no financial conflicts regarding this study, which was supported by governmental research grants.
bjancin@mdedge.com
SOURCE: Howell KB et al. IEC 2019, Abstract P053.
BANGKOK – Katherine B. Howell, MD, reported at the International Epilepsy Congress.
“This is an important finding. It’s a considerably larger number than might have been expected and likely has two contributing factors. Neonatal seizures were previously not considered epilepsy, so many previous studies excluded neonates and the conditions were underrecognized. And our large number of ictal EEGs allowed identification of ictal activation, which is a feature of EIMFS [epilepsy of infancy with migrating focal seizures]. Without those ictal recordings, the diagnosis of EIMFS may not have been made,” according to Dr. Howell, a neurologist at the Royal Children’s Hospital and University of Melbourne.
She presented a population-based study of all infants born with severe epilepsies of infancy (SEI) during a 2-year period in the Australian state of Victoria, which is considered an ideal environment for epidemiologic studies because government-funded health care is available to all. SEI was defined as seizures beginning before age 18 months, occurring at a rate of at least one per day for 1 week or weekly for 1 month, refractory to adequate trials of at least two antiepileptic drugs, and accompanied by an epileptiform EEG abnormality. Her focus was on the electroclinical phenotypes of the affected children because of the high clinical utility of this information.
“Assigning an epileptic syndrome is highly useful for clinician-to-clinician communication of an infant’s phenotype. It guides investigation of etiology and possibly selection of optimal therapy, such as steroids in West syndrome. And it can inform prognosis,” Dr. Howell said at the congress sponsored by the International League Against Epilepsy.
She and her coinvestigators analyzed the detailed records of all 114 infants with SEI born during the study period. The incidence was 1 in 2,000 live births.
“Among infants with epilepsy, this patient group with SEI is most critical to better understand. Effective treatment is often not available, the seizure and developmental outcomes are frequently devastating, and the health burden massive,” the neurologist observed.
The full spectrum of SEI
With the help of ictal EEGs, home seizure recordings, MRI scans, and genomic testing, the investigators were able to classify more than 85% of the infants. About 64% had a prototypic syndrome at onset, such as West syndrome, which accounted for 33% of all SEI, or Dravet syndrome, which was diagnosed in 3%.
The prevalence of the prototypic neonatal and early infantile epileptic syndromes was notably higher than previously reported by others: EIMFS accounted for 9% of total SEI, early infantile epileptic encephalopathy (EIEE) for 7%, and early myoclonic encephalopathy (EME) for 2%. This translated to an incidence of 1 in 28,000 live births for EIEE, 1 in 111,000 for EME, and 1 in 22,500 for EIMFS.
“While neither EIEE nor EIMFS are common, these incidences are actually not that much lower than the reported incidence of Dravet syndrome,” the neurologist pointed out.
About 36% of SEI didn’t fit into any of the prototypic syndromes. However, more than half of this subgroup, or 19% of total SEI, were prototypic syndrome like, a designation Dr. Howell and her coworkers used for cases that possessed most but not all of the well-recognized features of a particular prototypic syndrome; for example, West syndrome–like seizures but without hypsarrhythmia. Whether these prototypic syndrome-like SEI have etiologies and outcomes similar to or distinct from the prototypic syndromes remains a topic for further study.
SEI etiologies
A total of 14 patients had SEI because of an acquired syndrome attributed to brain injury, 31 were because of brain malformation, 21 involved single gene disorders, 9 were of chromosomal etiology, and 7 had a metabolic cause.
The key finding with regard to etiology was the glaring difference between children with West syndrome, its variants, or unifocal epilepsies as compared with the rest of the SEI patients. Those with West syndrome, a West syndrome–like designation, or unifocal epilepsies most commonly had a structural etiology for their SEI. Indeed, of the 52 children with West syndrome or a variant, 10 had an acquired brain injury as their etiology and 17 had a brain malformation. And of the 12 patients with unifocal SEI, 1 had a brain injury and 9 had brain malformations.
In contrast, children with neonatal or early infantile epileptic syndromes had predominantly genetic rather than structural etiologies. Of the 20 children with EIEE, EIMFS, or EME, none had brain injury as the etiology, only 1 had a brain malformation, but 9 had a single gene or chromosomal etiology.
Outcomes
“The outcome data highlight the extreme severity of SEI and the imperative for novel treatments: 16% mortality overall, so one in six was deceased by age 2 years. The infants who died after the neonatal period all had profound delays, and almost all had ongoing seizures until their death. Most survivors also had developmental delay, with severity ranging from mild to moderate in 49% to severe/profound in 41%. Just 10 of 114 children had normal development,” Dr. Howell reported.
However, there was a notable difference in outcomes between the various syndromes, and this information is highly relevant prognostically. Of the 20 children with neonatal and early infantile epileptic syndromes, 11 died and the other 9 had profound developmental delay. In contrast, the outlook was far better for children with West syndrome, West syndrome–like variants, or focal epilepsies: Among 64 affected patients, there were just 2 deaths, normal development in 9 patients, mild to moderate developmental delay in 34, and severe/profound delay in 19.
Dr. Howell reported having no financial conflicts regarding this study, which was supported by governmental research grants.
bjancin@mdedge.com
SOURCE: Howell KB et al. IEC 2019, Abstract P053.
BANGKOK – Katherine B. Howell, MD, reported at the International Epilepsy Congress.
“This is an important finding. It’s a considerably larger number than might have been expected and likely has two contributing factors. Neonatal seizures were previously not considered epilepsy, so many previous studies excluded neonates and the conditions were underrecognized. And our large number of ictal EEGs allowed identification of ictal activation, which is a feature of EIMFS [epilepsy of infancy with migrating focal seizures]. Without those ictal recordings, the diagnosis of EIMFS may not have been made,” according to Dr. Howell, a neurologist at the Royal Children’s Hospital and University of Melbourne.
She presented a population-based study of all infants born with severe epilepsies of infancy (SEI) during a 2-year period in the Australian state of Victoria, which is considered an ideal environment for epidemiologic studies because government-funded health care is available to all. SEI was defined as seizures beginning before age 18 months, occurring at a rate of at least one per day for 1 week or weekly for 1 month, refractory to adequate trials of at least two antiepileptic drugs, and accompanied by an epileptiform EEG abnormality. Her focus was on the electroclinical phenotypes of the affected children because of the high clinical utility of this information.
“Assigning an epileptic syndrome is highly useful for clinician-to-clinician communication of an infant’s phenotype. It guides investigation of etiology and possibly selection of optimal therapy, such as steroids in West syndrome. And it can inform prognosis,” Dr. Howell said at the congress sponsored by the International League Against Epilepsy.
She and her coinvestigators analyzed the detailed records of all 114 infants with SEI born during the study period. The incidence was 1 in 2,000 live births.
“Among infants with epilepsy, this patient group with SEI is most critical to better understand. Effective treatment is often not available, the seizure and developmental outcomes are frequently devastating, and the health burden massive,” the neurologist observed.
The full spectrum of SEI
With the help of ictal EEGs, home seizure recordings, MRI scans, and genomic testing, the investigators were able to classify more than 85% of the infants. About 64% had a prototypic syndrome at onset, such as West syndrome, which accounted for 33% of all SEI, or Dravet syndrome, which was diagnosed in 3%.
The prevalence of the prototypic neonatal and early infantile epileptic syndromes was notably higher than previously reported by others: EIMFS accounted for 9% of total SEI, early infantile epileptic encephalopathy (EIEE) for 7%, and early myoclonic encephalopathy (EME) for 2%. This translated to an incidence of 1 in 28,000 live births for EIEE, 1 in 111,000 for EME, and 1 in 22,500 for EIMFS.
“While neither EIEE nor EIMFS are common, these incidences are actually not that much lower than the reported incidence of Dravet syndrome,” the neurologist pointed out.
About 36% of SEI didn’t fit into any of the prototypic syndromes. However, more than half of this subgroup, or 19% of total SEI, were prototypic syndrome like, a designation Dr. Howell and her coworkers used for cases that possessed most but not all of the well-recognized features of a particular prototypic syndrome; for example, West syndrome–like seizures but without hypsarrhythmia. Whether these prototypic syndrome-like SEI have etiologies and outcomes similar to or distinct from the prototypic syndromes remains a topic for further study.
SEI etiologies
A total of 14 patients had SEI because of an acquired syndrome attributed to brain injury, 31 were because of brain malformation, 21 involved single gene disorders, 9 were of chromosomal etiology, and 7 had a metabolic cause.
The key finding with regard to etiology was the glaring difference between children with West syndrome, its variants, or unifocal epilepsies as compared with the rest of the SEI patients. Those with West syndrome, a West syndrome–like designation, or unifocal epilepsies most commonly had a structural etiology for their SEI. Indeed, of the 52 children with West syndrome or a variant, 10 had an acquired brain injury as their etiology and 17 had a brain malformation. And of the 12 patients with unifocal SEI, 1 had a brain injury and 9 had brain malformations.
In contrast, children with neonatal or early infantile epileptic syndromes had predominantly genetic rather than structural etiologies. Of the 20 children with EIEE, EIMFS, or EME, none had brain injury as the etiology, only 1 had a brain malformation, but 9 had a single gene or chromosomal etiology.
Outcomes
“The outcome data highlight the extreme severity of SEI and the imperative for novel treatments: 16% mortality overall, so one in six was deceased by age 2 years. The infants who died after the neonatal period all had profound delays, and almost all had ongoing seizures until their death. Most survivors also had developmental delay, with severity ranging from mild to moderate in 49% to severe/profound in 41%. Just 10 of 114 children had normal development,” Dr. Howell reported.
However, there was a notable difference in outcomes between the various syndromes, and this information is highly relevant prognostically. Of the 20 children with neonatal and early infantile epileptic syndromes, 11 died and the other 9 had profound developmental delay. In contrast, the outlook was far better for children with West syndrome, West syndrome–like variants, or focal epilepsies: Among 64 affected patients, there were just 2 deaths, normal development in 9 patients, mild to moderate developmental delay in 34, and severe/profound delay in 19.
Dr. Howell reported having no financial conflicts regarding this study, which was supported by governmental research grants.
bjancin@mdedge.com
SOURCE: Howell KB et al. IEC 2019, Abstract P053.
REPORTING FROM IEC 2019
