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Epilepsy
New guidance on cannabis use for treatment-resistant epilepsy
A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.
The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.
“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.
“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
Appropriate patient populations
Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.
Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.
“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”
Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.
No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.
The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.
The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
Considerations for unapproved cannabinoids
The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.
The guidance document notes several reasons to use a regulated medication instead of an unregulated product:
- Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
- Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
- More scientific evidence is available for regulated products.
- Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
- Nonregulated products are rarely covered by insurance or other reimbursement.
Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.
The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.
Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”
“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
Dosing and adverse effects
Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.
“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.
The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.
Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.
“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”
Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.
“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”
Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.
A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.
The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.
“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.
“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
Appropriate patient populations
Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.
Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.
“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”
Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.
No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.
The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.
The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
Considerations for unapproved cannabinoids
The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.
The guidance document notes several reasons to use a regulated medication instead of an unregulated product:
- Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
- Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
- More scientific evidence is available for regulated products.
- Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
- Nonregulated products are rarely covered by insurance or other reimbursement.
Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.
The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.
Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”
“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
Dosing and adverse effects
Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.
“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.
The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.
Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.
“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”
Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.
“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”
Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.
A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.
The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.
“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.
“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
Appropriate patient populations
Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.
Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.
“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”
Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.
No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.
The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.
The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
Considerations for unapproved cannabinoids
The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.
The guidance document notes several reasons to use a regulated medication instead of an unregulated product:
- Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
- Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
- More scientific evidence is available for regulated products.
- Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
- Nonregulated products are rarely covered by insurance or other reimbursement.
Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.
The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.
Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”
“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
Dosing and adverse effects
Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.
“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.
The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.
Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.
“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”
Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.
“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”
Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.
FROM THE BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
ILAE offers first guide to treating depression in epilepsy
The new guidance highlights the high prevalence of depression among patients with epilepsy while offering the first systematic approach to treatment, reported lead author Marco Mula, MD, PhD, of Atkinson Morley Regional Neuroscience Centre at St George’s University Hospital, London, and colleagues.
“Despite evidence that depression represents a frequently encountered comorbidity [among patients with epilepsy], data on the treatment of depression in epilepsy [are] still limited and recommendations rely mostly on individual clinical experience and expertise,” the investigators wrote in Epilepsia.
Recommendations cover first-line treatment of unipolar depression in epilepsy without other psychiatric disorders.
For patients with mild depression, the guidance supports psychological intervention without pharmacologic therapy; however, if the patient wishes to use medication, has had a positive response to medication in the past, or nonpharmacologic treatments have previously failed or are unavailable, then SSRIs should be considered first-choice therapy. For moderate to severe depression, SSRIs are the first choice, according to Dr. Mula and colleagues.
“It has to be acknowledged that there is considerable debate in the psychiatric literature about the treatment of mild depression in adults,” the investigators noted. “A patient-level meta-analysis pointed out that the magnitude of benefit of antidepressant medications compared with placebo increases with severity of depression symptoms and it may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.”
If a patient does not respond to first-line therapy, then venlafaxine should be considered, according to the guidance. When a patient does respond to therapy, treatment should be continued for at least 6 months, and when residual symptoms persist, treatment should be continued until resolution.
“In people with depression it is established that around two-thirds of patients do not achieve full remission with first-line treatment,” Dr. Mula and colleagues wrote. “In people with epilepsy, current data show that up to 50% of patients do not achieve full remission from depression. For this reason, augmentation strategies are often needed. They should be adopted by psychiatrists, neuropsychiatrists, or mental health professionals familiar with such therapeutic strategies.”
Beyond these key recommendations, the guidance covers a range of additional topics, including other pharmacologic options, medication discontinuation strategies, electroconvulsive therapy, light therapy, exercise training, vagus nerve stimulation, and repetitive transcranial magnetic stimulation.
Useful advice that counters common misconceptions
According to Jacqueline A. French, MD, a professor at NYU Langone Medical Center, Dr. Mula and colleagues are “top notch,” and their recommendations “hit every nail on the head.”
Dr. French, chief medical officer of The Epilepsy Foundation, emphasized the importance of the publication, which addresses two common misconceptions within the medical community: First, that standard antidepressants are insufficient to treat depression in patients with epilepsy, and second, that antidepressants may trigger seizures.
“The first purpose [of the publication] is to say, yes, these antidepressants do work,” Dr. French said, “and no, they don’t worsen seizures, and you can use them safely, and they are appropriate to use.”
Dr. French explained that managing depression remains a practice gap among epileptologists and neurologists because it is a diagnosis that doesn’t traditionally fall into their purview, yet many patients with epilepsy forgo visiting their primary care providers, who more frequently diagnose and manage depression. Dr. French agreed with the guidance that epilepsy specialists should fill this gap.
“We need to at least be able to take people through their first antidepressant, even though we were not trained to be psychiatrists,” Dr. French said. “That’s part of the best care of our patients.”
Imad Najm, MD, director of the Charles Shor Epilepsy Center, Cleveland Clinic, said the recommendations are a step forward in the field, as they are supported by clinical data, instead of just clinical experience and expertise.
Still, Dr. Najm noted that more work is needed to stratify risk of depression in epilepsy and evaluate a possible causal relationship between epilepsy therapies and depression.
He went on to emphasizes the scale of issue at hand, and the stakes involved.
“Depression, anxiety, and psychosis affect a large number of patients with epilepsy,” Dr. Najm said. “Clinical screening and recognition of these comorbidities leads to the institution of treatment options and significant improvement in quality of life. Mental health professionals should be an integral part of any comprehensive epilepsy center.”
The investigators disclosed relationships with Esai, UCB, Elsevier, and others. Dr. French is indirectly involved with multiple pharmaceutical companies developing epilepsy drugs through her role as director of The Epilepsy Study Consortium, a nonprofit organization. Dr. Najm reported no conflicts of interest.
The new guidance highlights the high prevalence of depression among patients with epilepsy while offering the first systematic approach to treatment, reported lead author Marco Mula, MD, PhD, of Atkinson Morley Regional Neuroscience Centre at St George’s University Hospital, London, and colleagues.
“Despite evidence that depression represents a frequently encountered comorbidity [among patients with epilepsy], data on the treatment of depression in epilepsy [are] still limited and recommendations rely mostly on individual clinical experience and expertise,” the investigators wrote in Epilepsia.
Recommendations cover first-line treatment of unipolar depression in epilepsy without other psychiatric disorders.
For patients with mild depression, the guidance supports psychological intervention without pharmacologic therapy; however, if the patient wishes to use medication, has had a positive response to medication in the past, or nonpharmacologic treatments have previously failed or are unavailable, then SSRIs should be considered first-choice therapy. For moderate to severe depression, SSRIs are the first choice, according to Dr. Mula and colleagues.
“It has to be acknowledged that there is considerable debate in the psychiatric literature about the treatment of mild depression in adults,” the investigators noted. “A patient-level meta-analysis pointed out that the magnitude of benefit of antidepressant medications compared with placebo increases with severity of depression symptoms and it may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.”
If a patient does not respond to first-line therapy, then venlafaxine should be considered, according to the guidance. When a patient does respond to therapy, treatment should be continued for at least 6 months, and when residual symptoms persist, treatment should be continued until resolution.
“In people with depression it is established that around two-thirds of patients do not achieve full remission with first-line treatment,” Dr. Mula and colleagues wrote. “In people with epilepsy, current data show that up to 50% of patients do not achieve full remission from depression. For this reason, augmentation strategies are often needed. They should be adopted by psychiatrists, neuropsychiatrists, or mental health professionals familiar with such therapeutic strategies.”
Beyond these key recommendations, the guidance covers a range of additional topics, including other pharmacologic options, medication discontinuation strategies, electroconvulsive therapy, light therapy, exercise training, vagus nerve stimulation, and repetitive transcranial magnetic stimulation.
Useful advice that counters common misconceptions
According to Jacqueline A. French, MD, a professor at NYU Langone Medical Center, Dr. Mula and colleagues are “top notch,” and their recommendations “hit every nail on the head.”
Dr. French, chief medical officer of The Epilepsy Foundation, emphasized the importance of the publication, which addresses two common misconceptions within the medical community: First, that standard antidepressants are insufficient to treat depression in patients with epilepsy, and second, that antidepressants may trigger seizures.
“The first purpose [of the publication] is to say, yes, these antidepressants do work,” Dr. French said, “and no, they don’t worsen seizures, and you can use them safely, and they are appropriate to use.”
Dr. French explained that managing depression remains a practice gap among epileptologists and neurologists because it is a diagnosis that doesn’t traditionally fall into their purview, yet many patients with epilepsy forgo visiting their primary care providers, who more frequently diagnose and manage depression. Dr. French agreed with the guidance that epilepsy specialists should fill this gap.
“We need to at least be able to take people through their first antidepressant, even though we were not trained to be psychiatrists,” Dr. French said. “That’s part of the best care of our patients.”
Imad Najm, MD, director of the Charles Shor Epilepsy Center, Cleveland Clinic, said the recommendations are a step forward in the field, as they are supported by clinical data, instead of just clinical experience and expertise.
Still, Dr. Najm noted that more work is needed to stratify risk of depression in epilepsy and evaluate a possible causal relationship between epilepsy therapies and depression.
He went on to emphasizes the scale of issue at hand, and the stakes involved.
“Depression, anxiety, and psychosis affect a large number of patients with epilepsy,” Dr. Najm said. “Clinical screening and recognition of these comorbidities leads to the institution of treatment options and significant improvement in quality of life. Mental health professionals should be an integral part of any comprehensive epilepsy center.”
The investigators disclosed relationships with Esai, UCB, Elsevier, and others. Dr. French is indirectly involved with multiple pharmaceutical companies developing epilepsy drugs through her role as director of The Epilepsy Study Consortium, a nonprofit organization. Dr. Najm reported no conflicts of interest.
The new guidance highlights the high prevalence of depression among patients with epilepsy while offering the first systematic approach to treatment, reported lead author Marco Mula, MD, PhD, of Atkinson Morley Regional Neuroscience Centre at St George’s University Hospital, London, and colleagues.
“Despite evidence that depression represents a frequently encountered comorbidity [among patients with epilepsy], data on the treatment of depression in epilepsy [are] still limited and recommendations rely mostly on individual clinical experience and expertise,” the investigators wrote in Epilepsia.
Recommendations cover first-line treatment of unipolar depression in epilepsy without other psychiatric disorders.
For patients with mild depression, the guidance supports psychological intervention without pharmacologic therapy; however, if the patient wishes to use medication, has had a positive response to medication in the past, or nonpharmacologic treatments have previously failed or are unavailable, then SSRIs should be considered first-choice therapy. For moderate to severe depression, SSRIs are the first choice, according to Dr. Mula and colleagues.
“It has to be acknowledged that there is considerable debate in the psychiatric literature about the treatment of mild depression in adults,” the investigators noted. “A patient-level meta-analysis pointed out that the magnitude of benefit of antidepressant medications compared with placebo increases with severity of depression symptoms and it may be minimal or nonexistent, on average, in patients with mild or moderate symptoms.”
If a patient does not respond to first-line therapy, then venlafaxine should be considered, according to the guidance. When a patient does respond to therapy, treatment should be continued for at least 6 months, and when residual symptoms persist, treatment should be continued until resolution.
“In people with depression it is established that around two-thirds of patients do not achieve full remission with first-line treatment,” Dr. Mula and colleagues wrote. “In people with epilepsy, current data show that up to 50% of patients do not achieve full remission from depression. For this reason, augmentation strategies are often needed. They should be adopted by psychiatrists, neuropsychiatrists, or mental health professionals familiar with such therapeutic strategies.”
Beyond these key recommendations, the guidance covers a range of additional topics, including other pharmacologic options, medication discontinuation strategies, electroconvulsive therapy, light therapy, exercise training, vagus nerve stimulation, and repetitive transcranial magnetic stimulation.
Useful advice that counters common misconceptions
According to Jacqueline A. French, MD, a professor at NYU Langone Medical Center, Dr. Mula and colleagues are “top notch,” and their recommendations “hit every nail on the head.”
Dr. French, chief medical officer of The Epilepsy Foundation, emphasized the importance of the publication, which addresses two common misconceptions within the medical community: First, that standard antidepressants are insufficient to treat depression in patients with epilepsy, and second, that antidepressants may trigger seizures.
“The first purpose [of the publication] is to say, yes, these antidepressants do work,” Dr. French said, “and no, they don’t worsen seizures, and you can use them safely, and they are appropriate to use.”
Dr. French explained that managing depression remains a practice gap among epileptologists and neurologists because it is a diagnosis that doesn’t traditionally fall into their purview, yet many patients with epilepsy forgo visiting their primary care providers, who more frequently diagnose and manage depression. Dr. French agreed with the guidance that epilepsy specialists should fill this gap.
“We need to at least be able to take people through their first antidepressant, even though we were not trained to be psychiatrists,” Dr. French said. “That’s part of the best care of our patients.”
Imad Najm, MD, director of the Charles Shor Epilepsy Center, Cleveland Clinic, said the recommendations are a step forward in the field, as they are supported by clinical data, instead of just clinical experience and expertise.
Still, Dr. Najm noted that more work is needed to stratify risk of depression in epilepsy and evaluate a possible causal relationship between epilepsy therapies and depression.
He went on to emphasizes the scale of issue at hand, and the stakes involved.
“Depression, anxiety, and psychosis affect a large number of patients with epilepsy,” Dr. Najm said. “Clinical screening and recognition of these comorbidities leads to the institution of treatment options and significant improvement in quality of life. Mental health professionals should be an integral part of any comprehensive epilepsy center.”
The investigators disclosed relationships with Esai, UCB, Elsevier, and others. Dr. French is indirectly involved with multiple pharmaceutical companies developing epilepsy drugs through her role as director of The Epilepsy Study Consortium, a nonprofit organization. Dr. Najm reported no conflicts of interest.
FROM EPILEPSIA
Gene mutations may drive sudden unexplained deaths in children
, researchers have found.
Previous studies have found de novo genetic variants – those not found in either parent but which occur for the first time in their offspring – that increase the risk of cardiac and seizure disorders, but research on sudden unexplained deaths in children (SUDC) is limited, according to Matthew Halvorsen, PhD, of the University of North Carolina at Chapel Hill, and colleagues. Most cases of SUDC occur in children aged 1-4 years, and a lack of standardized investigation systems likely leads to misclassification of these deaths, they said.
Compared with sudden infant death syndrome (SIDS), which occurs in approximately 1,400 children in the United States each year, approximately 400 children aged 1 year and older die from SUDC annually. A major obstacle to studying these cases is that so-called molecular autopsies – which incorporate genetic analysis into the postmortem examination – typically do not assess the parents’ genetic information and thus limit the ability to identify de novo mutations, they added.
In a study published in the Proceedings of the National Academy of Sciences, Dr. Halvorsen’s group obtained whole exome sequence data from 124 “trios,” meaning a dead child and two living parents. They tested for excessive de novo mutations for different genes involved in conditions that included cardiac arrhythmias and epilepsy. The average age at the time of death for the children was 34.2 months; 54% were male, and 82% were White.
Children who died of SUDC were nearly 10 times as likely to have de novo mutations in genes associated with cardiac and seizure disorders as were unrelated healthy controls (odds ratio, 9.76). Most pathogenic variants were de novo, which highlights the importance of trio studies, the researchers noted.
The researchers identified 11 variants associated with increased risk of SUDC, 7 of which were de novo. Three of the 124 cases carried mutations (two for RYR2 and 1 for TNNI3) affecting genes in the CardiacEpilepsy dataset proposed by the American College of Medical Genetics and Genomics, strengthening the connection to seizure disorders.
Another notable finding was the identification of six de novo mutations involved in altering calcium-related regulation, which suggests a cardiac susceptibility to sudden death.
The data support “novel genetic causes of pediatric sudden deaths that could be discovered with larger cohorts,” the researchers noted. Taken together, they say, the gene mutations could play a role in approximately 9% of SUDC cases.
The study findings were limited by several factors, including lack of population-based case ascertainment, exclusive focus on unexplained deaths, potentially missed mutations, and use of DNA from blood as opposed to organs, the researchers noted.
However, they concluded, “the data indicate that deleterious de novo mutations are significant genetic risk factors for childhood sudden unexplained death, and that their identification may lead to medical intervention that ultimately saves lives.”
Findings highlight impact of SUDC
“This study is important because SUDC is a much more pressing medical need than most people realize,” said Richard Tsien, PhD, of New York University Langone Medical Center, and the corresponding author of the study.
Although SUDC is less common than SIDS, SUDC has essentially no targeted research funding, Dr. Tsien said. Study coauthor Laura Gould, MA, a researcher and mother who lost a young child to SUDC, worked with Orrin Devinsky, MD, to create a registry for families with cases of SUDC. This registry was instrumental in allowing the researchers to “do the molecular detective work we need to do” to see whether a genetic basis exists for SUDC, Dr. Tsien said.
“The detective work comes up with a consistent story,” he said. “More than half of the genes that we found are involved in the normal function of the heart and brain,” performing such functions as delivering calcium ions to the inside of the heart cells and nerve cells.
The study “is the first of its kind,” given the difficulty of acquiring DNA from the child and two parents in SUDC cases, Dr. Tsien said.
Overall, approximately 10% of the cases have a compelling explanation based on the coding of DNA, Dr. Tsien said. From a clinical standpoint, that information might affect what a clinician says to a parent.
A key takeaway is that most of the genetic mutations are spontaneous and are not inherited from the parents, Dr. Tsien said. The study findings indicate that parents who suffer an SUDC loss need not be discouraged from having children, he added.
For the long term, “the more we understand about these disorders, the more information we can offer to families,” he said. Eventually, clinicians might be able to use genetics to identify signs of when SUDC might be more likely. “For example, if a child shows a very mild seizure, this would alert them that there might be potential for a more drastic outcome.”
Meanwhile, families with SUDC cases may find support and benefit in signing up for the registry and knowing that other families have been through a similar experience, Dr. Tsien said.
Genetic studies create opportunities
A significant portion of pediatric mortality remains unexplained, according to Richard D. Goldstein, MD, of Boston Children’s Hospital. One reason is the lack of a formal diagnostic code to identify these deaths.
Research to date has suggested links between SUDC and a family history of febrile seizures, as well as differences in brain structure associated with epilepsy, Dr. Goldstein said.
“An important hypothesis is that these deaths are part of a continuum that also includes stillbirths, SIDS, and sudden unexpected death in epilepsy [SUDEP],” Dr. Goldstein said. “By mandate, investigations of these deaths occur under the jurisdiction of medical examiners and coroners and have, for the most part, been insulated from developments in modern medicine like genomics and proteomics, elements of what are referred to as the molecular autopsy, and studies such as the current study bring attention to what is being missed.”
Dr. Goldstein said the new study buttresses the “conventional clinical suspicion” about the likely causes of SUDC, “but also strengthens the association between sudden unexpected death in pediatrics (SUDP) and SUDEP that we and others have been positing. I think the researchers very nicely make the point that epilepsy and cardiac arrhythmia genes are not as separated in their effects as many would believe.”
As for the clinical applicability of the findings, Dr. Goldstein said medicine needs to offer parents more: “Pediatric deaths without explanation deserve more than a forensic investigation that concerns itself mostly with whether there has been foul play,” he said. “We need to figure out how to engage families, at an incredibly vulnerable time, in helping find the cause of the child’s death and also contributing to needed research. Most of the reported variants were de novo, which means that parent participation is needed to figure out these genetic factors but also that we can offer reassurance to families that other children are not at risk.”
The study was supported by the SUDC Foundation and Finding a Cure for Epilepsy and Seizures (New York University). Dr. Tsien disclosed support from the National Institutes of Health and a grant from FACES. Dr. Goldstein reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, researchers have found.
Previous studies have found de novo genetic variants – those not found in either parent but which occur for the first time in their offspring – that increase the risk of cardiac and seizure disorders, but research on sudden unexplained deaths in children (SUDC) is limited, according to Matthew Halvorsen, PhD, of the University of North Carolina at Chapel Hill, and colleagues. Most cases of SUDC occur in children aged 1-4 years, and a lack of standardized investigation systems likely leads to misclassification of these deaths, they said.
Compared with sudden infant death syndrome (SIDS), which occurs in approximately 1,400 children in the United States each year, approximately 400 children aged 1 year and older die from SUDC annually. A major obstacle to studying these cases is that so-called molecular autopsies – which incorporate genetic analysis into the postmortem examination – typically do not assess the parents’ genetic information and thus limit the ability to identify de novo mutations, they added.
In a study published in the Proceedings of the National Academy of Sciences, Dr. Halvorsen’s group obtained whole exome sequence data from 124 “trios,” meaning a dead child and two living parents. They tested for excessive de novo mutations for different genes involved in conditions that included cardiac arrhythmias and epilepsy. The average age at the time of death for the children was 34.2 months; 54% were male, and 82% were White.
Children who died of SUDC were nearly 10 times as likely to have de novo mutations in genes associated with cardiac and seizure disorders as were unrelated healthy controls (odds ratio, 9.76). Most pathogenic variants were de novo, which highlights the importance of trio studies, the researchers noted.
The researchers identified 11 variants associated with increased risk of SUDC, 7 of which were de novo. Three of the 124 cases carried mutations (two for RYR2 and 1 for TNNI3) affecting genes in the CardiacEpilepsy dataset proposed by the American College of Medical Genetics and Genomics, strengthening the connection to seizure disorders.
Another notable finding was the identification of six de novo mutations involved in altering calcium-related regulation, which suggests a cardiac susceptibility to sudden death.
The data support “novel genetic causes of pediatric sudden deaths that could be discovered with larger cohorts,” the researchers noted. Taken together, they say, the gene mutations could play a role in approximately 9% of SUDC cases.
The study findings were limited by several factors, including lack of population-based case ascertainment, exclusive focus on unexplained deaths, potentially missed mutations, and use of DNA from blood as opposed to organs, the researchers noted.
However, they concluded, “the data indicate that deleterious de novo mutations are significant genetic risk factors for childhood sudden unexplained death, and that their identification may lead to medical intervention that ultimately saves lives.”
Findings highlight impact of SUDC
“This study is important because SUDC is a much more pressing medical need than most people realize,” said Richard Tsien, PhD, of New York University Langone Medical Center, and the corresponding author of the study.
Although SUDC is less common than SIDS, SUDC has essentially no targeted research funding, Dr. Tsien said. Study coauthor Laura Gould, MA, a researcher and mother who lost a young child to SUDC, worked with Orrin Devinsky, MD, to create a registry for families with cases of SUDC. This registry was instrumental in allowing the researchers to “do the molecular detective work we need to do” to see whether a genetic basis exists for SUDC, Dr. Tsien said.
“The detective work comes up with a consistent story,” he said. “More than half of the genes that we found are involved in the normal function of the heart and brain,” performing such functions as delivering calcium ions to the inside of the heart cells and nerve cells.
The study “is the first of its kind,” given the difficulty of acquiring DNA from the child and two parents in SUDC cases, Dr. Tsien said.
Overall, approximately 10% of the cases have a compelling explanation based on the coding of DNA, Dr. Tsien said. From a clinical standpoint, that information might affect what a clinician says to a parent.
A key takeaway is that most of the genetic mutations are spontaneous and are not inherited from the parents, Dr. Tsien said. The study findings indicate that parents who suffer an SUDC loss need not be discouraged from having children, he added.
For the long term, “the more we understand about these disorders, the more information we can offer to families,” he said. Eventually, clinicians might be able to use genetics to identify signs of when SUDC might be more likely. “For example, if a child shows a very mild seizure, this would alert them that there might be potential for a more drastic outcome.”
Meanwhile, families with SUDC cases may find support and benefit in signing up for the registry and knowing that other families have been through a similar experience, Dr. Tsien said.
Genetic studies create opportunities
A significant portion of pediatric mortality remains unexplained, according to Richard D. Goldstein, MD, of Boston Children’s Hospital. One reason is the lack of a formal diagnostic code to identify these deaths.
Research to date has suggested links between SUDC and a family history of febrile seizures, as well as differences in brain structure associated with epilepsy, Dr. Goldstein said.
“An important hypothesis is that these deaths are part of a continuum that also includes stillbirths, SIDS, and sudden unexpected death in epilepsy [SUDEP],” Dr. Goldstein said. “By mandate, investigations of these deaths occur under the jurisdiction of medical examiners and coroners and have, for the most part, been insulated from developments in modern medicine like genomics and proteomics, elements of what are referred to as the molecular autopsy, and studies such as the current study bring attention to what is being missed.”
Dr. Goldstein said the new study buttresses the “conventional clinical suspicion” about the likely causes of SUDC, “but also strengthens the association between sudden unexpected death in pediatrics (SUDP) and SUDEP that we and others have been positing. I think the researchers very nicely make the point that epilepsy and cardiac arrhythmia genes are not as separated in their effects as many would believe.”
As for the clinical applicability of the findings, Dr. Goldstein said medicine needs to offer parents more: “Pediatric deaths without explanation deserve more than a forensic investigation that concerns itself mostly with whether there has been foul play,” he said. “We need to figure out how to engage families, at an incredibly vulnerable time, in helping find the cause of the child’s death and also contributing to needed research. Most of the reported variants were de novo, which means that parent participation is needed to figure out these genetic factors but also that we can offer reassurance to families that other children are not at risk.”
The study was supported by the SUDC Foundation and Finding a Cure for Epilepsy and Seizures (New York University). Dr. Tsien disclosed support from the National Institutes of Health and a grant from FACES. Dr. Goldstein reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, researchers have found.
Previous studies have found de novo genetic variants – those not found in either parent but which occur for the first time in their offspring – that increase the risk of cardiac and seizure disorders, but research on sudden unexplained deaths in children (SUDC) is limited, according to Matthew Halvorsen, PhD, of the University of North Carolina at Chapel Hill, and colleagues. Most cases of SUDC occur in children aged 1-4 years, and a lack of standardized investigation systems likely leads to misclassification of these deaths, they said.
Compared with sudden infant death syndrome (SIDS), which occurs in approximately 1,400 children in the United States each year, approximately 400 children aged 1 year and older die from SUDC annually. A major obstacle to studying these cases is that so-called molecular autopsies – which incorporate genetic analysis into the postmortem examination – typically do not assess the parents’ genetic information and thus limit the ability to identify de novo mutations, they added.
In a study published in the Proceedings of the National Academy of Sciences, Dr. Halvorsen’s group obtained whole exome sequence data from 124 “trios,” meaning a dead child and two living parents. They tested for excessive de novo mutations for different genes involved in conditions that included cardiac arrhythmias and epilepsy. The average age at the time of death for the children was 34.2 months; 54% were male, and 82% were White.
Children who died of SUDC were nearly 10 times as likely to have de novo mutations in genes associated with cardiac and seizure disorders as were unrelated healthy controls (odds ratio, 9.76). Most pathogenic variants were de novo, which highlights the importance of trio studies, the researchers noted.
The researchers identified 11 variants associated with increased risk of SUDC, 7 of which were de novo. Three of the 124 cases carried mutations (two for RYR2 and 1 for TNNI3) affecting genes in the CardiacEpilepsy dataset proposed by the American College of Medical Genetics and Genomics, strengthening the connection to seizure disorders.
Another notable finding was the identification of six de novo mutations involved in altering calcium-related regulation, which suggests a cardiac susceptibility to sudden death.
The data support “novel genetic causes of pediatric sudden deaths that could be discovered with larger cohorts,” the researchers noted. Taken together, they say, the gene mutations could play a role in approximately 9% of SUDC cases.
The study findings were limited by several factors, including lack of population-based case ascertainment, exclusive focus on unexplained deaths, potentially missed mutations, and use of DNA from blood as opposed to organs, the researchers noted.
However, they concluded, “the data indicate that deleterious de novo mutations are significant genetic risk factors for childhood sudden unexplained death, and that their identification may lead to medical intervention that ultimately saves lives.”
Findings highlight impact of SUDC
“This study is important because SUDC is a much more pressing medical need than most people realize,” said Richard Tsien, PhD, of New York University Langone Medical Center, and the corresponding author of the study.
Although SUDC is less common than SIDS, SUDC has essentially no targeted research funding, Dr. Tsien said. Study coauthor Laura Gould, MA, a researcher and mother who lost a young child to SUDC, worked with Orrin Devinsky, MD, to create a registry for families with cases of SUDC. This registry was instrumental in allowing the researchers to “do the molecular detective work we need to do” to see whether a genetic basis exists for SUDC, Dr. Tsien said.
“The detective work comes up with a consistent story,” he said. “More than half of the genes that we found are involved in the normal function of the heart and brain,” performing such functions as delivering calcium ions to the inside of the heart cells and nerve cells.
The study “is the first of its kind,” given the difficulty of acquiring DNA from the child and two parents in SUDC cases, Dr. Tsien said.
Overall, approximately 10% of the cases have a compelling explanation based on the coding of DNA, Dr. Tsien said. From a clinical standpoint, that information might affect what a clinician says to a parent.
A key takeaway is that most of the genetic mutations are spontaneous and are not inherited from the parents, Dr. Tsien said. The study findings indicate that parents who suffer an SUDC loss need not be discouraged from having children, he added.
For the long term, “the more we understand about these disorders, the more information we can offer to families,” he said. Eventually, clinicians might be able to use genetics to identify signs of when SUDC might be more likely. “For example, if a child shows a very mild seizure, this would alert them that there might be potential for a more drastic outcome.”
Meanwhile, families with SUDC cases may find support and benefit in signing up for the registry and knowing that other families have been through a similar experience, Dr. Tsien said.
Genetic studies create opportunities
A significant portion of pediatric mortality remains unexplained, according to Richard D. Goldstein, MD, of Boston Children’s Hospital. One reason is the lack of a formal diagnostic code to identify these deaths.
Research to date has suggested links between SUDC and a family history of febrile seizures, as well as differences in brain structure associated with epilepsy, Dr. Goldstein said.
“An important hypothesis is that these deaths are part of a continuum that also includes stillbirths, SIDS, and sudden unexpected death in epilepsy [SUDEP],” Dr. Goldstein said. “By mandate, investigations of these deaths occur under the jurisdiction of medical examiners and coroners and have, for the most part, been insulated from developments in modern medicine like genomics and proteomics, elements of what are referred to as the molecular autopsy, and studies such as the current study bring attention to what is being missed.”
Dr. Goldstein said the new study buttresses the “conventional clinical suspicion” about the likely causes of SUDC, “but also strengthens the association between sudden unexpected death in pediatrics (SUDP) and SUDEP that we and others have been positing. I think the researchers very nicely make the point that epilepsy and cardiac arrhythmia genes are not as separated in their effects as many would believe.”
As for the clinical applicability of the findings, Dr. Goldstein said medicine needs to offer parents more: “Pediatric deaths without explanation deserve more than a forensic investigation that concerns itself mostly with whether there has been foul play,” he said. “We need to figure out how to engage families, at an incredibly vulnerable time, in helping find the cause of the child’s death and also contributing to needed research. Most of the reported variants were de novo, which means that parent participation is needed to figure out these genetic factors but also that we can offer reassurance to families that other children are not at risk.”
The study was supported by the SUDC Foundation and Finding a Cure for Epilepsy and Seizures (New York University). Dr. Tsien disclosed support from the National Institutes of Health and a grant from FACES. Dr. Goldstein reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Posttraumatic epilepsy is common, even after ‘mild’ TBI
, new research suggests.
Results from a multicenter, prospective cohort study showed 2.7% of nearly 1,500 participants with TBI reported also having posttraumatic epilepsy, and these patients had significantly worse outcomes than those without posttraumatic epilepsy.
“Posttraumatic epilepsy is common even in so-called mild TBI, and we should be on the lookout for patients reporting these kinds of spells,” said coinvestigator Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the TBI Clinical Research Center, University of Pennsylvania, Philadelphia.
Dr. Diaz-Arrastia said he dislikes the term “mild TBI” because many of these injuries have “pretty substantial consequences.”
The findings were published online Dec. 29 in JAMA Network Open.
Novel study
Seizures can occur after TBI, most commonly after a severe brain injury, such as those leading to coma or bleeding in the brain or requiring surgical intervention. However, there have been “hints” that some patients with milder brain injuries are also at increased risk for epilepsy, said Dr. Diaz-Arrastia.
To investigate, the researchers assessed data from the large, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) database. Participants with TBI, defined as a Glasgow Coma Scale (GCS) score of 3-15, had presented to a level I trauma center within 24 hours of a head trauma needing evaluation with a CT scan.
The study included patients with relatively mild TBI (GCS score, 13-15), which is a “novel feature” of the study, the authors noted. Most prior studies of posttraumatic epilepsy focused on moderate to severe TBI.
The researchers included two sex- and age-matched control groups. The orthopedic trauma control (OTC) group consisted of patients with isolated trauma to the limbs, pelvis, and/or ribs. The “friend” or peer control group had backgrounds and lifestyles similar to those with TBI but had no history of TBI, concussion, or traumatic injury in the previous year.
The analysis included 1,885 participants (mean age, 41.3 years; 65.8% men). Of these, 1,493 had TBI, 182 were in the OTC group, and 210 were in the friends group. At 6- and 12-month follow-ups, investigators administered the Epilepsy Screening Questionnaire (ESQ), developed by the National Institute of Neurological Disorders and Stroke (NINDS).
Confirmatory data
Participants were asked about experiencing uncontrolled movements, unexplained changes in mental state, and repeated unusual attacks or convulsions, and whether they had been told they had epilepsy or seizures. If they answered yes to any of these questions, they received second-level screening, which asked about seizures.
Patients were deemed to have posttraumatic epilepsy if they answered affirmatively to any first-level screening item, experienced seizures 7 days after injury, and were diagnosed with epilepsy.
The primary outcome was rate of positive posttraumatic epilepsy diagnoses. At 12 months, 2.7% of those with TBI reported a posttraumatic epilepsy diagnosis compared with none of either of the control groups (P < .001).
This rate is consistent with prior literature and is “pretty close to what we expected,” said Dr. Diaz-Arrastia.
Among those with TBI and posttraumatic epilepsy, 12.2% had GCS scores of 3-8 (severe), 5.3% had scores of 9-12 (moderate), and 0.9% had scores of 13-15 (mild). That figure for mild TBI is not insignificant, said Dr. Diaz-Arrastia.
“Probably 90% of all those coming to the emergency room with a brain injury are diagnosed with mild TBI not requiring admission,” he noted.
The risk for posttraumatic epilepsy was higher the more severe the head injury, and among those with hemorrhage on head CT imaging. In patients with mild TBI, hemorrhage was associated with a two- to threefold risk of developing posttraumatic epilepsy.
“This prospective observational study confirms the epidemiologic data that even after mild brain injury, there is an increased risk for epilepsy,” said Dr. Diaz-Arrastia.
Universal screening?
The researchers also looked at whether seizures worsen other outcomes. Compared with those who had TBI but not posttraumatic epilepsy, those with posttraumatic epilepsy had significantly lower Glasgow Outcome Scale Extended (GOSE) scores (mean, 4.7 vs. 6.1; P < .001), higher Brief Symptom Inventory (BSI) scores (58.6 vs. 50.2; P = .02), and higher Rivermead Cognitive Metric (RCM) scores (5.3 vs. 3.1; P = .002) at 12 months after adjustment for age, initial GCS score, and imaging findings.
Higher GOSE and RCM scores reflect better outcomes, but a higher score on the BSI, which assesses overall mood, reflects a worse outcome, the investigators noted.
Previous evidence suggests prophylactic use of antiepileptic drugs in patients with TBI does not reduce risks. These drugs “are neither 100% safe nor 100% effective,” said Dr. Diaz-Arrastia. Some studies showed that certain agents actually worsen outcomes, he added.
What the field needs instead are antiepileptogenic drugs – those that interfere with the maladaptive synaptic plasticity that ends up in an epileptic circuit, he noted.
The new results suggest screening for posttraumatic epilepsy using the NINDS-ESQ “should be done pretty much routinely as a follow-up for all brain injuries,” Dr. Diaz-Arrastia said.
The investigators plan to have study participants assessed by an epileptologist later. A significant number of people with TBI, he noted, won’t develop posttraumatic epilepsy until 1-5 years after their injury – and even later in some cases.
A limitation of the study was that some patients reporting posttraumatic epilepsy may have had psychogenic nonepileptiform seizures, which are common in TBI patients, the investigators noted.
The study was supported by grants from One Mind, National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS, and Department of Defence. Dr. Diaz-Arrastia reported receiving grants from the NIH, NINDS, and DOD during the conduct of the study.
A version of this article first appeared on Medscape.com.
, new research suggests.
Results from a multicenter, prospective cohort study showed 2.7% of nearly 1,500 participants with TBI reported also having posttraumatic epilepsy, and these patients had significantly worse outcomes than those without posttraumatic epilepsy.
“Posttraumatic epilepsy is common even in so-called mild TBI, and we should be on the lookout for patients reporting these kinds of spells,” said coinvestigator Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the TBI Clinical Research Center, University of Pennsylvania, Philadelphia.
Dr. Diaz-Arrastia said he dislikes the term “mild TBI” because many of these injuries have “pretty substantial consequences.”
The findings were published online Dec. 29 in JAMA Network Open.
Novel study
Seizures can occur after TBI, most commonly after a severe brain injury, such as those leading to coma or bleeding in the brain or requiring surgical intervention. However, there have been “hints” that some patients with milder brain injuries are also at increased risk for epilepsy, said Dr. Diaz-Arrastia.
To investigate, the researchers assessed data from the large, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) database. Participants with TBI, defined as a Glasgow Coma Scale (GCS) score of 3-15, had presented to a level I trauma center within 24 hours of a head trauma needing evaluation with a CT scan.
The study included patients with relatively mild TBI (GCS score, 13-15), which is a “novel feature” of the study, the authors noted. Most prior studies of posttraumatic epilepsy focused on moderate to severe TBI.
The researchers included two sex- and age-matched control groups. The orthopedic trauma control (OTC) group consisted of patients with isolated trauma to the limbs, pelvis, and/or ribs. The “friend” or peer control group had backgrounds and lifestyles similar to those with TBI but had no history of TBI, concussion, or traumatic injury in the previous year.
The analysis included 1,885 participants (mean age, 41.3 years; 65.8% men). Of these, 1,493 had TBI, 182 were in the OTC group, and 210 were in the friends group. At 6- and 12-month follow-ups, investigators administered the Epilepsy Screening Questionnaire (ESQ), developed by the National Institute of Neurological Disorders and Stroke (NINDS).
Confirmatory data
Participants were asked about experiencing uncontrolled movements, unexplained changes in mental state, and repeated unusual attacks or convulsions, and whether they had been told they had epilepsy or seizures. If they answered yes to any of these questions, they received second-level screening, which asked about seizures.
Patients were deemed to have posttraumatic epilepsy if they answered affirmatively to any first-level screening item, experienced seizures 7 days after injury, and were diagnosed with epilepsy.
The primary outcome was rate of positive posttraumatic epilepsy diagnoses. At 12 months, 2.7% of those with TBI reported a posttraumatic epilepsy diagnosis compared with none of either of the control groups (P < .001).
This rate is consistent with prior literature and is “pretty close to what we expected,” said Dr. Diaz-Arrastia.
Among those with TBI and posttraumatic epilepsy, 12.2% had GCS scores of 3-8 (severe), 5.3% had scores of 9-12 (moderate), and 0.9% had scores of 13-15 (mild). That figure for mild TBI is not insignificant, said Dr. Diaz-Arrastia.
“Probably 90% of all those coming to the emergency room with a brain injury are diagnosed with mild TBI not requiring admission,” he noted.
The risk for posttraumatic epilepsy was higher the more severe the head injury, and among those with hemorrhage on head CT imaging. In patients with mild TBI, hemorrhage was associated with a two- to threefold risk of developing posttraumatic epilepsy.
“This prospective observational study confirms the epidemiologic data that even after mild brain injury, there is an increased risk for epilepsy,” said Dr. Diaz-Arrastia.
Universal screening?
The researchers also looked at whether seizures worsen other outcomes. Compared with those who had TBI but not posttraumatic epilepsy, those with posttraumatic epilepsy had significantly lower Glasgow Outcome Scale Extended (GOSE) scores (mean, 4.7 vs. 6.1; P < .001), higher Brief Symptom Inventory (BSI) scores (58.6 vs. 50.2; P = .02), and higher Rivermead Cognitive Metric (RCM) scores (5.3 vs. 3.1; P = .002) at 12 months after adjustment for age, initial GCS score, and imaging findings.
Higher GOSE and RCM scores reflect better outcomes, but a higher score on the BSI, which assesses overall mood, reflects a worse outcome, the investigators noted.
Previous evidence suggests prophylactic use of antiepileptic drugs in patients with TBI does not reduce risks. These drugs “are neither 100% safe nor 100% effective,” said Dr. Diaz-Arrastia. Some studies showed that certain agents actually worsen outcomes, he added.
What the field needs instead are antiepileptogenic drugs – those that interfere with the maladaptive synaptic plasticity that ends up in an epileptic circuit, he noted.
The new results suggest screening for posttraumatic epilepsy using the NINDS-ESQ “should be done pretty much routinely as a follow-up for all brain injuries,” Dr. Diaz-Arrastia said.
The investigators plan to have study participants assessed by an epileptologist later. A significant number of people with TBI, he noted, won’t develop posttraumatic epilepsy until 1-5 years after their injury – and even later in some cases.
A limitation of the study was that some patients reporting posttraumatic epilepsy may have had psychogenic nonepileptiform seizures, which are common in TBI patients, the investigators noted.
The study was supported by grants from One Mind, National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS, and Department of Defence. Dr. Diaz-Arrastia reported receiving grants from the NIH, NINDS, and DOD during the conduct of the study.
A version of this article first appeared on Medscape.com.
, new research suggests.
Results from a multicenter, prospective cohort study showed 2.7% of nearly 1,500 participants with TBI reported also having posttraumatic epilepsy, and these patients had significantly worse outcomes than those without posttraumatic epilepsy.
“Posttraumatic epilepsy is common even in so-called mild TBI, and we should be on the lookout for patients reporting these kinds of spells,” said coinvestigator Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the TBI Clinical Research Center, University of Pennsylvania, Philadelphia.
Dr. Diaz-Arrastia said he dislikes the term “mild TBI” because many of these injuries have “pretty substantial consequences.”
The findings were published online Dec. 29 in JAMA Network Open.
Novel study
Seizures can occur after TBI, most commonly after a severe brain injury, such as those leading to coma or bleeding in the brain or requiring surgical intervention. However, there have been “hints” that some patients with milder brain injuries are also at increased risk for epilepsy, said Dr. Diaz-Arrastia.
To investigate, the researchers assessed data from the large, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) database. Participants with TBI, defined as a Glasgow Coma Scale (GCS) score of 3-15, had presented to a level I trauma center within 24 hours of a head trauma needing evaluation with a CT scan.
The study included patients with relatively mild TBI (GCS score, 13-15), which is a “novel feature” of the study, the authors noted. Most prior studies of posttraumatic epilepsy focused on moderate to severe TBI.
The researchers included two sex- and age-matched control groups. The orthopedic trauma control (OTC) group consisted of patients with isolated trauma to the limbs, pelvis, and/or ribs. The “friend” or peer control group had backgrounds and lifestyles similar to those with TBI but had no history of TBI, concussion, or traumatic injury in the previous year.
The analysis included 1,885 participants (mean age, 41.3 years; 65.8% men). Of these, 1,493 had TBI, 182 were in the OTC group, and 210 were in the friends group. At 6- and 12-month follow-ups, investigators administered the Epilepsy Screening Questionnaire (ESQ), developed by the National Institute of Neurological Disorders and Stroke (NINDS).
Confirmatory data
Participants were asked about experiencing uncontrolled movements, unexplained changes in mental state, and repeated unusual attacks or convulsions, and whether they had been told they had epilepsy or seizures. If they answered yes to any of these questions, they received second-level screening, which asked about seizures.
Patients were deemed to have posttraumatic epilepsy if they answered affirmatively to any first-level screening item, experienced seizures 7 days after injury, and were diagnosed with epilepsy.
The primary outcome was rate of positive posttraumatic epilepsy diagnoses. At 12 months, 2.7% of those with TBI reported a posttraumatic epilepsy diagnosis compared with none of either of the control groups (P < .001).
This rate is consistent with prior literature and is “pretty close to what we expected,” said Dr. Diaz-Arrastia.
Among those with TBI and posttraumatic epilepsy, 12.2% had GCS scores of 3-8 (severe), 5.3% had scores of 9-12 (moderate), and 0.9% had scores of 13-15 (mild). That figure for mild TBI is not insignificant, said Dr. Diaz-Arrastia.
“Probably 90% of all those coming to the emergency room with a brain injury are diagnosed with mild TBI not requiring admission,” he noted.
The risk for posttraumatic epilepsy was higher the more severe the head injury, and among those with hemorrhage on head CT imaging. In patients with mild TBI, hemorrhage was associated with a two- to threefold risk of developing posttraumatic epilepsy.
“This prospective observational study confirms the epidemiologic data that even after mild brain injury, there is an increased risk for epilepsy,” said Dr. Diaz-Arrastia.
Universal screening?
The researchers also looked at whether seizures worsen other outcomes. Compared with those who had TBI but not posttraumatic epilepsy, those with posttraumatic epilepsy had significantly lower Glasgow Outcome Scale Extended (GOSE) scores (mean, 4.7 vs. 6.1; P < .001), higher Brief Symptom Inventory (BSI) scores (58.6 vs. 50.2; P = .02), and higher Rivermead Cognitive Metric (RCM) scores (5.3 vs. 3.1; P = .002) at 12 months after adjustment for age, initial GCS score, and imaging findings.
Higher GOSE and RCM scores reflect better outcomes, but a higher score on the BSI, which assesses overall mood, reflects a worse outcome, the investigators noted.
Previous evidence suggests prophylactic use of antiepileptic drugs in patients with TBI does not reduce risks. These drugs “are neither 100% safe nor 100% effective,” said Dr. Diaz-Arrastia. Some studies showed that certain agents actually worsen outcomes, he added.
What the field needs instead are antiepileptogenic drugs – those that interfere with the maladaptive synaptic plasticity that ends up in an epileptic circuit, he noted.
The new results suggest screening for posttraumatic epilepsy using the NINDS-ESQ “should be done pretty much routinely as a follow-up for all brain injuries,” Dr. Diaz-Arrastia said.
The investigators plan to have study participants assessed by an epileptologist later. A significant number of people with TBI, he noted, won’t develop posttraumatic epilepsy until 1-5 years after their injury – and even later in some cases.
A limitation of the study was that some patients reporting posttraumatic epilepsy may have had psychogenic nonepileptiform seizures, which are common in TBI patients, the investigators noted.
The study was supported by grants from One Mind, National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS, and Department of Defence. Dr. Diaz-Arrastia reported receiving grants from the NIH, NINDS, and DOD during the conduct of the study.
A version of this article first appeared on Medscape.com.
Epilepsy in older adults: Misdiagnosis and case complexity are common
, a neurologist told an audience at the annual meeting of the American Epilepsy Society. She urged colleagues to focus on possible interactions with other neurological conditions, consider various complicating factors, and embrace a team strategy.
“There are lots of nuances,” said Rebecca O’Dwyer, MD, an adult epilepsy specialist with Rush Epilepsy Center in Chicago. “It takes a lot of time and requires a multidisciplinary approach. Taking care of older individuals with epilepsy truly is a team sport.”
According to a 2014 report highlighted by Dr. O’Dwyer, “nearly 25% of new-onset seizures occur after age 65. The incidence of epilepsy in this age group is almost twice the rate in children, and in people over age 80, it is triple the rate in children.”
Research suggests it can take up to 2 years to correctly diagnose epilepsy in older people, Dr. O’Dwyer said, and nearly two-thirds of cases may be misdiagnosed. “Some of it is just limited awareness. There’s this perception in the public that epilepsy is something that occurs in younger adults or young children, and that when you come to a certain age, you cannot have epilepsy. Also, there are differences in the clinical manifestations of their seizures, and many comorbid possibilities could also present in similar fashion to epilepsy. Some of our usual tools that we use to come to the diagnosis such as EEG are also known to be less sensitive in this age group.”
According to the 2014 report, research finds that the elderly are much more likely than young adults to have postictal sleepiness or unresponsiveness and seizures manifesting as brief moments of subtle confusion. They’re much less likely to have epileptic aura and generalized tonic seizures.
“An epileptic seizure in an older adult tends to be less dramatic with fewer motor manifestations, and they often tend to be monophasic. They may be so subtle that they’re missed by family members and other medical providers,” Dr. O’Dwyer said. “I had a patient whose seizure consisted of her tapping her left shoulder. She had been doing this for at least 6 months, and she came to my clinic after her daughter realized that she was a little confused afterward. She’d already seen a behavioral neurologist and been given the diagnosis of dementia. We were fortunate enough to catch one of these episodes while we were doing an EEG, and we diagnosed her with focal epilepsy. With one antiseizure medication, we stopped the seizures, and her memory came back.”
Make sure to take detailed histories and keep an eye out for descriptions of behaviors that are episodic but perhaps not typical of seizures, she said.
Epilepsy can be misdiagnosed as a variety of conditions, she said, such as syncope, Alzheimer’s disease, stroke, Parkinson’s disease, and atrial fibrillation. “When you do diagnose somebody older with new-onset epilepsy, you should work them up for a stroke. Because we know that within the first 4 weeks after their first seizure the likelihood that they could have a stroke is three times higher.”
It’s also possible that neurological conditions can be followed by new-onset epilepsy, she said, making dementia even worse. Low-dose antiepileptic drugs can be helpful in these patients.
But seniors are especially vulnerable to side effects of antiepileptic drugs such as sedation, dizziness, and cardiac-conduction abnormalities. “You must adhere to the mantra of going low and going slow because they are exquisitely susceptible,” Dr. O’Dwyer said.
She recommends lamotrigine, which is well tolerated with helpful mood-stabilizing effects, and levetiracetam, which attenuates cognitive decline in dementia but may cause side effects such as irritable mood. Zonisamide is showing promise in patients with parkinsonian syndromes, she said, and it may be helpful to maximize drugs that patients are already taking such as gabapentin or pregabalin.
Finally, Dr. O’Dwyer urged colleagues to work in teams that include caregivers, primary care doctors, social workers, and pharmacists. “Sometimes in all this,” she said, “my job is the easiest.”
Dr. O’Dwyer discloses research support from the Shapiro Foundation.
, a neurologist told an audience at the annual meeting of the American Epilepsy Society. She urged colleagues to focus on possible interactions with other neurological conditions, consider various complicating factors, and embrace a team strategy.
“There are lots of nuances,” said Rebecca O’Dwyer, MD, an adult epilepsy specialist with Rush Epilepsy Center in Chicago. “It takes a lot of time and requires a multidisciplinary approach. Taking care of older individuals with epilepsy truly is a team sport.”
According to a 2014 report highlighted by Dr. O’Dwyer, “nearly 25% of new-onset seizures occur after age 65. The incidence of epilepsy in this age group is almost twice the rate in children, and in people over age 80, it is triple the rate in children.”
Research suggests it can take up to 2 years to correctly diagnose epilepsy in older people, Dr. O’Dwyer said, and nearly two-thirds of cases may be misdiagnosed. “Some of it is just limited awareness. There’s this perception in the public that epilepsy is something that occurs in younger adults or young children, and that when you come to a certain age, you cannot have epilepsy. Also, there are differences in the clinical manifestations of their seizures, and many comorbid possibilities could also present in similar fashion to epilepsy. Some of our usual tools that we use to come to the diagnosis such as EEG are also known to be less sensitive in this age group.”
According to the 2014 report, research finds that the elderly are much more likely than young adults to have postictal sleepiness or unresponsiveness and seizures manifesting as brief moments of subtle confusion. They’re much less likely to have epileptic aura and generalized tonic seizures.
“An epileptic seizure in an older adult tends to be less dramatic with fewer motor manifestations, and they often tend to be monophasic. They may be so subtle that they’re missed by family members and other medical providers,” Dr. O’Dwyer said. “I had a patient whose seizure consisted of her tapping her left shoulder. She had been doing this for at least 6 months, and she came to my clinic after her daughter realized that she was a little confused afterward. She’d already seen a behavioral neurologist and been given the diagnosis of dementia. We were fortunate enough to catch one of these episodes while we were doing an EEG, and we diagnosed her with focal epilepsy. With one antiseizure medication, we stopped the seizures, and her memory came back.”
Make sure to take detailed histories and keep an eye out for descriptions of behaviors that are episodic but perhaps not typical of seizures, she said.
Epilepsy can be misdiagnosed as a variety of conditions, she said, such as syncope, Alzheimer’s disease, stroke, Parkinson’s disease, and atrial fibrillation. “When you do diagnose somebody older with new-onset epilepsy, you should work them up for a stroke. Because we know that within the first 4 weeks after their first seizure the likelihood that they could have a stroke is three times higher.”
It’s also possible that neurological conditions can be followed by new-onset epilepsy, she said, making dementia even worse. Low-dose antiepileptic drugs can be helpful in these patients.
But seniors are especially vulnerable to side effects of antiepileptic drugs such as sedation, dizziness, and cardiac-conduction abnormalities. “You must adhere to the mantra of going low and going slow because they are exquisitely susceptible,” Dr. O’Dwyer said.
She recommends lamotrigine, which is well tolerated with helpful mood-stabilizing effects, and levetiracetam, which attenuates cognitive decline in dementia but may cause side effects such as irritable mood. Zonisamide is showing promise in patients with parkinsonian syndromes, she said, and it may be helpful to maximize drugs that patients are already taking such as gabapentin or pregabalin.
Finally, Dr. O’Dwyer urged colleagues to work in teams that include caregivers, primary care doctors, social workers, and pharmacists. “Sometimes in all this,” she said, “my job is the easiest.”
Dr. O’Dwyer discloses research support from the Shapiro Foundation.
, a neurologist told an audience at the annual meeting of the American Epilepsy Society. She urged colleagues to focus on possible interactions with other neurological conditions, consider various complicating factors, and embrace a team strategy.
“There are lots of nuances,” said Rebecca O’Dwyer, MD, an adult epilepsy specialist with Rush Epilepsy Center in Chicago. “It takes a lot of time and requires a multidisciplinary approach. Taking care of older individuals with epilepsy truly is a team sport.”
According to a 2014 report highlighted by Dr. O’Dwyer, “nearly 25% of new-onset seizures occur after age 65. The incidence of epilepsy in this age group is almost twice the rate in children, and in people over age 80, it is triple the rate in children.”
Research suggests it can take up to 2 years to correctly diagnose epilepsy in older people, Dr. O’Dwyer said, and nearly two-thirds of cases may be misdiagnosed. “Some of it is just limited awareness. There’s this perception in the public that epilepsy is something that occurs in younger adults or young children, and that when you come to a certain age, you cannot have epilepsy. Also, there are differences in the clinical manifestations of their seizures, and many comorbid possibilities could also present in similar fashion to epilepsy. Some of our usual tools that we use to come to the diagnosis such as EEG are also known to be less sensitive in this age group.”
According to the 2014 report, research finds that the elderly are much more likely than young adults to have postictal sleepiness or unresponsiveness and seizures manifesting as brief moments of subtle confusion. They’re much less likely to have epileptic aura and generalized tonic seizures.
“An epileptic seizure in an older adult tends to be less dramatic with fewer motor manifestations, and they often tend to be monophasic. They may be so subtle that they’re missed by family members and other medical providers,” Dr. O’Dwyer said. “I had a patient whose seizure consisted of her tapping her left shoulder. She had been doing this for at least 6 months, and she came to my clinic after her daughter realized that she was a little confused afterward. She’d already seen a behavioral neurologist and been given the diagnosis of dementia. We were fortunate enough to catch one of these episodes while we were doing an EEG, and we diagnosed her with focal epilepsy. With one antiseizure medication, we stopped the seizures, and her memory came back.”
Make sure to take detailed histories and keep an eye out for descriptions of behaviors that are episodic but perhaps not typical of seizures, she said.
Epilepsy can be misdiagnosed as a variety of conditions, she said, such as syncope, Alzheimer’s disease, stroke, Parkinson’s disease, and atrial fibrillation. “When you do diagnose somebody older with new-onset epilepsy, you should work them up for a stroke. Because we know that within the first 4 weeks after their first seizure the likelihood that they could have a stroke is three times higher.”
It’s also possible that neurological conditions can be followed by new-onset epilepsy, she said, making dementia even worse. Low-dose antiepileptic drugs can be helpful in these patients.
But seniors are especially vulnerable to side effects of antiepileptic drugs such as sedation, dizziness, and cardiac-conduction abnormalities. “You must adhere to the mantra of going low and going slow because they are exquisitely susceptible,” Dr. O’Dwyer said.
She recommends lamotrigine, which is well tolerated with helpful mood-stabilizing effects, and levetiracetam, which attenuates cognitive decline in dementia but may cause side effects such as irritable mood. Zonisamide is showing promise in patients with parkinsonian syndromes, she said, and it may be helpful to maximize drugs that patients are already taking such as gabapentin or pregabalin.
Finally, Dr. O’Dwyer urged colleagues to work in teams that include caregivers, primary care doctors, social workers, and pharmacists. “Sometimes in all this,” she said, “my job is the easiest.”
Dr. O’Dwyer discloses research support from the Shapiro Foundation.
FROM AES 2021
Don’t panic over lamotrigine, but beware of cardiac risks
New York University neurologist Jacqueline A. French, MD, told colleagues at the annual meeting of the American Epilepsy Society. But it’s now crucial to take special precautions in high-risk groups such as older people and heart patients.
“We need to plan more carefully when we use it, which we hate to do, as we know. But we’ve still got to do it,” said Dr. French, former president of the AES. “The risks are very small, but keep in mind that they’re not zero.”
In October 2020, the Food and Drug Administration added a warning to the lamotrigine label that said the drug “could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in patients with structural heart disease or myocardial ischemia.”
The FDA recommended avoiding the sodium channel blocker’s use “in patients who have cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies). Concomitant use of other sodium channel blockers may increase the risk of proarrhythmia.”
Later, in March 2021, the FDA announced that a review of in vitro findings “showed a potential increased risk of heart rhythm problems.”
As Dr. French noted, lamotrigine remains widely prescribed even though there’s “no pharmaceutical company out there pushing [it].” It’s an especially beneficial drug for certain groups such as the elderly and women of child-bearing age, she said.
But older people are also at higher risk of drug-related heart complications because of the fact that many already have cardiac disease, Dr. French said. She highlighted a 2005 trial of lamotrigine that found 48% of 593 patients aged 60 years and older had cardiac disease.
Special precautions
So what should neurologists know about prescribing lamotrigine in light of the new warning? Dr. French recommended guidelines that she cowrote with the AES and International League Against Epilepsy.
- Prescribe as normal in patients under 60 with no cardiac risk factors. In patients older than 60, or younger with risk factors, consider an EKG before prescribing lamotrigine.
- “Nonspecific EKG abnormalities (e.g., nonspecific ST and T wave abnormalities) are not concerning, and should not preclude these individuals from being prescribed lamotrigine.”
- Beware of higher risk and consider consulting a cardiologist before starting treatment in patients with second- or third-degree heart block, Brugada syndrome, arrhythmogenic ventricular cardiomyopathy, left bundle branch block, and right bundle branch block with left anterior or posterior fascicular block.
- “In most cases the initial EKG can be obtained while titrating, mainly when the individual is at the first dose of 25 mg/day because lamotrigine must be titrated slowly, and because cardiac adverse events are dose related.”
- “Clinicians should consider obtaining an EKG and/or cardiology consultation in people on lamotrigine with sudden-onset syncope or presyncope with loss of muscular tone without a clear vasovagal or orthostatic cause.”
Dr. French cautioned colleagues that they shouldn’t assume that lamotrigine stands alone among sodium channel blockers in terms of cardiac risk. As she noted, the FDA is asking manufacturers of other drugs in that class to provide data. “At some point, maybe sometime in the near future, we are going to hear in this particular in vitro sense how the other sodium channel blockers do stack up, compared with lamotrigine. At presence, in the absence of the availability of all of the rest of the data, it would be incorrect to presume that lamotrigine has more cardiac effects than other sodium channel blocking antiseizure medicines or all antiseizure medicines.”
For now, she said, although the guidelines are for lamotrigine, it’s “prudent” to follow them for all sodium channel blockers.
Dr. French reported no disclosures.
New York University neurologist Jacqueline A. French, MD, told colleagues at the annual meeting of the American Epilepsy Society. But it’s now crucial to take special precautions in high-risk groups such as older people and heart patients.
“We need to plan more carefully when we use it, which we hate to do, as we know. But we’ve still got to do it,” said Dr. French, former president of the AES. “The risks are very small, but keep in mind that they’re not zero.”
In October 2020, the Food and Drug Administration added a warning to the lamotrigine label that said the drug “could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in patients with structural heart disease or myocardial ischemia.”
The FDA recommended avoiding the sodium channel blocker’s use “in patients who have cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies). Concomitant use of other sodium channel blockers may increase the risk of proarrhythmia.”
Later, in March 2021, the FDA announced that a review of in vitro findings “showed a potential increased risk of heart rhythm problems.”
As Dr. French noted, lamotrigine remains widely prescribed even though there’s “no pharmaceutical company out there pushing [it].” It’s an especially beneficial drug for certain groups such as the elderly and women of child-bearing age, she said.
But older people are also at higher risk of drug-related heart complications because of the fact that many already have cardiac disease, Dr. French said. She highlighted a 2005 trial of lamotrigine that found 48% of 593 patients aged 60 years and older had cardiac disease.
Special precautions
So what should neurologists know about prescribing lamotrigine in light of the new warning? Dr. French recommended guidelines that she cowrote with the AES and International League Against Epilepsy.
- Prescribe as normal in patients under 60 with no cardiac risk factors. In patients older than 60, or younger with risk factors, consider an EKG before prescribing lamotrigine.
- “Nonspecific EKG abnormalities (e.g., nonspecific ST and T wave abnormalities) are not concerning, and should not preclude these individuals from being prescribed lamotrigine.”
- Beware of higher risk and consider consulting a cardiologist before starting treatment in patients with second- or third-degree heart block, Brugada syndrome, arrhythmogenic ventricular cardiomyopathy, left bundle branch block, and right bundle branch block with left anterior or posterior fascicular block.
- “In most cases the initial EKG can be obtained while titrating, mainly when the individual is at the first dose of 25 mg/day because lamotrigine must be titrated slowly, and because cardiac adverse events are dose related.”
- “Clinicians should consider obtaining an EKG and/or cardiology consultation in people on lamotrigine with sudden-onset syncope or presyncope with loss of muscular tone without a clear vasovagal or orthostatic cause.”
Dr. French cautioned colleagues that they shouldn’t assume that lamotrigine stands alone among sodium channel blockers in terms of cardiac risk. As she noted, the FDA is asking manufacturers of other drugs in that class to provide data. “At some point, maybe sometime in the near future, we are going to hear in this particular in vitro sense how the other sodium channel blockers do stack up, compared with lamotrigine. At presence, in the absence of the availability of all of the rest of the data, it would be incorrect to presume that lamotrigine has more cardiac effects than other sodium channel blocking antiseizure medicines or all antiseizure medicines.”
For now, she said, although the guidelines are for lamotrigine, it’s “prudent” to follow them for all sodium channel blockers.
Dr. French reported no disclosures.
New York University neurologist Jacqueline A. French, MD, told colleagues at the annual meeting of the American Epilepsy Society. But it’s now crucial to take special precautions in high-risk groups such as older people and heart patients.
“We need to plan more carefully when we use it, which we hate to do, as we know. But we’ve still got to do it,” said Dr. French, former president of the AES. “The risks are very small, but keep in mind that they’re not zero.”
In October 2020, the Food and Drug Administration added a warning to the lamotrigine label that said the drug “could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in patients with structural heart disease or myocardial ischemia.”
The FDA recommended avoiding the sodium channel blocker’s use “in patients who have cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies). Concomitant use of other sodium channel blockers may increase the risk of proarrhythmia.”
Later, in March 2021, the FDA announced that a review of in vitro findings “showed a potential increased risk of heart rhythm problems.”
As Dr. French noted, lamotrigine remains widely prescribed even though there’s “no pharmaceutical company out there pushing [it].” It’s an especially beneficial drug for certain groups such as the elderly and women of child-bearing age, she said.
But older people are also at higher risk of drug-related heart complications because of the fact that many already have cardiac disease, Dr. French said. She highlighted a 2005 trial of lamotrigine that found 48% of 593 patients aged 60 years and older had cardiac disease.
Special precautions
So what should neurologists know about prescribing lamotrigine in light of the new warning? Dr. French recommended guidelines that she cowrote with the AES and International League Against Epilepsy.
- Prescribe as normal in patients under 60 with no cardiac risk factors. In patients older than 60, or younger with risk factors, consider an EKG before prescribing lamotrigine.
- “Nonspecific EKG abnormalities (e.g., nonspecific ST and T wave abnormalities) are not concerning, and should not preclude these individuals from being prescribed lamotrigine.”
- Beware of higher risk and consider consulting a cardiologist before starting treatment in patients with second- or third-degree heart block, Brugada syndrome, arrhythmogenic ventricular cardiomyopathy, left bundle branch block, and right bundle branch block with left anterior or posterior fascicular block.
- “In most cases the initial EKG can be obtained while titrating, mainly when the individual is at the first dose of 25 mg/day because lamotrigine must be titrated slowly, and because cardiac adverse events are dose related.”
- “Clinicians should consider obtaining an EKG and/or cardiology consultation in people on lamotrigine with sudden-onset syncope or presyncope with loss of muscular tone without a clear vasovagal or orthostatic cause.”
Dr. French cautioned colleagues that they shouldn’t assume that lamotrigine stands alone among sodium channel blockers in terms of cardiac risk. As she noted, the FDA is asking manufacturers of other drugs in that class to provide data. “At some point, maybe sometime in the near future, we are going to hear in this particular in vitro sense how the other sodium channel blockers do stack up, compared with lamotrigine. At presence, in the absence of the availability of all of the rest of the data, it would be incorrect to presume that lamotrigine has more cardiac effects than other sodium channel blocking antiseizure medicines or all antiseizure medicines.”
For now, she said, although the guidelines are for lamotrigine, it’s “prudent” to follow them for all sodium channel blockers.
Dr. French reported no disclosures.
FROM AES 2021
Genetic tests prompt therapy adjustments in children with epilepsy
Physicians at a Boston hospital adjusted medical management for nearly three-quarters of patients with infantile- or childhood-onset epilepsy who were diagnosed with genetic epilepsy, researchers reported at the annual meeting of the American Epilepsy Society. The findings provide new insight into the usefulness of genetic tests in children with epilepsy of unknown cause.
“. Genetic testing should be included as part of the standard evaluation of individuals with unexplained pediatric epilepsy as a means of achieving diagnostic precision and informing clinical management,” study lead author Isabel Haviland, MD, a neurologist with Boston Children’s Hospital/Harvard Medical School, said in an interview.
According to Dr. Haviland, the causes of epilepsy are unexplained in an estimated two-thirds of pediatric epilepsy cases. “Increasingly, when genetic testing is available, previously unexplained cases of pediatric epilepsy are being found to have single-gene etiologies,” she said. “Though a genetic diagnosis in this population has implications for medical care, the direct impact on medical management in a clinical setting has not been measured. We aimed to describe the impact of genetic diagnosis on medical management in a cohort of individuals with pediatric epilepsy.”
Researchers tracked 602 patients at Boston Children’s Hospital who received next-generation gene sequencing testing from 2012 to 2019. Of those, Dr. Haviland said, 152 (25%) had a positive result that indicated genetic epilepsy (46% female, median age of onset = 6 months [2-15 months]). These patients were included in the study.
“We documented an impact on medical management in nearly three-fourths of participants (72%),” Dr. Haviland said. “A genetic diagnosis affected at least one of four categories of medical management, including care coordination (48%), treatment (45%), counseling about a change in prognosis (28%), and change in diagnosis for a few individuals who had a prior established diagnosis (1%).”
As examples, she mentioned three cases:
- Testing revealed that a subject has a disease-causing genetic variant in a gene called PRRT2. “This gene is involved in the release of neurotransmitters in the brain,” Dr. Haviland said. “Thanks to his diagnosis, he was treated with the antiseizure medication oxcarbazepine, which is often effective for epilepsy caused by variants in this gene. He had excellent response to the medication and later became seizure free.”
- A subject had a variation in the SCN1A gene that causes types of epilepsy. “At the time of his diagnosis, there was a trial for a medication called fenfluramine being offered for individuals with SCN1A variants, and his family elected to participate,” she said. “This medication was later approved by the [Food and Drug Administration] for SCN1A-related epilepsy.”
- Testing identified disease-causing variant in the GRIN2A gene in another subject. “This gene is involved in brain cell communication,” Dr. Haviland said. “This individual was treated with memantine, which acts on the specific biological pathway affected by the gene. This treatment would not have been considered without the genetic diagnosis as it is currently only approved for Alzheimer’s disease.”
In addition, Dr. Haviland said, researchers found that “there was impact on medical management both in those with earlier age of epilepsy onset (under 2 years) and those with later age of onset, as well as both in those with developmental disorders (such as autism spectrum disorder, intellectual disability and developmental delay) and those with normal development.
As for the cost of genetic tests, Dr. Haviland pointed to a 2019 study that she said estimated epilepsy panel testing runs from $1,500 to $7,500, and the whole exome sequencing from $4,500 to $7,000. “Insurers sometimes cover testing, but not always,” she said. “In some cases, insurance will only cover testing if it is documented that results will directly alter medical management, which highlights the importance of our findings.”
No study funding was reported. Dr. Haviland and several other authors report no disclosures. One author reports consulting fees from Takeda, Zogenix, Marinus, and FOXG1 Research Foundation. Another author reports research support from the International Foundation for CDKL5 Research.
Physicians at a Boston hospital adjusted medical management for nearly three-quarters of patients with infantile- or childhood-onset epilepsy who were diagnosed with genetic epilepsy, researchers reported at the annual meeting of the American Epilepsy Society. The findings provide new insight into the usefulness of genetic tests in children with epilepsy of unknown cause.
“. Genetic testing should be included as part of the standard evaluation of individuals with unexplained pediatric epilepsy as a means of achieving diagnostic precision and informing clinical management,” study lead author Isabel Haviland, MD, a neurologist with Boston Children’s Hospital/Harvard Medical School, said in an interview.
According to Dr. Haviland, the causes of epilepsy are unexplained in an estimated two-thirds of pediatric epilepsy cases. “Increasingly, when genetic testing is available, previously unexplained cases of pediatric epilepsy are being found to have single-gene etiologies,” she said. “Though a genetic diagnosis in this population has implications for medical care, the direct impact on medical management in a clinical setting has not been measured. We aimed to describe the impact of genetic diagnosis on medical management in a cohort of individuals with pediatric epilepsy.”
Researchers tracked 602 patients at Boston Children’s Hospital who received next-generation gene sequencing testing from 2012 to 2019. Of those, Dr. Haviland said, 152 (25%) had a positive result that indicated genetic epilepsy (46% female, median age of onset = 6 months [2-15 months]). These patients were included in the study.
“We documented an impact on medical management in nearly three-fourths of participants (72%),” Dr. Haviland said. “A genetic diagnosis affected at least one of four categories of medical management, including care coordination (48%), treatment (45%), counseling about a change in prognosis (28%), and change in diagnosis for a few individuals who had a prior established diagnosis (1%).”
As examples, she mentioned three cases:
- Testing revealed that a subject has a disease-causing genetic variant in a gene called PRRT2. “This gene is involved in the release of neurotransmitters in the brain,” Dr. Haviland said. “Thanks to his diagnosis, he was treated with the antiseizure medication oxcarbazepine, which is often effective for epilepsy caused by variants in this gene. He had excellent response to the medication and later became seizure free.”
- A subject had a variation in the SCN1A gene that causes types of epilepsy. “At the time of his diagnosis, there was a trial for a medication called fenfluramine being offered for individuals with SCN1A variants, and his family elected to participate,” she said. “This medication was later approved by the [Food and Drug Administration] for SCN1A-related epilepsy.”
- Testing identified disease-causing variant in the GRIN2A gene in another subject. “This gene is involved in brain cell communication,” Dr. Haviland said. “This individual was treated with memantine, which acts on the specific biological pathway affected by the gene. This treatment would not have been considered without the genetic diagnosis as it is currently only approved for Alzheimer’s disease.”
In addition, Dr. Haviland said, researchers found that “there was impact on medical management both in those with earlier age of epilepsy onset (under 2 years) and those with later age of onset, as well as both in those with developmental disorders (such as autism spectrum disorder, intellectual disability and developmental delay) and those with normal development.
As for the cost of genetic tests, Dr. Haviland pointed to a 2019 study that she said estimated epilepsy panel testing runs from $1,500 to $7,500, and the whole exome sequencing from $4,500 to $7,000. “Insurers sometimes cover testing, but not always,” she said. “In some cases, insurance will only cover testing if it is documented that results will directly alter medical management, which highlights the importance of our findings.”
No study funding was reported. Dr. Haviland and several other authors report no disclosures. One author reports consulting fees from Takeda, Zogenix, Marinus, and FOXG1 Research Foundation. Another author reports research support from the International Foundation for CDKL5 Research.
Physicians at a Boston hospital adjusted medical management for nearly three-quarters of patients with infantile- or childhood-onset epilepsy who were diagnosed with genetic epilepsy, researchers reported at the annual meeting of the American Epilepsy Society. The findings provide new insight into the usefulness of genetic tests in children with epilepsy of unknown cause.
“. Genetic testing should be included as part of the standard evaluation of individuals with unexplained pediatric epilepsy as a means of achieving diagnostic precision and informing clinical management,” study lead author Isabel Haviland, MD, a neurologist with Boston Children’s Hospital/Harvard Medical School, said in an interview.
According to Dr. Haviland, the causes of epilepsy are unexplained in an estimated two-thirds of pediatric epilepsy cases. “Increasingly, when genetic testing is available, previously unexplained cases of pediatric epilepsy are being found to have single-gene etiologies,” she said. “Though a genetic diagnosis in this population has implications for medical care, the direct impact on medical management in a clinical setting has not been measured. We aimed to describe the impact of genetic diagnosis on medical management in a cohort of individuals with pediatric epilepsy.”
Researchers tracked 602 patients at Boston Children’s Hospital who received next-generation gene sequencing testing from 2012 to 2019. Of those, Dr. Haviland said, 152 (25%) had a positive result that indicated genetic epilepsy (46% female, median age of onset = 6 months [2-15 months]). These patients were included in the study.
“We documented an impact on medical management in nearly three-fourths of participants (72%),” Dr. Haviland said. “A genetic diagnosis affected at least one of four categories of medical management, including care coordination (48%), treatment (45%), counseling about a change in prognosis (28%), and change in diagnosis for a few individuals who had a prior established diagnosis (1%).”
As examples, she mentioned three cases:
- Testing revealed that a subject has a disease-causing genetic variant in a gene called PRRT2. “This gene is involved in the release of neurotransmitters in the brain,” Dr. Haviland said. “Thanks to his diagnosis, he was treated with the antiseizure medication oxcarbazepine, which is often effective for epilepsy caused by variants in this gene. He had excellent response to the medication and later became seizure free.”
- A subject had a variation in the SCN1A gene that causes types of epilepsy. “At the time of his diagnosis, there was a trial for a medication called fenfluramine being offered for individuals with SCN1A variants, and his family elected to participate,” she said. “This medication was later approved by the [Food and Drug Administration] for SCN1A-related epilepsy.”
- Testing identified disease-causing variant in the GRIN2A gene in another subject. “This gene is involved in brain cell communication,” Dr. Haviland said. “This individual was treated with memantine, which acts on the specific biological pathway affected by the gene. This treatment would not have been considered without the genetic diagnosis as it is currently only approved for Alzheimer’s disease.”
In addition, Dr. Haviland said, researchers found that “there was impact on medical management both in those with earlier age of epilepsy onset (under 2 years) and those with later age of onset, as well as both in those with developmental disorders (such as autism spectrum disorder, intellectual disability and developmental delay) and those with normal development.
As for the cost of genetic tests, Dr. Haviland pointed to a 2019 study that she said estimated epilepsy panel testing runs from $1,500 to $7,500, and the whole exome sequencing from $4,500 to $7,000. “Insurers sometimes cover testing, but not always,” she said. “In some cases, insurance will only cover testing if it is documented that results will directly alter medical management, which highlights the importance of our findings.”
No study funding was reported. Dr. Haviland and several other authors report no disclosures. One author reports consulting fees from Takeda, Zogenix, Marinus, and FOXG1 Research Foundation. Another author reports research support from the International Foundation for CDKL5 Research.
FROM AES 2021
COVID-19 hospital data: New-onset seizures more common than breakthrough seizures
An analysis of hospitalized patients with COVID-19 finds that those with no history of epilepsy had more than 3 times the odds of suffering a new-onset seizure than patients with epilepsy were to have breakthrough seizures (odds radio [OR] 3.15, P < .0001), researchers reported at the annual meeting of the American Epilepsy Society.
study lead author Neeraj Singh, MD, a neurologist at the New York-based Northwell Health system, said in an interview. “That’s new. We don’t normally see that when someone has a bacterial or viral infection. It’s demonstrating that this infection is having direct effect on the brain and brain signals.”
According to Dr. Singh, there’s little data about seizures in patients with COVID-19 because doctors have focused on other symptoms. A 2021 multicenter study found that electrographic seizures were detected in 9.6% of 197 patients with COVID-19 who were referred for cEEG.
For the new study, Dr. Singh and a colleague tracked 917 patients with COVID-19 in the Northwell Health system who were treated from Feb. 14 to June 14, 2020, with antiepileptic medication. Of the patients, 451 had a history of epilepsy, and 466 did not.
According to Dr. Singh, 27.6% of the patients without a history of epilepsy had new-onset seizures, while 10.1% of the patients with history of epilepsy had breakthrough seizures. The difference in odds was more than threefold after adjustment. (Among all COVID-19 patients, he said, perhaps 8%-16% had seizures).
The researchers also found that patients with new-onset seizures stayed in the hospital much longer (average, 26.9 days) than any patients with a known history of epilepsy (12.8 days, P < .0001, for those who had breakthrough seizures and 10.9 days, P < .0001, for those who didn’t).
In addition, the researchers found that having any seizures – new-onset or breakthrough – was linked to higher risk of death (OR 1.41, P = .03).
Antiseizure medications are key treatments for these patients, Dr. Singh said. As for the patients with new-onset seizures who recover from COVID-19, Dr. Singh said, “it’s suspected that these people are going to have a new diagnosis of epilepsy, not just a one-time seizure.”
The findings suggest that some patients with epilepsy are protected against COVID-19-related seizures because they take antiepileptic medications that “protect the brain from getting a trigger for an abnormal signal that leads to a seizure,” he said. “That’s one possibility.”
What can neurologists learn from the study? Dr. Singh recommends a “lower threshold” to recommend or approve EEGs in patients with COVID-19 who are confused/altered when they come in, especially if this is not normal. “They may actually be having silent seizures that no one’s noticing,” he said.
No study funding was reported. The authors reported no relevant disclosures.
An analysis of hospitalized patients with COVID-19 finds that those with no history of epilepsy had more than 3 times the odds of suffering a new-onset seizure than patients with epilepsy were to have breakthrough seizures (odds radio [OR] 3.15, P < .0001), researchers reported at the annual meeting of the American Epilepsy Society.
study lead author Neeraj Singh, MD, a neurologist at the New York-based Northwell Health system, said in an interview. “That’s new. We don’t normally see that when someone has a bacterial or viral infection. It’s demonstrating that this infection is having direct effect on the brain and brain signals.”
According to Dr. Singh, there’s little data about seizures in patients with COVID-19 because doctors have focused on other symptoms. A 2021 multicenter study found that electrographic seizures were detected in 9.6% of 197 patients with COVID-19 who were referred for cEEG.
For the new study, Dr. Singh and a colleague tracked 917 patients with COVID-19 in the Northwell Health system who were treated from Feb. 14 to June 14, 2020, with antiepileptic medication. Of the patients, 451 had a history of epilepsy, and 466 did not.
According to Dr. Singh, 27.6% of the patients without a history of epilepsy had new-onset seizures, while 10.1% of the patients with history of epilepsy had breakthrough seizures. The difference in odds was more than threefold after adjustment. (Among all COVID-19 patients, he said, perhaps 8%-16% had seizures).
The researchers also found that patients with new-onset seizures stayed in the hospital much longer (average, 26.9 days) than any patients with a known history of epilepsy (12.8 days, P < .0001, for those who had breakthrough seizures and 10.9 days, P < .0001, for those who didn’t).
In addition, the researchers found that having any seizures – new-onset or breakthrough – was linked to higher risk of death (OR 1.41, P = .03).
Antiseizure medications are key treatments for these patients, Dr. Singh said. As for the patients with new-onset seizures who recover from COVID-19, Dr. Singh said, “it’s suspected that these people are going to have a new diagnosis of epilepsy, not just a one-time seizure.”
The findings suggest that some patients with epilepsy are protected against COVID-19-related seizures because they take antiepileptic medications that “protect the brain from getting a trigger for an abnormal signal that leads to a seizure,” he said. “That’s one possibility.”
What can neurologists learn from the study? Dr. Singh recommends a “lower threshold” to recommend or approve EEGs in patients with COVID-19 who are confused/altered when they come in, especially if this is not normal. “They may actually be having silent seizures that no one’s noticing,” he said.
No study funding was reported. The authors reported no relevant disclosures.
An analysis of hospitalized patients with COVID-19 finds that those with no history of epilepsy had more than 3 times the odds of suffering a new-onset seizure than patients with epilepsy were to have breakthrough seizures (odds radio [OR] 3.15, P < .0001), researchers reported at the annual meeting of the American Epilepsy Society.
study lead author Neeraj Singh, MD, a neurologist at the New York-based Northwell Health system, said in an interview. “That’s new. We don’t normally see that when someone has a bacterial or viral infection. It’s demonstrating that this infection is having direct effect on the brain and brain signals.”
According to Dr. Singh, there’s little data about seizures in patients with COVID-19 because doctors have focused on other symptoms. A 2021 multicenter study found that electrographic seizures were detected in 9.6% of 197 patients with COVID-19 who were referred for cEEG.
For the new study, Dr. Singh and a colleague tracked 917 patients with COVID-19 in the Northwell Health system who were treated from Feb. 14 to June 14, 2020, with antiepileptic medication. Of the patients, 451 had a history of epilepsy, and 466 did not.
According to Dr. Singh, 27.6% of the patients without a history of epilepsy had new-onset seizures, while 10.1% of the patients with history of epilepsy had breakthrough seizures. The difference in odds was more than threefold after adjustment. (Among all COVID-19 patients, he said, perhaps 8%-16% had seizures).
The researchers also found that patients with new-onset seizures stayed in the hospital much longer (average, 26.9 days) than any patients with a known history of epilepsy (12.8 days, P < .0001, for those who had breakthrough seizures and 10.9 days, P < .0001, for those who didn’t).
In addition, the researchers found that having any seizures – new-onset or breakthrough – was linked to higher risk of death (OR 1.41, P = .03).
Antiseizure medications are key treatments for these patients, Dr. Singh said. As for the patients with new-onset seizures who recover from COVID-19, Dr. Singh said, “it’s suspected that these people are going to have a new diagnosis of epilepsy, not just a one-time seizure.”
The findings suggest that some patients with epilepsy are protected against COVID-19-related seizures because they take antiepileptic medications that “protect the brain from getting a trigger for an abnormal signal that leads to a seizure,” he said. “That’s one possibility.”
What can neurologists learn from the study? Dr. Singh recommends a “lower threshold” to recommend or approve EEGs in patients with COVID-19 who are confused/altered when they come in, especially if this is not normal. “They may actually be having silent seizures that no one’s noticing,” he said.
No study funding was reported. The authors reported no relevant disclosures.
FROM AES 2021
Epilepsy linked to 1.5-fold higher COVID-19 mortality in hospital
according to a new study presented at the annual meeting of the American Epilepsy Society. While the findings are preliminary and not yet adjusted for various confounders, the authors say they are a warning sign that patients with epilepsy may face higher risks.
“These findings suggest that epilepsy may be a pre-existing condition that places patients at increased risk for death if hospitalized with a COVID-19 infection. It may offer neurologists guidance when counseling patients on critical preventative measures such as masking, social distancing, and most importantly, vaccination,” lead author Claire Ufongene, a student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.
According to Ms. Ufongene, there’s sparse data about COVID-19 outcomes in patients with epilepsy, although she highlighted a 2021 meta-analysis of 13 studies that found a higher risk of severity (odds ratio, 1.69; 95% confidence interval, 1.11-2.59, P = .010) and mortality (OR, 1.71; 95% CI, 1.14-2.56, P = .010).
For the new study, researchers retrospectively tracked identified 334 patients with epilepsy and COVID-19 and 9,499 other patients with COVID-19 from March 15, 2020, to May 17, 2021. All were treated at hospitals within the New York–based Icahn School of Medicine at Mount Sinai.
The groups of patients with and without epilepsy were similar in some ways: 45% and 46%, respectively, were female (P = .674), and their ages were similar (average, 62 years and 65 years, respectively; P = .02). Racial makeup was also similar (non-Hispanic groups made up 27.8% of those with epilepsy and 24.5% of those without; the difference was not statistically significant).
“In addition, more of those with epilepsy were English speaking [83.2% vs. 77.9%] and had Medicaid insurance [50.9% vs. 38.9%], while fewer of those with epilepsy had private insurance [16.2% vs. 25.5%] or were Spanish speaking [14.0% vs. 9.3%],” study coauthor Nathalie Jette, MD, MSc, a neurologist at Icahn School of Medicine at Mount Sinai, said in an interview.
In terms of outcomes, patients with epilepsy were much more likely to need ventilator support (37.7% vs. 14.3%; P < .001), to be admitted to the ICU (39.2% vs. 17.7%; P < .001), and to die in the hospital (29.6% vs. 19.9%; P < .001).
“Most patients we follow in our practices with epilepsy who experienced COVID-19 in general have had symptoms similar to the general population,” Dr. Jette said. “There are rare instances where COVID-19 can result in an exacerbation of seizures in some with pre-existing epilepsy. This is not surprising as infections in particular can decrease the seizure threshold and result in breakthrough seizures in people living with epilepsy.”
Loss of seizure control
How might epilepsy be related to worse outcomes in COVID-19? Andrew Wilner, MD, a neurologist and internist at University of Tennessee Health Science Center, Memphis, who’s familiar with the study findings, said COVID-19 itself may not worsen epilepsy. “Evidence to suggest that COVID-19 directly affects the central nervous system is extremely limited. As such, one would not expect that a COVID-19 infection would cause epilepsy or exacerbate epilepsy,” he said. “However, patients with epilepsy who suffer from infections may be predisposed to decreased seizure control. Consequently, it would not be surprising if patients with epilepsy who also had COVID-19 had loss of seizure control and even status epilepticus, which could adversely affect their hospital course. However, there are no data on this potential phenomenon.”
Dr. Wilner suspected that comorbidities explain the higher mortality in patients with epilepsy. “The findings are probably most useful in that they call attention to the fact that epilepsy patients are more vulnerable to a host of comorbidities and resultant poorer outcomes due to any acute illness.”
As for treatment, Dr. Wilner urged colleagues to make sure that hospitalized patients with epilepsy “continue to receive their antiepileptic medications, which they may no longer be able to take orally. They may need to be switched temporarily to an intravenous formulation.”
In an interview, Selim Benbadis, MD, a neurologist from the University of South Florida, Tampa, suggested that antiseizure medications may play a role in the COVID-19 disease course because they can reduce the efficacy of other medications, although he noted that drug treatments for COVID-19 were limited early on. He recommended that neurologists “avoid old enzyme-inducing seizure medications, as is generally recommended.”
No study funding is reported. The study authors and Dr. Benbadis reported no relevant disclosures. Dr. Wilner is a medical adviser for the epilepsy disease management program for CVS/Health.
according to a new study presented at the annual meeting of the American Epilepsy Society. While the findings are preliminary and not yet adjusted for various confounders, the authors say they are a warning sign that patients with epilepsy may face higher risks.
“These findings suggest that epilepsy may be a pre-existing condition that places patients at increased risk for death if hospitalized with a COVID-19 infection. It may offer neurologists guidance when counseling patients on critical preventative measures such as masking, social distancing, and most importantly, vaccination,” lead author Claire Ufongene, a student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.
According to Ms. Ufongene, there’s sparse data about COVID-19 outcomes in patients with epilepsy, although she highlighted a 2021 meta-analysis of 13 studies that found a higher risk of severity (odds ratio, 1.69; 95% confidence interval, 1.11-2.59, P = .010) and mortality (OR, 1.71; 95% CI, 1.14-2.56, P = .010).
For the new study, researchers retrospectively tracked identified 334 patients with epilepsy and COVID-19 and 9,499 other patients with COVID-19 from March 15, 2020, to May 17, 2021. All were treated at hospitals within the New York–based Icahn School of Medicine at Mount Sinai.
The groups of patients with and without epilepsy were similar in some ways: 45% and 46%, respectively, were female (P = .674), and their ages were similar (average, 62 years and 65 years, respectively; P = .02). Racial makeup was also similar (non-Hispanic groups made up 27.8% of those with epilepsy and 24.5% of those without; the difference was not statistically significant).
“In addition, more of those with epilepsy were English speaking [83.2% vs. 77.9%] and had Medicaid insurance [50.9% vs. 38.9%], while fewer of those with epilepsy had private insurance [16.2% vs. 25.5%] or were Spanish speaking [14.0% vs. 9.3%],” study coauthor Nathalie Jette, MD, MSc, a neurologist at Icahn School of Medicine at Mount Sinai, said in an interview.
In terms of outcomes, patients with epilepsy were much more likely to need ventilator support (37.7% vs. 14.3%; P < .001), to be admitted to the ICU (39.2% vs. 17.7%; P < .001), and to die in the hospital (29.6% vs. 19.9%; P < .001).
“Most patients we follow in our practices with epilepsy who experienced COVID-19 in general have had symptoms similar to the general population,” Dr. Jette said. “There are rare instances where COVID-19 can result in an exacerbation of seizures in some with pre-existing epilepsy. This is not surprising as infections in particular can decrease the seizure threshold and result in breakthrough seizures in people living with epilepsy.”
Loss of seizure control
How might epilepsy be related to worse outcomes in COVID-19? Andrew Wilner, MD, a neurologist and internist at University of Tennessee Health Science Center, Memphis, who’s familiar with the study findings, said COVID-19 itself may not worsen epilepsy. “Evidence to suggest that COVID-19 directly affects the central nervous system is extremely limited. As such, one would not expect that a COVID-19 infection would cause epilepsy or exacerbate epilepsy,” he said. “However, patients with epilepsy who suffer from infections may be predisposed to decreased seizure control. Consequently, it would not be surprising if patients with epilepsy who also had COVID-19 had loss of seizure control and even status epilepticus, which could adversely affect their hospital course. However, there are no data on this potential phenomenon.”
Dr. Wilner suspected that comorbidities explain the higher mortality in patients with epilepsy. “The findings are probably most useful in that they call attention to the fact that epilepsy patients are more vulnerable to a host of comorbidities and resultant poorer outcomes due to any acute illness.”
As for treatment, Dr. Wilner urged colleagues to make sure that hospitalized patients with epilepsy “continue to receive their antiepileptic medications, which they may no longer be able to take orally. They may need to be switched temporarily to an intravenous formulation.”
In an interview, Selim Benbadis, MD, a neurologist from the University of South Florida, Tampa, suggested that antiseizure medications may play a role in the COVID-19 disease course because they can reduce the efficacy of other medications, although he noted that drug treatments for COVID-19 were limited early on. He recommended that neurologists “avoid old enzyme-inducing seizure medications, as is generally recommended.”
No study funding is reported. The study authors and Dr. Benbadis reported no relevant disclosures. Dr. Wilner is a medical adviser for the epilepsy disease management program for CVS/Health.
according to a new study presented at the annual meeting of the American Epilepsy Society. While the findings are preliminary and not yet adjusted for various confounders, the authors say they are a warning sign that patients with epilepsy may face higher risks.
“These findings suggest that epilepsy may be a pre-existing condition that places patients at increased risk for death if hospitalized with a COVID-19 infection. It may offer neurologists guidance when counseling patients on critical preventative measures such as masking, social distancing, and most importantly, vaccination,” lead author Claire Ufongene, a student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.
According to Ms. Ufongene, there’s sparse data about COVID-19 outcomes in patients with epilepsy, although she highlighted a 2021 meta-analysis of 13 studies that found a higher risk of severity (odds ratio, 1.69; 95% confidence interval, 1.11-2.59, P = .010) and mortality (OR, 1.71; 95% CI, 1.14-2.56, P = .010).
For the new study, researchers retrospectively tracked identified 334 patients with epilepsy and COVID-19 and 9,499 other patients with COVID-19 from March 15, 2020, to May 17, 2021. All were treated at hospitals within the New York–based Icahn School of Medicine at Mount Sinai.
The groups of patients with and without epilepsy were similar in some ways: 45% and 46%, respectively, were female (P = .674), and their ages were similar (average, 62 years and 65 years, respectively; P = .02). Racial makeup was also similar (non-Hispanic groups made up 27.8% of those with epilepsy and 24.5% of those without; the difference was not statistically significant).
“In addition, more of those with epilepsy were English speaking [83.2% vs. 77.9%] and had Medicaid insurance [50.9% vs. 38.9%], while fewer of those with epilepsy had private insurance [16.2% vs. 25.5%] or were Spanish speaking [14.0% vs. 9.3%],” study coauthor Nathalie Jette, MD, MSc, a neurologist at Icahn School of Medicine at Mount Sinai, said in an interview.
In terms of outcomes, patients with epilepsy were much more likely to need ventilator support (37.7% vs. 14.3%; P < .001), to be admitted to the ICU (39.2% vs. 17.7%; P < .001), and to die in the hospital (29.6% vs. 19.9%; P < .001).
“Most patients we follow in our practices with epilepsy who experienced COVID-19 in general have had symptoms similar to the general population,” Dr. Jette said. “There are rare instances where COVID-19 can result in an exacerbation of seizures in some with pre-existing epilepsy. This is not surprising as infections in particular can decrease the seizure threshold and result in breakthrough seizures in people living with epilepsy.”
Loss of seizure control
How might epilepsy be related to worse outcomes in COVID-19? Andrew Wilner, MD, a neurologist and internist at University of Tennessee Health Science Center, Memphis, who’s familiar with the study findings, said COVID-19 itself may not worsen epilepsy. “Evidence to suggest that COVID-19 directly affects the central nervous system is extremely limited. As such, one would not expect that a COVID-19 infection would cause epilepsy or exacerbate epilepsy,” he said. “However, patients with epilepsy who suffer from infections may be predisposed to decreased seizure control. Consequently, it would not be surprising if patients with epilepsy who also had COVID-19 had loss of seizure control and even status epilepticus, which could adversely affect their hospital course. However, there are no data on this potential phenomenon.”
Dr. Wilner suspected that comorbidities explain the higher mortality in patients with epilepsy. “The findings are probably most useful in that they call attention to the fact that epilepsy patients are more vulnerable to a host of comorbidities and resultant poorer outcomes due to any acute illness.”
As for treatment, Dr. Wilner urged colleagues to make sure that hospitalized patients with epilepsy “continue to receive their antiepileptic medications, which they may no longer be able to take orally. They may need to be switched temporarily to an intravenous formulation.”
In an interview, Selim Benbadis, MD, a neurologist from the University of South Florida, Tampa, suggested that antiseizure medications may play a role in the COVID-19 disease course because they can reduce the efficacy of other medications, although he noted that drug treatments for COVID-19 were limited early on. He recommended that neurologists “avoid old enzyme-inducing seizure medications, as is generally recommended.”
No study funding is reported. The study authors and Dr. Benbadis reported no relevant disclosures. Dr. Wilner is a medical adviser for the epilepsy disease management program for CVS/Health.
FROM AES 2021
More brain aging observed in older patients with child-onset epilepsy
While the meaning of the findings aren’t entirely clear, new research offers insight into the aging brains of people who developed child-onset epilepsy: A cohort with an average age of 63 appears to be more likely than controls to show signs of brain deterioration, according to a study presented at the annual meeting of the American Epilepsy Society.
“,” lead author Matti Sillanpää, MD, PhD, a researcher and former child neurologist based at the University of Turko in Finland, said in an interview.
The study began 60 years ago when Finnish researchers started to track 99 subjects who were under 16 and had developed uncomplicated epilepsy. In 2012, 51 participants returned for assessments (9 of the original cohort had died, 2 didn’t speak Finnish as a mother tongue, and 15 had left the country or couldn’t be found).
In 2017, 41 participants agreed to take part in follow-up assessments (1 of the 2012 cohort could not be traced, and 9 declined to participate.)
Researchers launched the follow-up assessments to provide more insight into aging and epilepsy, Dr. Sillanpää said. “While we are in the early stages of understanding the brain and cognitive aging processes of people with epilepsy, there are enough worrisome signs from neuroimaging and cognitive studies to suggest that much more clinical and research attention is warranted. Especially important are population-based investigations that include persons with both remitted as well as active epilepsy in order to obtain a clearer understanding of the overall aging risks involved.”
The average age of the 41 subjects in the second assessment was 63.2 (4.1), and 58% were female. Just over half (52%) had focal epilepsy, and 48% had generalized epilepsy. In 74%, epilepsy had remitted, and it remained active in the rest (26%).
For the study, researchers compared the subjects with a control group of 46 subjects, 50% of whom were female, with an average age of 63.0 (4.13). The original control group had 99 participants, and 52 took part in 2012. Of those, 6 declined to participate in the 2017 assessments.
The researchers report these findings:
- Patients with active epilepsy were more likely to have neurologic signs than were those with remitted epilepsy (P = .015), especially the most common signs – cerebellar signs (P < .001). There was a trend toward cerebellar atrophy but it wasn’t statistically significant (P = .06).
- Patients with focal epilepsies were more likely to have neurologic signs (P = .008) and, specifically, cerebellar signs (P = .018) than were those with generalized epilepsies.
- The study authors calculated the lifetime usage of four drugs: carbamazepine, diphenylhydantoin, phenobarbital, and valproate. They found that patients with higher usage had more peripheral neuropathy, especially those with high levels of diphenylhydantoin, and phenobarbital usage.
- Overall, patients with epilepsy versus controls and those with active epilepsy versus remitting epilepsy were more likely to show adjusted declines in “cognitive trajectories” (both P < .05)
The researchers also estimated beta-amyloid levels via Pittsburgh Compound B positron emission tomography (PIB-PET); some specialists consider PIB-positive levels to be a sign of more beta amyloid.
From 2012 to 2017, the percentage of patients with epilepsy who were PIB positive grew from 22% to 33% (P = .03), while the percentage grew from 7% to 11% in the controls (P = .04). “The presence of amyloid and increasing positivity is cause for concern, and further research into the course of the participants is critical,” Dr. Sillanpää said.
It’s not clear if higher levels of brain aging are affecting the lives of participants, he said. “No one in the cohort has a diagnosed dementia at present, but going forward it will be important to pay close attention to the day-to-day functional status of participants.”
The mechanisms that may cause more brain aging in epilepsy aren’t known. However, “the CDC has shown through population-based investigations that people with epilepsy as a group may be more socially isolated, more physically inactive, and may harbor other lifestyle issues that we now know to be counterproductive to successful cognitive and brain aging in the general population,” Dr. Sillanpää said. “These factors need to be examined in depth in aging persons with epilepsy to gain a sound understanding of the risk and resilience factors that are most important so that people with epilepsy can act accordingly.”
The researchers also report that in patients with epilepsy, there’s evidence of a link between hypertension and hippocampal atrophy. They reported trends toward links between obesity and ischemic disease and between type 2 diabetes and hippocampal atrophy.
Going forward, “the findings may be helpful in the treatment and counseling of patients with epilepsy and especially advocating for those health and lifestyle practices that may be beneficial to long-term courses,” Dr. Sillanpää said. As for the study cohort, he said, researchers plan to continue monitoring them to track their long-term outcomes and any development of neurological disorders such as Alzheimer’s disease.
This work was funded by CURE Epilepsy, the National Governmental Research Grant, and the Pro Humanitate Foundation Grant. The study authors report no disclosures.
While the meaning of the findings aren’t entirely clear, new research offers insight into the aging brains of people who developed child-onset epilepsy: A cohort with an average age of 63 appears to be more likely than controls to show signs of brain deterioration, according to a study presented at the annual meeting of the American Epilepsy Society.
“,” lead author Matti Sillanpää, MD, PhD, a researcher and former child neurologist based at the University of Turko in Finland, said in an interview.
The study began 60 years ago when Finnish researchers started to track 99 subjects who were under 16 and had developed uncomplicated epilepsy. In 2012, 51 participants returned for assessments (9 of the original cohort had died, 2 didn’t speak Finnish as a mother tongue, and 15 had left the country or couldn’t be found).
In 2017, 41 participants agreed to take part in follow-up assessments (1 of the 2012 cohort could not be traced, and 9 declined to participate.)
Researchers launched the follow-up assessments to provide more insight into aging and epilepsy, Dr. Sillanpää said. “While we are in the early stages of understanding the brain and cognitive aging processes of people with epilepsy, there are enough worrisome signs from neuroimaging and cognitive studies to suggest that much more clinical and research attention is warranted. Especially important are population-based investigations that include persons with both remitted as well as active epilepsy in order to obtain a clearer understanding of the overall aging risks involved.”
The average age of the 41 subjects in the second assessment was 63.2 (4.1), and 58% were female. Just over half (52%) had focal epilepsy, and 48% had generalized epilepsy. In 74%, epilepsy had remitted, and it remained active in the rest (26%).
For the study, researchers compared the subjects with a control group of 46 subjects, 50% of whom were female, with an average age of 63.0 (4.13). The original control group had 99 participants, and 52 took part in 2012. Of those, 6 declined to participate in the 2017 assessments.
The researchers report these findings:
- Patients with active epilepsy were more likely to have neurologic signs than were those with remitted epilepsy (P = .015), especially the most common signs – cerebellar signs (P < .001). There was a trend toward cerebellar atrophy but it wasn’t statistically significant (P = .06).
- Patients with focal epilepsies were more likely to have neurologic signs (P = .008) and, specifically, cerebellar signs (P = .018) than were those with generalized epilepsies.
- The study authors calculated the lifetime usage of four drugs: carbamazepine, diphenylhydantoin, phenobarbital, and valproate. They found that patients with higher usage had more peripheral neuropathy, especially those with high levels of diphenylhydantoin, and phenobarbital usage.
- Overall, patients with epilepsy versus controls and those with active epilepsy versus remitting epilepsy were more likely to show adjusted declines in “cognitive trajectories” (both P < .05)
The researchers also estimated beta-amyloid levels via Pittsburgh Compound B positron emission tomography (PIB-PET); some specialists consider PIB-positive levels to be a sign of more beta amyloid.
From 2012 to 2017, the percentage of patients with epilepsy who were PIB positive grew from 22% to 33% (P = .03), while the percentage grew from 7% to 11% in the controls (P = .04). “The presence of amyloid and increasing positivity is cause for concern, and further research into the course of the participants is critical,” Dr. Sillanpää said.
It’s not clear if higher levels of brain aging are affecting the lives of participants, he said. “No one in the cohort has a diagnosed dementia at present, but going forward it will be important to pay close attention to the day-to-day functional status of participants.”
The mechanisms that may cause more brain aging in epilepsy aren’t known. However, “the CDC has shown through population-based investigations that people with epilepsy as a group may be more socially isolated, more physically inactive, and may harbor other lifestyle issues that we now know to be counterproductive to successful cognitive and brain aging in the general population,” Dr. Sillanpää said. “These factors need to be examined in depth in aging persons with epilepsy to gain a sound understanding of the risk and resilience factors that are most important so that people with epilepsy can act accordingly.”
The researchers also report that in patients with epilepsy, there’s evidence of a link between hypertension and hippocampal atrophy. They reported trends toward links between obesity and ischemic disease and between type 2 diabetes and hippocampal atrophy.
Going forward, “the findings may be helpful in the treatment and counseling of patients with epilepsy and especially advocating for those health and lifestyle practices that may be beneficial to long-term courses,” Dr. Sillanpää said. As for the study cohort, he said, researchers plan to continue monitoring them to track their long-term outcomes and any development of neurological disorders such as Alzheimer’s disease.
This work was funded by CURE Epilepsy, the National Governmental Research Grant, and the Pro Humanitate Foundation Grant. The study authors report no disclosures.
While the meaning of the findings aren’t entirely clear, new research offers insight into the aging brains of people who developed child-onset epilepsy: A cohort with an average age of 63 appears to be more likely than controls to show signs of brain deterioration, according to a study presented at the annual meeting of the American Epilepsy Society.
“,” lead author Matti Sillanpää, MD, PhD, a researcher and former child neurologist based at the University of Turko in Finland, said in an interview.
The study began 60 years ago when Finnish researchers started to track 99 subjects who were under 16 and had developed uncomplicated epilepsy. In 2012, 51 participants returned for assessments (9 of the original cohort had died, 2 didn’t speak Finnish as a mother tongue, and 15 had left the country or couldn’t be found).
In 2017, 41 participants agreed to take part in follow-up assessments (1 of the 2012 cohort could not be traced, and 9 declined to participate.)
Researchers launched the follow-up assessments to provide more insight into aging and epilepsy, Dr. Sillanpää said. “While we are in the early stages of understanding the brain and cognitive aging processes of people with epilepsy, there are enough worrisome signs from neuroimaging and cognitive studies to suggest that much more clinical and research attention is warranted. Especially important are population-based investigations that include persons with both remitted as well as active epilepsy in order to obtain a clearer understanding of the overall aging risks involved.”
The average age of the 41 subjects in the second assessment was 63.2 (4.1), and 58% were female. Just over half (52%) had focal epilepsy, and 48% had generalized epilepsy. In 74%, epilepsy had remitted, and it remained active in the rest (26%).
For the study, researchers compared the subjects with a control group of 46 subjects, 50% of whom were female, with an average age of 63.0 (4.13). The original control group had 99 participants, and 52 took part in 2012. Of those, 6 declined to participate in the 2017 assessments.
The researchers report these findings:
- Patients with active epilepsy were more likely to have neurologic signs than were those with remitted epilepsy (P = .015), especially the most common signs – cerebellar signs (P < .001). There was a trend toward cerebellar atrophy but it wasn’t statistically significant (P = .06).
- Patients with focal epilepsies were more likely to have neurologic signs (P = .008) and, specifically, cerebellar signs (P = .018) than were those with generalized epilepsies.
- The study authors calculated the lifetime usage of four drugs: carbamazepine, diphenylhydantoin, phenobarbital, and valproate. They found that patients with higher usage had more peripheral neuropathy, especially those with high levels of diphenylhydantoin, and phenobarbital usage.
- Overall, patients with epilepsy versus controls and those with active epilepsy versus remitting epilepsy were more likely to show adjusted declines in “cognitive trajectories” (both P < .05)
The researchers also estimated beta-amyloid levels via Pittsburgh Compound B positron emission tomography (PIB-PET); some specialists consider PIB-positive levels to be a sign of more beta amyloid.
From 2012 to 2017, the percentage of patients with epilepsy who were PIB positive grew from 22% to 33% (P = .03), while the percentage grew from 7% to 11% in the controls (P = .04). “The presence of amyloid and increasing positivity is cause for concern, and further research into the course of the participants is critical,” Dr. Sillanpää said.
It’s not clear if higher levels of brain aging are affecting the lives of participants, he said. “No one in the cohort has a diagnosed dementia at present, but going forward it will be important to pay close attention to the day-to-day functional status of participants.”
The mechanisms that may cause more brain aging in epilepsy aren’t known. However, “the CDC has shown through population-based investigations that people with epilepsy as a group may be more socially isolated, more physically inactive, and may harbor other lifestyle issues that we now know to be counterproductive to successful cognitive and brain aging in the general population,” Dr. Sillanpää said. “These factors need to be examined in depth in aging persons with epilepsy to gain a sound understanding of the risk and resilience factors that are most important so that people with epilepsy can act accordingly.”
The researchers also report that in patients with epilepsy, there’s evidence of a link between hypertension and hippocampal atrophy. They reported trends toward links between obesity and ischemic disease and between type 2 diabetes and hippocampal atrophy.
Going forward, “the findings may be helpful in the treatment and counseling of patients with epilepsy and especially advocating for those health and lifestyle practices that may be beneficial to long-term courses,” Dr. Sillanpää said. As for the study cohort, he said, researchers plan to continue monitoring them to track their long-term outcomes and any development of neurological disorders such as Alzheimer’s disease.
This work was funded by CURE Epilepsy, the National Governmental Research Grant, and the Pro Humanitate Foundation Grant. The study authors report no disclosures.
FROM AES 2021