TBD Meeting (3271-23)

ORLANDO — Experts shed light on the applications, benefits, and pitfalls of artificial intelligence (AI) during the Merrit-Putnam Symposium at the annual meeting of the American Epilepsy Society (AES).

In a session titled “Artificial Intelligence Fundamentals and Breakthrough Applications in Epilepsy,” University of Pittsburgh neurologist and assistant professor Wesley Kerr, MD, PhD, provided an overview of AI as well its applications in neurology. He began by addressing perhaps one of the most controversial topics regarding AI in the medical community: clinicians’ fear of being replaced by technology.

“Artificial intelligence will not replace clinicians, but clinicians assisted by artificial intelligence will replace clinicians without artificial intelligence,” he told the audience.
 

To Optimize AI, Clinicians Must Lay the Proper Foundation

Dr. Kerr’s presentation focused on providing audience members with tools to help them evaluate new technologies, recognize benefits, and identify key costs and limitations associated with AI implementation and integration into clinical practice.

Before delving deeper, one must first understand basic terminology regarding AI. Without this knowledge, clinicians may inadvertently introduce bias or errata or fail to understand how to best leverage the technology to enhance the quality of the practice while improving patient outcomes.

Machine learning (ML) describes the process of using data to learn a specific task. Deep learning (DL) stacks multiple layers of ML to improve performance on the task. Lastly, generative AI generates content such as text, images, and media.

Utilizing AI effectively in clinical applications involves tapping into select features most related to prediction (for example, disease factors) and grouping features into categories based on measuring commonalities such as factor composition in a population. This information should be used in training data only.

Fully understanding ML/AI allows clinicians to use it as a diagnostic test by exploiting a combination of accuracy, sensitivity, and specificity, along with positive and negative predictive values.
 

Data Fidelity and Integrity Hinge on Optimal Data Inputs

In the case of epilepsy, calibration curves can provide practical guidance in terms of predicting impending seizures.

“ML/AI needs gold-standard labels for evaluation,” Dr. Kerr said. He went on to stress the importance of quality data inputs to optimize the fidelity of AI’s predictive analytics.

“If you input garbage, you’ll get garbage out,” he said. “So a lot of garbage going in means a lot of garbage out.”

Such “garbage” can result in missed or erroneous diagnoses, or even faulty predictions. Even when the data are complete, AI can draw incorrect conclusions based on trends for which it lacks proper context.

Dr. Kerr used epilepsy trends in the Black population to illustrate this problem.

“One potential bias is that AI can figure out a patient is Black without being told, and based on data that Black patients are less likely to get epilepsy surgery,” he said, “AI would say they don’t need it because they’re Black, which isn’t true.”

In other words, ML/AI can use systematic determinants of health, such as race, to learn what Dr. Kerr referred to as an “inappropriate association.”

For that reason, ML/AI users must test for bias.

Such data are often retrieved from electronic health records (EHR), which serve as an important source of data ML/AI input. Using EHR makes sense, as they are a major source of missed potential in improving prompt treatment. According to Dr. Kerr, 20% of academic neurologists’ notes miss seizure frequency, and 30% miss the age of onset.

In addition, International Classification of Diseases (ICD) codes create another hurdle depending on the type of code used. For example, epilepsy with G40 or 2 codes of R56 is reliable, while focal to bilateral versus generalized epilepsy proves more challenging.
 

AI Improves Efficiency in National Language Generation

Large language models (LLM) look at first drafts and can save time on formatting, image selection, and construction. Perhaps ChatGPT is the most famous LLM, but other tools in this category include Open AI and Bard. LLMs are trained on “the whole internet” and use publicly accessible text.

In these cases, prompts serve as input data. Output data are predictions of the first and subsequent words.

Many users appreciate the foundation LLMs provide in terms of facilitating and collating research and summarizing ideas. The LLM-generated text actually serves as a first draft, saving users time on more clerical tasks such as formatting, image selection, and structure. Notwithstanding, these tools still require human supervision to screen for hallucinations or to add specialized content.

“LLMs are a great starting place to save time but are loaded with errors,” Dr. Kerr said.

Even if the tools could produce error-free content, ethics still come into play when using AI-generated content without any alterations. Any ML/AI that has not been modified or supervised is considered plagiarism.

Yet, interestingly enough, Dr. Kerr found that patients respond more positively to AI than physicians when interacting.

“Patients felt that AI was more sensitive and compassionate because it was longer-winded and humans are short,” he said. He went on to argue that AI might actually prove useful in helping physicians to improve the quality of their patient interactions.

Dr. Kerr left the audience with these key takeaways:

• ML/AI is just one type of clinical tool with benefits and limitations. The technology conveys the advantages of freeing up the clinician’s time to focus on more human-centered tasks, improving clinical decisions in challenging situations, and improving efficiency.
• However, healthcare systems should understand that ML/AI is not 100% foolproof, as the software’s knowledge is limited to its training exposure, and proper use requires supervision.

ORLANDO — Experts shed light on the applications, benefits, and pitfalls of artificial intelligence (AI) during the Merrit-Putnam Symposium at the annual meeting of the American Epilepsy Society (AES).

In a session titled “Artificial Intelligence Fundamentals and Breakthrough Applications in Epilepsy,” University of Pittsburgh neurologist and assistant professor Wesley Kerr, MD, PhD, provided an overview of AI as well its applications in neurology. He began by addressing perhaps one of the most controversial topics regarding AI in the medical community: clinicians’ fear of being replaced by technology.

“Artificial intelligence will not replace clinicians, but clinicians assisted by artificial intelligence will replace clinicians without artificial intelligence,” he told the audience.
 

To Optimize AI, Clinicians Must Lay the Proper Foundation

Dr. Kerr’s presentation focused on providing audience members with tools to help them evaluate new technologies, recognize benefits, and identify key costs and limitations associated with AI implementation and integration into clinical practice.

Before delving deeper, one must first understand basic terminology regarding AI. Without this knowledge, clinicians may inadvertently introduce bias or errata or fail to understand how to best leverage the technology to enhance the quality of the practice while improving patient outcomes.

Machine learning (ML) describes the process of using data to learn a specific task. Deep learning (DL) stacks multiple layers of ML to improve performance on the task. Lastly, generative AI generates content such as text, images, and media.

Utilizing AI effectively in clinical applications involves tapping into select features most related to prediction (for example, disease factors) and grouping features into categories based on measuring commonalities such as factor composition in a population. This information should be used in training data only.

Fully understanding ML/AI allows clinicians to use it as a diagnostic test by exploiting a combination of accuracy, sensitivity, and specificity, along with positive and negative predictive values.
 

Data Fidelity and Integrity Hinge on Optimal Data Inputs

In the case of epilepsy, calibration curves can provide practical guidance in terms of predicting impending seizures.

“ML/AI needs gold-standard labels for evaluation,” Dr. Kerr said. He went on to stress the importance of quality data inputs to optimize the fidelity of AI’s predictive analytics.

“If you input garbage, you’ll get garbage out,” he said. “So a lot of garbage going in means a lot of garbage out.”

Such “garbage” can result in missed or erroneous diagnoses, or even faulty predictions. Even when the data are complete, AI can draw incorrect conclusions based on trends for which it lacks proper context.

Dr. Kerr used epilepsy trends in the Black population to illustrate this problem.

“One potential bias is that AI can figure out a patient is Black without being told, and based on data that Black patients are less likely to get epilepsy surgery,” he said, “AI would say they don’t need it because they’re Black, which isn’t true.”

In other words, ML/AI can use systematic determinants of health, such as race, to learn what Dr. Kerr referred to as an “inappropriate association.”

For that reason, ML/AI users must test for bias.

Such data are often retrieved from electronic health records (EHR), which serve as an important source of data ML/AI input. Using EHR makes sense, as they are a major source of missed potential in improving prompt treatment. According to Dr. Kerr, 20% of academic neurologists’ notes miss seizure frequency, and 30% miss the age of onset.

In addition, International Classification of Diseases (ICD) codes create another hurdle depending on the type of code used. For example, epilepsy with G40 or 2 codes of R56 is reliable, while focal to bilateral versus generalized epilepsy proves more challenging.
 

AI Improves Efficiency in National Language Generation

Large language models (LLM) look at first drafts and can save time on formatting, image selection, and construction. Perhaps ChatGPT is the most famous LLM, but other tools in this category include Open AI and Bard. LLMs are trained on “the whole internet” and use publicly accessible text.

In these cases, prompts serve as input data. Output data are predictions of the first and subsequent words.

Many users appreciate the foundation LLMs provide in terms of facilitating and collating research and summarizing ideas. The LLM-generated text actually serves as a first draft, saving users time on more clerical tasks such as formatting, image selection, and structure. Notwithstanding, these tools still require human supervision to screen for hallucinations or to add specialized content.

“LLMs are a great starting place to save time but are loaded with errors,” Dr. Kerr said.

Even if the tools could produce error-free content, ethics still come into play when using AI-generated content without any alterations. Any ML/AI that has not been modified or supervised is considered plagiarism.

Yet, interestingly enough, Dr. Kerr found that patients respond more positively to AI than physicians when interacting.

“Patients felt that AI was more sensitive and compassionate because it was longer-winded and humans are short,” he said. He went on to argue that AI might actually prove useful in helping physicians to improve the quality of their patient interactions.

Dr. Kerr left the audience with these key takeaways:

• ML/AI is just one type of clinical tool with benefits and limitations. The technology conveys the advantages of freeing up the clinician’s time to focus on more human-centered tasks, improving clinical decisions in challenging situations, and improving efficiency.
• However, healthcare systems should understand that ML/AI is not 100% foolproof, as the software’s knowledge is limited to its training exposure, and proper use requires supervision.

ORLANDO — Experts shed light on the applications, benefits, and pitfalls of artificial intelligence (AI) during the Merrit-Putnam Symposium at the annual meeting of the American Epilepsy Society (AES).

In a session titled “Artificial Intelligence Fundamentals and Breakthrough Applications in Epilepsy,” University of Pittsburgh neurologist and assistant professor Wesley Kerr, MD, PhD, provided an overview of AI as well its applications in neurology. He began by addressing perhaps one of the most controversial topics regarding AI in the medical community: clinicians’ fear of being replaced by technology.

“Artificial intelligence will not replace clinicians, but clinicians assisted by artificial intelligence will replace clinicians without artificial intelligence,” he told the audience.
 

To Optimize AI, Clinicians Must Lay the Proper Foundation

Dr. Kerr’s presentation focused on providing audience members with tools to help them evaluate new technologies, recognize benefits, and identify key costs and limitations associated with AI implementation and integration into clinical practice.

Before delving deeper, one must first understand basic terminology regarding AI. Without this knowledge, clinicians may inadvertently introduce bias or errata or fail to understand how to best leverage the technology to enhance the quality of the practice while improving patient outcomes.

Machine learning (ML) describes the process of using data to learn a specific task. Deep learning (DL) stacks multiple layers of ML to improve performance on the task. Lastly, generative AI generates content such as text, images, and media.

Utilizing AI effectively in clinical applications involves tapping into select features most related to prediction (for example, disease factors) and grouping features into categories based on measuring commonalities such as factor composition in a population. This information should be used in training data only.

Fully understanding ML/AI allows clinicians to use it as a diagnostic test by exploiting a combination of accuracy, sensitivity, and specificity, along with positive and negative predictive values.
 

Data Fidelity and Integrity Hinge on Optimal Data Inputs

In the case of epilepsy, calibration curves can provide practical guidance in terms of predicting impending seizures.

“ML/AI needs gold-standard labels for evaluation,” Dr. Kerr said. He went on to stress the importance of quality data inputs to optimize the fidelity of AI’s predictive analytics.

“If you input garbage, you’ll get garbage out,” he said. “So a lot of garbage going in means a lot of garbage out.”

Such “garbage” can result in missed or erroneous diagnoses, or even faulty predictions. Even when the data are complete, AI can draw incorrect conclusions based on trends for which it lacks proper context.

Dr. Kerr used epilepsy trends in the Black population to illustrate this problem.

“One potential bias is that AI can figure out a patient is Black without being told, and based on data that Black patients are less likely to get epilepsy surgery,” he said, “AI would say they don’t need it because they’re Black, which isn’t true.”

In other words, ML/AI can use systematic determinants of health, such as race, to learn what Dr. Kerr referred to as an “inappropriate association.”

For that reason, ML/AI users must test for bias.

Such data are often retrieved from electronic health records (EHR), which serve as an important source of data ML/AI input. Using EHR makes sense, as they are a major source of missed potential in improving prompt treatment. According to Dr. Kerr, 20% of academic neurologists’ notes miss seizure frequency, and 30% miss the age of onset.

In addition, International Classification of Diseases (ICD) codes create another hurdle depending on the type of code used. For example, epilepsy with G40 or 2 codes of R56 is reliable, while focal to bilateral versus generalized epilepsy proves more challenging.
 

AI Improves Efficiency in National Language Generation

Large language models (LLM) look at first drafts and can save time on formatting, image selection, and construction. Perhaps ChatGPT is the most famous LLM, but other tools in this category include Open AI and Bard. LLMs are trained on “the whole internet” and use publicly accessible text.

In these cases, prompts serve as input data. Output data are predictions of the first and subsequent words.

Many users appreciate the foundation LLMs provide in terms of facilitating and collating research and summarizing ideas. The LLM-generated text actually serves as a first draft, saving users time on more clerical tasks such as formatting, image selection, and structure. Notwithstanding, these tools still require human supervision to screen for hallucinations or to add specialized content.

“LLMs are a great starting place to save time but are loaded with errors,” Dr. Kerr said.

Even if the tools could produce error-free content, ethics still come into play when using AI-generated content without any alterations. Any ML/AI that has not been modified or supervised is considered plagiarism.

Yet, interestingly enough, Dr. Kerr found that patients respond more positively to AI than physicians when interacting.

“Patients felt that AI was more sensitive and compassionate because it was longer-winded and humans are short,” he said. He went on to argue that AI might actually prove useful in helping physicians to improve the quality of their patient interactions.

Dr. Kerr left the audience with these key takeaways:

• ML/AI is just one type of clinical tool with benefits and limitations. The technology conveys the advantages of freeing up the clinician’s time to focus on more human-centered tasks, improving clinical decisions in challenging situations, and improving efficiency.
• However, healthcare systems should understand that ML/AI is not 100% foolproof, as the software’s knowledge is limited to its training exposure, and proper use requires supervision.

ORLANDO — The epilepsy community has yet to come to a consensus on genetic testing. During a session at the annual meeting of the American Epilepsy Society (AES), researchers and clinicians convened to share their insights on genetic testing of adult patients with epilepsy.

Colin Ellis, MD, assistant professor of neurology at the Hospital of the University of Pennsylvania in Philadelphia, shared his clinical experience to explain the importance of genetic testing in adults patients despite access challenges, limited information on certain variants, and physician reticence.

“There’s a false misconception that genetic testing should only apply to children,” Dr. Ellis told the audience. “The earlier the onset of seizures, the more likely you are to find a genetic cause.”
 

Guidelines Differ

The International League Against Epilepsy Task Force for Clinical Genetic Testing, Development and Epileptic Encephalopathies (DEE) recommends conducting genetic testing in patients who have focal or generalized epilepsies to whom the following circumstances apply: autism or dysmorphism, familial history, or drug-resistant epilepsy.

However, the National Society of Genetic Counselors’ guidelines recommends genetic testing for patients who have any unexplained or idiopathic epilepsies.

Guidelines identify the patients who should get tested regardless of their age.
 

Personal Experience

Dr. Ellis, who has spent nearly 5 years running tests on patients with epilepsy, recently tested the 300th patient at his clinic. According to him, the yield is higher in focal epilepsy than in general epilepsy — an occurrence that counters what many believe.

“Focal epilepsies are more common than monogenic epilepsies but not intuitive to many people in the industry, despite being stated in the literature,” he said. “The absence of family history shouldn’t preclude you from genetic testing because it’s still possible to have a de novo variant not inherited from either parent.”

Genetic testing can be conducted by interrogating either the exome or the genome. However, cost remains a major barrier to access.

Dr. Ellis made several arguments supporting the use of genetic testing. First, genetic testing allows for a higher diagnostic yield (i.e., 24% versus 19% in panels and 9% in microarrays). Genetic testing provides a more comprehensive overview of a patient’s genetic landscape, and it can enhance the ability to identify certain epileptic conditions, such as those caused by monogenic epilepsy — a condition associated with 926 different genes.

“You’re also less likely to find variants of uncertain significance (VUS),” Dr. Ellis said. “Regardless, you should provide the lab with phenotype information because it will help them help you.”
 

Variants of Uncertain Significance

The National Human Genome Research Institute defines VUS as a variant found in a patient’s genome for which it remains unclear as to whether a health condition is causing the variant. Oftentimes, such variants have very little information available due to their rarity.

In order to resolve VUS, Dr. Ellis recommended family segregation. “If the VUS appears to be de novo, you should test the parent because if they carry the gene, then it’s probably not the cause,” he said.

Dr. Ellis outlined several steps in resolving VUS.

For starters, clinicians should determine the phenotypic fit and run some ancillary tests. For example, in the case of Glu 1 abnormalities, one should consider conducting a spinal tap to determine whether the patient has cerebral spinal fluid before taking additional action.

In addition, Dr. Ellis recommends defining variant characteristics, as it becomes important in determining whether it is appropriate to take action because the majority of variances are benign.

“The take-home point is that you should not act clinically on a VUS unless you know what you’re doing,” he said. “I also disagree with the belief that VUS are rare — it’s just that they cause so much anxiety because we’re uncomfortable with this kind of testing.”

ORLANDO — The epilepsy community has yet to come to a consensus on genetic testing. During a session at the annual meeting of the American Epilepsy Society (AES), researchers and clinicians convened to share their insights on genetic testing of adult patients with epilepsy.

Colin Ellis, MD, assistant professor of neurology at the Hospital of the University of Pennsylvania in Philadelphia, shared his clinical experience to explain the importance of genetic testing in adults patients despite access challenges, limited information on certain variants, and physician reticence.

“There’s a false misconception that genetic testing should only apply to children,” Dr. Ellis told the audience. “The earlier the onset of seizures, the more likely you are to find a genetic cause.”
 

Guidelines Differ

The International League Against Epilepsy Task Force for Clinical Genetic Testing, Development and Epileptic Encephalopathies (DEE) recommends conducting genetic testing in patients who have focal or generalized epilepsies to whom the following circumstances apply: autism or dysmorphism, familial history, or drug-resistant epilepsy.

However, the National Society of Genetic Counselors’ guidelines recommends genetic testing for patients who have any unexplained or idiopathic epilepsies.

Guidelines identify the patients who should get tested regardless of their age.
 

Personal Experience

Dr. Ellis, who has spent nearly 5 years running tests on patients with epilepsy, recently tested the 300th patient at his clinic. According to him, the yield is higher in focal epilepsy than in general epilepsy — an occurrence that counters what many believe.

“Focal epilepsies are more common than monogenic epilepsies but not intuitive to many people in the industry, despite being stated in the literature,” he said. “The absence of family history shouldn’t preclude you from genetic testing because it’s still possible to have a de novo variant not inherited from either parent.”

Genetic testing can be conducted by interrogating either the exome or the genome. However, cost remains a major barrier to access.

Dr. Ellis made several arguments supporting the use of genetic testing. First, genetic testing allows for a higher diagnostic yield (i.e., 24% versus 19% in panels and 9% in microarrays). Genetic testing provides a more comprehensive overview of a patient’s genetic landscape, and it can enhance the ability to identify certain epileptic conditions, such as those caused by monogenic epilepsy — a condition associated with 926 different genes.

“You’re also less likely to find variants of uncertain significance (VUS),” Dr. Ellis said. “Regardless, you should provide the lab with phenotype information because it will help them help you.”
 

Variants of Uncertain Significance

The National Human Genome Research Institute defines VUS as a variant found in a patient’s genome for which it remains unclear as to whether a health condition is causing the variant. Oftentimes, such variants have very little information available due to their rarity.

In order to resolve VUS, Dr. Ellis recommended family segregation. “If the VUS appears to be de novo, you should test the parent because if they carry the gene, then it’s probably not the cause,” he said.

Dr. Ellis outlined several steps in resolving VUS.

For starters, clinicians should determine the phenotypic fit and run some ancillary tests. For example, in the case of Glu 1 abnormalities, one should consider conducting a spinal tap to determine whether the patient has cerebral spinal fluid before taking additional action.

In addition, Dr. Ellis recommends defining variant characteristics, as it becomes important in determining whether it is appropriate to take action because the majority of variances are benign.

“The take-home point is that you should not act clinically on a VUS unless you know what you’re doing,” he said. “I also disagree with the belief that VUS are rare — it’s just that they cause so much anxiety because we’re uncomfortable with this kind of testing.”

ORLANDO — The epilepsy community has yet to come to a consensus on genetic testing. During a session at the annual meeting of the American Epilepsy Society (AES), researchers and clinicians convened to share their insights on genetic testing of adult patients with epilepsy.

Colin Ellis, MD, assistant professor of neurology at the Hospital of the University of Pennsylvania in Philadelphia, shared his clinical experience to explain the importance of genetic testing in adults patients despite access challenges, limited information on certain variants, and physician reticence.

“There’s a false misconception that genetic testing should only apply to children,” Dr. Ellis told the audience. “The earlier the onset of seizures, the more likely you are to find a genetic cause.”
 

Guidelines Differ

The International League Against Epilepsy Task Force for Clinical Genetic Testing, Development and Epileptic Encephalopathies (DEE) recommends conducting genetic testing in patients who have focal or generalized epilepsies to whom the following circumstances apply: autism or dysmorphism, familial history, or drug-resistant epilepsy.

However, the National Society of Genetic Counselors’ guidelines recommends genetic testing for patients who have any unexplained or idiopathic epilepsies.

Guidelines identify the patients who should get tested regardless of their age.
 

Personal Experience

Dr. Ellis, who has spent nearly 5 years running tests on patients with epilepsy, recently tested the 300th patient at his clinic. According to him, the yield is higher in focal epilepsy than in general epilepsy — an occurrence that counters what many believe.

“Focal epilepsies are more common than monogenic epilepsies but not intuitive to many people in the industry, despite being stated in the literature,” he said. “The absence of family history shouldn’t preclude you from genetic testing because it’s still possible to have a de novo variant not inherited from either parent.”

Genetic testing can be conducted by interrogating either the exome or the genome. However, cost remains a major barrier to access.

Dr. Ellis made several arguments supporting the use of genetic testing. First, genetic testing allows for a higher diagnostic yield (i.e., 24% versus 19% in panels and 9% in microarrays). Genetic testing provides a more comprehensive overview of a patient’s genetic landscape, and it can enhance the ability to identify certain epileptic conditions, such as those caused by monogenic epilepsy — a condition associated with 926 different genes.

“You’re also less likely to find variants of uncertain significance (VUS),” Dr. Ellis said. “Regardless, you should provide the lab with phenotype information because it will help them help you.”
 

Variants of Uncertain Significance

The National Human Genome Research Institute defines VUS as a variant found in a patient’s genome for which it remains unclear as to whether a health condition is causing the variant. Oftentimes, such variants have very little information available due to their rarity.

In order to resolve VUS, Dr. Ellis recommended family segregation. “If the VUS appears to be de novo, you should test the parent because if they carry the gene, then it’s probably not the cause,” he said.

Dr. Ellis outlined several steps in resolving VUS.

For starters, clinicians should determine the phenotypic fit and run some ancillary tests. For example, in the case of Glu 1 abnormalities, one should consider conducting a spinal tap to determine whether the patient has cerebral spinal fluid before taking additional action.

In addition, Dr. Ellis recommends defining variant characteristics, as it becomes important in determining whether it is appropriate to take action because the majority of variances are benign.

“The take-home point is that you should not act clinically on a VUS unless you know what you’re doing,” he said. “I also disagree with the belief that VUS are rare — it’s just that they cause so much anxiety because we’re uncomfortable with this kind of testing.”

ORLANDO — “There are similarities between Alzheimer’s disease and epilepsy,” said Delia Marias Talos, MD, at a session of the annual meeting of the American Epilepsy Society (AES).

A Closer Look at the Brain

“Phosphorylated tau correlates with cognitive function and executive function recorded presurgery, but it looks like the generative changes are more associated with temporal lobe and aging.”

Alzheimer’s disease is a degenerative condition marked by progressive memory deficits and cognitive decline noted by amyloid plaques and a formation of neurofibrillary tangles resulting from tau hyperphosphorylation.

Epilepsy, on the other hand, is a multifactorial condition with causes ranging from metabolic disorders, structural defects, infections, genetic mutations, and autoimmune disorders. In addition, nearly 50% of all epileptic seizures are idiopathic in nature.

Dr. Talos, professor of neurology at the University of Pennsylvania Perlman School of Medicine in Philadelphia, and her team did not see neurofibrillary tangles in the presurgical brains of epilepsy patients they studied; however, they saw tau plaques. In the future, they seek to investigate the features that distinguish epilepsy from Alzheimer’s disease.

Toxic fragments are probably there because amyloid precursor protein is highly upregulated, she told conference attendees. “We hypothesized that amyloid plaque is cleared but not impaired in epilepsy.”

The prognosis looks comparatively worse for patients who have Alzheimer’s disease and comorbid epilepsy than for patients who have only epilepsy. In addition, Dr. Talos stated that seizures appear to have an additive effort on Alzheimer’s disease.
 

Fyn-disruptive Therapy

Marson Putra, MD, PhD, a neuroscientist and postdoctoral researcher at Iowa State in Ames, Iowa, presented on the potential impact of a novel fyn-tau interaction as an unexplored target for epileptogensis and epilepsy.

Dr. Putra studied whether fyn-tau interactions exist in epilepsy. In both Alzheimer’s disease and epilepsy, Fyn belongs to the Src family of nonreceptor tyrosine kinases (SFKs), which are involved in cell proliferation and migration. Fyn contains an SH3 domain, which serves as a target for tau’s proline-rich (PxxP) motif. Fyn phosphorylates tau, specifically at tyrosine residue Y18, making fyn-disruptive therapy worth exploring.

Dr. Putra shared several currently proposed mechanisms of action regarding the pathogenesis of the tau plaque. In the first theory, the tau protein assumes a closed conformation in its normal state, thereby concealing the PxxP motif. However, in the second theory, pathogenesis causes the tau protein to assume an open conformation in the disease state, exposing pAT8 sites and making them available to fyn phosphorylation. In the second scenario, which involves Alzheimer’s disease, the fyn-tau interaction still occurs in open conformation state and is thought to occur in the postsynaptic terminal of the dendritic spine.

To investigate the proposed disease-causing mechanisms, Dr. Putra and her team studied status epilepticus in a rodent model of status epilepticus (SE). They used proximity ligation assay to measure interactions between Fyn and tau. They found AT8 and Y18 Fyn and N-methyl-D-aspartate (NMDA) receptor activation in a rat model and increased Fyn interaction. In addition, neuronal nitric oxide synthase levels were elevated 24 hours post-status. When investigating the fyn activity and interactions in the human brain, they found fyn phosphorylation – something that had never been reported before.

From there, Dr. Putra’s team sought to answer whether manipulating fyn-tau interactions could modify epilepsy. To do so, they conducted an experiment using the pharmacological Fyn inhibitor sarcatinib (SAR) and found it modified dysregulated postsynaptic proteins 24 hours post-SE in rat models. Longer exposure also bore a positive effect on epileptic rats.

After treating epileptic rats with SAR for 7 weeks, Dr. Putra found that SAR therapy reduces convulsive seizures during 7 weeks post-SE in rats. Recruiting pharmacological Fyn inhibition sufficiently decreased Fyn-tau interaction, NR-PSD95 complex, and convulsive seizures in chronic epilepsy.

Ultimately, her findings showed that SE exacerbates fyn-tau interactions, with chronic epilepsy modeling showing sustained elevation. In addition, fyn-tau interactions mediate and sustain neuronal hyperexcitability in the epileptic population.

“The impact on clinical care will be bidirectional relevant therapeutic targets in epilepsy and Alzheimer’s disease,” Dr. Putra told the audience.
 

Trends in epilepsy comorbidity and mortality

The final presenter, University of Washington researcher Aaron del Pozo, PhD, explained the impact of early-onset Alzheimer’s disease on overall outcomes and epilepsy.

“Early-onset Alzheimer’s disease carries a high seizure risk that affects quality of life as well as mortality,” Dr. del Pozo said.

According to data published in the British Medical Journal in 2020, the number of patients with epilepsy who had degenerative disease of the central nervous system or vascular dementia and delirium increased by approximately 210% from 1999 to 2017. Cerebral palsy trailed in second place with malignant neoplasms increasing by 50%. Cerebrovascular disease­–related death in the epileptic population showed nearly negligible change, and ischemic heart disease and epilepsy decreased by approximately 25% and 15%, respectively. In addition, patients who have both epilepsy and Alzheimer’s disease are less likely to survive than patients who develop epilepsy after Alzheimer’s disease.

“We found that having epilepsy alone has decreased mortality, but having it in addition to other generative diseases of the central nervous system has a 200% increase in mortality,” Dr. del Pozo said.

ORLANDO — “There are similarities between Alzheimer’s disease and epilepsy,” said Delia Marias Talos, MD, at a session of the annual meeting of the American Epilepsy Society (AES).

A Closer Look at the Brain

“Phosphorylated tau correlates with cognitive function and executive function recorded presurgery, but it looks like the generative changes are more associated with temporal lobe and aging.”

Alzheimer’s disease is a degenerative condition marked by progressive memory deficits and cognitive decline noted by amyloid plaques and a formation of neurofibrillary tangles resulting from tau hyperphosphorylation.

Epilepsy, on the other hand, is a multifactorial condition with causes ranging from metabolic disorders, structural defects, infections, genetic mutations, and autoimmune disorders. In addition, nearly 50% of all epileptic seizures are idiopathic in nature.

Dr. Talos, professor of neurology at the University of Pennsylvania Perlman School of Medicine in Philadelphia, and her team did not see neurofibrillary tangles in the presurgical brains of epilepsy patients they studied; however, they saw tau plaques. In the future, they seek to investigate the features that distinguish epilepsy from Alzheimer’s disease.

Toxic fragments are probably there because amyloid precursor protein is highly upregulated, she told conference attendees. “We hypothesized that amyloid plaque is cleared but not impaired in epilepsy.”

The prognosis looks comparatively worse for patients who have Alzheimer’s disease and comorbid epilepsy than for patients who have only epilepsy. In addition, Dr. Talos stated that seizures appear to have an additive effort on Alzheimer’s disease.
 

Fyn-disruptive Therapy

Marson Putra, MD, PhD, a neuroscientist and postdoctoral researcher at Iowa State in Ames, Iowa, presented on the potential impact of a novel fyn-tau interaction as an unexplored target for epileptogensis and epilepsy.

Dr. Putra studied whether fyn-tau interactions exist in epilepsy. In both Alzheimer’s disease and epilepsy, Fyn belongs to the Src family of nonreceptor tyrosine kinases (SFKs), which are involved in cell proliferation and migration. Fyn contains an SH3 domain, which serves as a target for tau’s proline-rich (PxxP) motif. Fyn phosphorylates tau, specifically at tyrosine residue Y18, making fyn-disruptive therapy worth exploring.

Dr. Putra shared several currently proposed mechanisms of action regarding the pathogenesis of the tau plaque. In the first theory, the tau protein assumes a closed conformation in its normal state, thereby concealing the PxxP motif. However, in the second theory, pathogenesis causes the tau protein to assume an open conformation in the disease state, exposing pAT8 sites and making them available to fyn phosphorylation. In the second scenario, which involves Alzheimer’s disease, the fyn-tau interaction still occurs in open conformation state and is thought to occur in the postsynaptic terminal of the dendritic spine.

To investigate the proposed disease-causing mechanisms, Dr. Putra and her team studied status epilepticus in a rodent model of status epilepticus (SE). They used proximity ligation assay to measure interactions between Fyn and tau. They found AT8 and Y18 Fyn and N-methyl-D-aspartate (NMDA) receptor activation in a rat model and increased Fyn interaction. In addition, neuronal nitric oxide synthase levels were elevated 24 hours post-status. When investigating the fyn activity and interactions in the human brain, they found fyn phosphorylation – something that had never been reported before.

From there, Dr. Putra’s team sought to answer whether manipulating fyn-tau interactions could modify epilepsy. To do so, they conducted an experiment using the pharmacological Fyn inhibitor sarcatinib (SAR) and found it modified dysregulated postsynaptic proteins 24 hours post-SE in rat models. Longer exposure also bore a positive effect on epileptic rats.

After treating epileptic rats with SAR for 7 weeks, Dr. Putra found that SAR therapy reduces convulsive seizures during 7 weeks post-SE in rats. Recruiting pharmacological Fyn inhibition sufficiently decreased Fyn-tau interaction, NR-PSD95 complex, and convulsive seizures in chronic epilepsy.

Ultimately, her findings showed that SE exacerbates fyn-tau interactions, with chronic epilepsy modeling showing sustained elevation. In addition, fyn-tau interactions mediate and sustain neuronal hyperexcitability in the epileptic population.

“The impact on clinical care will be bidirectional relevant therapeutic targets in epilepsy and Alzheimer’s disease,” Dr. Putra told the audience.
 

Trends in epilepsy comorbidity and mortality

The final presenter, University of Washington researcher Aaron del Pozo, PhD, explained the impact of early-onset Alzheimer’s disease on overall outcomes and epilepsy.

“Early-onset Alzheimer’s disease carries a high seizure risk that affects quality of life as well as mortality,” Dr. del Pozo said.

According to data published in the British Medical Journal in 2020, the number of patients with epilepsy who had degenerative disease of the central nervous system or vascular dementia and delirium increased by approximately 210% from 1999 to 2017. Cerebral palsy trailed in second place with malignant neoplasms increasing by 50%. Cerebrovascular disease­–related death in the epileptic population showed nearly negligible change, and ischemic heart disease and epilepsy decreased by approximately 25% and 15%, respectively. In addition, patients who have both epilepsy and Alzheimer’s disease are less likely to survive than patients who develop epilepsy after Alzheimer’s disease.

“We found that having epilepsy alone has decreased mortality, but having it in addition to other generative diseases of the central nervous system has a 200% increase in mortality,” Dr. del Pozo said.

ORLANDO — “There are similarities between Alzheimer’s disease and epilepsy,” said Delia Marias Talos, MD, at a session of the annual meeting of the American Epilepsy Society (AES).

A Closer Look at the Brain

“Phosphorylated tau correlates with cognitive function and executive function recorded presurgery, but it looks like the generative changes are more associated with temporal lobe and aging.”

Alzheimer’s disease is a degenerative condition marked by progressive memory deficits and cognitive decline noted by amyloid plaques and a formation of neurofibrillary tangles resulting from tau hyperphosphorylation.

Epilepsy, on the other hand, is a multifactorial condition with causes ranging from metabolic disorders, structural defects, infections, genetic mutations, and autoimmune disorders. In addition, nearly 50% of all epileptic seizures are idiopathic in nature.

Dr. Talos, professor of neurology at the University of Pennsylvania Perlman School of Medicine in Philadelphia, and her team did not see neurofibrillary tangles in the presurgical brains of epilepsy patients they studied; however, they saw tau plaques. In the future, they seek to investigate the features that distinguish epilepsy from Alzheimer’s disease.

Toxic fragments are probably there because amyloid precursor protein is highly upregulated, she told conference attendees. “We hypothesized that amyloid plaque is cleared but not impaired in epilepsy.”

The prognosis looks comparatively worse for patients who have Alzheimer’s disease and comorbid epilepsy than for patients who have only epilepsy. In addition, Dr. Talos stated that seizures appear to have an additive effort on Alzheimer’s disease.
 

Fyn-disruptive Therapy

Marson Putra, MD, PhD, a neuroscientist and postdoctoral researcher at Iowa State in Ames, Iowa, presented on the potential impact of a novel fyn-tau interaction as an unexplored target for epileptogensis and epilepsy.

Dr. Putra studied whether fyn-tau interactions exist in epilepsy. In both Alzheimer’s disease and epilepsy, Fyn belongs to the Src family of nonreceptor tyrosine kinases (SFKs), which are involved in cell proliferation and migration. Fyn contains an SH3 domain, which serves as a target for tau’s proline-rich (PxxP) motif. Fyn phosphorylates tau, specifically at tyrosine residue Y18, making fyn-disruptive therapy worth exploring.

Dr. Putra shared several currently proposed mechanisms of action regarding the pathogenesis of the tau plaque. In the first theory, the tau protein assumes a closed conformation in its normal state, thereby concealing the PxxP motif. However, in the second theory, pathogenesis causes the tau protein to assume an open conformation in the disease state, exposing pAT8 sites and making them available to fyn phosphorylation. In the second scenario, which involves Alzheimer’s disease, the fyn-tau interaction still occurs in open conformation state and is thought to occur in the postsynaptic terminal of the dendritic spine.

To investigate the proposed disease-causing mechanisms, Dr. Putra and her team studied status epilepticus in a rodent model of status epilepticus (SE). They used proximity ligation assay to measure interactions between Fyn and tau. They found AT8 and Y18 Fyn and N-methyl-D-aspartate (NMDA) receptor activation in a rat model and increased Fyn interaction. In addition, neuronal nitric oxide synthase levels were elevated 24 hours post-status. When investigating the fyn activity and interactions in the human brain, they found fyn phosphorylation – something that had never been reported before.

From there, Dr. Putra’s team sought to answer whether manipulating fyn-tau interactions could modify epilepsy. To do so, they conducted an experiment using the pharmacological Fyn inhibitor sarcatinib (SAR) and found it modified dysregulated postsynaptic proteins 24 hours post-SE in rat models. Longer exposure also bore a positive effect on epileptic rats.

After treating epileptic rats with SAR for 7 weeks, Dr. Putra found that SAR therapy reduces convulsive seizures during 7 weeks post-SE in rats. Recruiting pharmacological Fyn inhibition sufficiently decreased Fyn-tau interaction, NR-PSD95 complex, and convulsive seizures in chronic epilepsy.

Ultimately, her findings showed that SE exacerbates fyn-tau interactions, with chronic epilepsy modeling showing sustained elevation. In addition, fyn-tau interactions mediate and sustain neuronal hyperexcitability in the epileptic population.

“The impact on clinical care will be bidirectional relevant therapeutic targets in epilepsy and Alzheimer’s disease,” Dr. Putra told the audience.
 

Trends in epilepsy comorbidity and mortality

The final presenter, University of Washington researcher Aaron del Pozo, PhD, explained the impact of early-onset Alzheimer’s disease on overall outcomes and epilepsy.

“Early-onset Alzheimer’s disease carries a high seizure risk that affects quality of life as well as mortality,” Dr. del Pozo said.

According to data published in the British Medical Journal in 2020, the number of patients with epilepsy who had degenerative disease of the central nervous system or vascular dementia and delirium increased by approximately 210% from 1999 to 2017. Cerebral palsy trailed in second place with malignant neoplasms increasing by 50%. Cerebrovascular disease­–related death in the epileptic population showed nearly negligible change, and ischemic heart disease and epilepsy decreased by approximately 25% and 15%, respectively. In addition, patients who have both epilepsy and Alzheimer’s disease are less likely to survive than patients who develop epilepsy after Alzheimer’s disease.

“We found that having epilepsy alone has decreased mortality, but having it in addition to other generative diseases of the central nervous system has a 200% increase in mortality,” Dr. del Pozo said.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — Scientists have made major strides in gene therapy, and experts convened to share their insights on gene therapy development and challenges at the annual meeting of the American Epilepsy Society during a session called “Recent Advances Gene Therapies for the Epilepsies: A Preclinical Perspective.”

Four types of gene therapy

Suzanne Paradis, PhD, cofounder and president of Severin Therapeutics Inc., initiated the session, giving the audience an overview of the four types of gene therapy — the first being gene replacements, where a copy of the gene is added back. The second type of therapy, transcriptional enhancement, entails upregulating an endogenous copy of the gene.

“Both gene replacement and transcriptional enhancement can prove effective in treating monogenetic genetic disorders,” she said.

The third type is transcriptional enhancement, which upregulates an endogenous copy of the gene.

Generalizable gene therapies, the fourth type of gene therapy, involve adding a gene that bypasses either or both ictogenesis and seizure propagation.

As it stands, of the nearly 30 gene therapies currently marketed for neurological disorders, only four are indicated for central nervous system (CNS) disorders. Of the four currently approved by the FDA for seizures, onasemnogene abeparvovec-xioi (Zolgensma) is the only one that truly targets the CNS.

“Developing treatment that targets the CNS requires several important considerations,” Dr. Paradis said. “These include the right model system, appropriate delivery method, a product that can cross the blood-brain barrier (BBB) and target neurons, and the durability of transgene expression.”
 

Epilepsy May Be Amenable to Gene Therapy

To illustrate these principles, Meghan Eller, a PhD candidate at the University of Texas Southwestern in Dallas, shared research on potential new gene therapies that might one day become effective options in treating CNS diseases.

She spoke on viral-mediated gene delivery, specifically by employing adeno-associated virus (AAV) treatment in this arena.

“We capitalized on the ability of viruses to infect genetic materials,” she told the audience. “Viruses are naturally designed to infect cells and deliver genetic material.”

The viruses have three components that make them attractive. One of three viruses is typically used for this work — adenoviruses, lentiviruses, or AAV. The virus type used may be dictated by the gene of interest, meaning whether the gene is expressed, knocked down, or edited. Lastly, several regulatory elements are required; these are the promoter, polyadenylation signal, and the regulatory binding sites necessary for transcription.

“More recent technologies are CRISPR for gene editing, and with promoter, we can control the specific cell type in which gene will be expressed,” Ms. Eller explained.

Regulatory binding sites within a binding site allow regulation within an endogenous transgene.

“AAV genome is naturally single-stranded, but we can introduce a mutation to form a self-complementary cassette,” she said.

Using AAV as a vector for gene delivery has several advantages. First and foremost, it is easy to engineer. Moreover, it can infect dividing and non-dividing cells. It also exhibits long-lasting expression and has a low immune response. In addition, the AAV virion particle has demonstrated activity on cells found in numerous organs, including those of the lymph nodes, adrenal glands, kidneys, various muscle tissue, retinal cells, and digestive system as well as the CNS.

Yet, for all its benefits, the AAV comes with some limitations. For example, it carries as preexisting immunity and exhibits lost expression in dividing cells.

Another important drawback is its package size constraints, as many genes do not fall within its 2.4 kb self-complementary of 4.8 kb single-stranded packaging capacity.

For her research, Ms. Eller and colleagues took into account several considerations for therapy development. The appropriate route helps ensure the therapy reaches critical regions of the brain and that there is adequate expression in the periphery. The immune response becomes important regarding the body’s reaction to non-self proteins — a property, which, at times, can be modified based on dose. Thirdly, expression level and cell type expression can affect the therapy’s activity. In addition, a small amount of the vector will be incorporated into the host DNA.

The fact that AAV can cross the BBB allows for intravenous delivery; however, it limits brain transduction.

“Gene therapy may not be as effective if the delivery window is missed or there is significant neuron loss,” Ms. Eller said.

She stressed the importance of determining the minimal dose necessary for therapeutic benefit to minimize dose-related toxicity. She also distinguished when and why one might choose one type of gene therapy over another, using gene addition to help illustrate her point.

“Gene addition is the most important approach when there is a monogenic gene,” she said. “SLC13A5 and SLC6A1 are examples where gene addition is effective.”

Modulation of ion channels can help the delivery of therapeutic. Such is the case for NaV1.1 and Kv1.1. Finally, AAV can enhance the delivery of therapeutic proteins, as seen with Sema4D and neuropeptide Y.

Ms. Eller explained how the path to developing a gene therapy as an investigational new drug mirrors those historically traveled in conventional drug development to some extent. Preclinical studies offer proof of concept by determining efficacy, dosing, and toxicity in small animals such as mice. From there, studies progress to the pre-IND state by exploring pharmacology and clinical trial design while further investigating toxicity. FDA and regulatory approval require addressing safety concerns and establishing therapeutic benefit, at which point the therapy progresses to the fourth and final stage: clinical trials. During this stage, investigators monitor dosage and safety while evaluating efficacy.Optimal transgene expression regulation requires scientists to create an environment that gives rise to the perfect level of transgene expression. Otherwise, too little protein will result in no therapeutic benefit, while too much protein can become toxic.

Ms. Eller presented her work on investigating whether the reduction of Scn8a is therapeutic, given that epileptogenic Scn8a mutations increase neuronal firing. She treated both the control and Scn8a mice with antisense oligonucleotides (ASO), which depresses neuronal activity. Upon comparing the effects in ASO-treated mice to control, she found that long-term downregulation of Scn8a (50%) prevents seizures and increases survival — regardless of whether ASO therapy was initiated before or during seizure onset.

Additional studies exploring novel and potential gene therapies for epilepsy are on the horizon.

Dr. Paradis is an employee of Severin Therapeutics Inc. Ms Eller has no relevant disclosures.

ORLANDO — People with epilepsy are more likely to decline cognitively compared with those without epilepsy, new research suggests.

Results of the large, longitudinal study show that seizures predicted earlier conversion time from normal cognition to mild cognitive impairment (MCI) but were not associated with conversion from MCI to dementia.

“Modifiable cardiovascular risk factors such as hypertension and diabetes need to be treated more aggressively because they can impact cognition, but epilepsy is another risk factor that needs to be treated in a timely fashion because it appears to be also associated with cognitive impairment,” said study investigator Ifrah Zawar MD, assistant professor, Department of Neurology, University of Virginia in Charlottesville.

The study (abstract #2.172) was presented on December 2 at the American Epilepsy Society annual meeting.
 

An Understudied Issue

Comorbid seizures occur in up to 64% of those with dementia, and patients with dementia and epilepsy have a more aggressive disease course, faster cognitive decline, and more severe neuronal loss, Dr. Zawar told Medscape Medical News.

But the impact of seizures on the conversion of cognitively healthy to MCI and from MCI to dementia, after accounting for cardiovascular risk factors, has not been well studied.

Researchers analyzed longitudinal data of 13,726 patients, mean age about 70 years, who were cognitively healthy or had mild cognitive impairment (MCI). Participants were recruited from 39 Alzheimer’s Disease (AD) centers in the United States from 2005 to 2021. 

Investigators categorized participants into three groups: active (having had seizures in the past year and/or requiring active treatment; N = 118), resolved (not on any treatment for the past year and not having seizures; N = 226), and no seizures (never having had seizures; N = 13,382).

The primary outcome was conversion from cognitively healthy to MCI/dementia and from MCI to dementia in those with and without active epilepsy and resolved epilepsy.

Factors associated with conversion from cognitively healthy to MCI among those with current or active epilepsy included older age (P <.001 for ages 60-80 years and P =.002 for age 80 years or older vs younger than 60 years), male sex (P <.001), lower education (P <.001), hypertension (P <.001), and diabetes (P <.001).

The hazard ratio (HR) for earlier conversion from healthy to worse cognition among those with active epilepsy was 1.76 (95% CI, 1.38-2.24; P <.001), even after accounting for risk factors.

Kaplan-Meier curves showed that the median time to convert from healthy cognition to MCI among people with active epilepsy was about 5 years compared with about 9 years for those with resolved epilepsy and 10.5 years for those without epilepsy.

The story was similar for faster conversion from MCI to dementia. Compared with having no epilepsy, the HR for faster conversion for active epilepsy was 1.44 (95% CI, 1.20-1.73; P <.001).

In addition, the median time to conversion from MCI to dementia was about 3 years for those with active epilepsy compared with about 5 years for those with resolved epilepsy and about 5 years for those without epilepsy.

“It’s important for physicians to understand that uncontrolled epilepsy or active epilepsy is going to impact patients’ cognition adversely, which in itself is associated with increased comorbidity and mortality,” said Dr. Zawar.

The mechanism driving the acceleration to worse cognition in people with epilepsy is “complicated and involves a multitude of factors,” she said.

The researchers did not specifically investigate how use of antiseizure medications correlated with cognitive outcomes, but Dr. Zawar believes that “epilepsy in itself impacts cognition.”

The researchers also didn’t have EEG data for study participants who were recruited from Alzheimer’s disease centers where EEGs aren’t routinely carried out, so such data for many patients may not necessarily exist, said Dr. Zawar.
 

Important Research

Commenting for this news organization, Bruce Hermann, PhD, professor emeritus, Department of Neurology, University of Wisconsin School of Medicine and Public Health,  said that the study is important because of the, “tremendous interest and concern about aging with epilepsy.”

“We want to know how people with chronic epilepsy age cognitively and what’s the cognitive course of those who have late onset epilepsy, particularly those with unknown etiology,” he added. 

Dr. Hermann noted that much of the research in this area has been relatively small and single-center investigations. 

“These larger-scale investigations from outside the epilepsy community are so important because they have data on large numbers of subjects, they have cognitive data, and follow-ups over long periods of time, and they’re providing some really novel information,” Dr. Hermann said. 

He added that terms used in the dementia world such as MCI and frank dementia are somewhat foreign to epileptologists. In addition, interventions to delay, treat, or prevent cognitive decline such as exercise, diet, social activity, and mental stimulation that are regularly discussed by dementia experts are underrepresented in the epilepsy world.

“The things they talk about in memory clinics in the aging world almost routinely have not penetrated to the epilepsy clinics for aging individuals and for the epilepsy community in general.”

The study used the Montreal Cognitive Assessment to identify cognitive decline. “It would be nice to see how these people look with traditional neuropsychological tests,” said Dr. Hermann.

He added that information on the impact of epilepsy on different MCI phenotypes, for example, pure memory impairment subtype; pure nonmemory subtype; and multiple domain subtype, would also be useful.

The study was supported by the AES and the Alzheimer’s Association. 

Dr. Zawar and Dr. Hermann report no relevant disclosures.

A version of this article appeared on Medscape.com.

ORLANDO — People with epilepsy are more likely to decline cognitively compared with those without epilepsy, new research suggests.

Results of the large, longitudinal study show that seizures predicted earlier conversion time from normal cognition to mild cognitive impairment (MCI) but were not associated with conversion from MCI to dementia.

“Modifiable cardiovascular risk factors such as hypertension and diabetes need to be treated more aggressively because they can impact cognition, but epilepsy is another risk factor that needs to be treated in a timely fashion because it appears to be also associated with cognitive impairment,” said study investigator Ifrah Zawar MD, assistant professor, Department of Neurology, University of Virginia in Charlottesville.

The study (abstract #2.172) was presented on December 2 at the American Epilepsy Society annual meeting.
 

An Understudied Issue

Comorbid seizures occur in up to 64% of those with dementia, and patients with dementia and epilepsy have a more aggressive disease course, faster cognitive decline, and more severe neuronal loss, Dr. Zawar told Medscape Medical News.

But the impact of seizures on the conversion of cognitively healthy to MCI and from MCI to dementia, after accounting for cardiovascular risk factors, has not been well studied.

Researchers analyzed longitudinal data of 13,726 patients, mean age about 70 years, who were cognitively healthy or had mild cognitive impairment (MCI). Participants were recruited from 39 Alzheimer’s Disease (AD) centers in the United States from 2005 to 2021. 

Investigators categorized participants into three groups: active (having had seizures in the past year and/or requiring active treatment; N = 118), resolved (not on any treatment for the past year and not having seizures; N = 226), and no seizures (never having had seizures; N = 13,382).

The primary outcome was conversion from cognitively healthy to MCI/dementia and from MCI to dementia in those with and without active epilepsy and resolved epilepsy.

Factors associated with conversion from cognitively healthy to MCI among those with current or active epilepsy included older age (P <.001 for ages 60-80 years and P =.002 for age 80 years or older vs younger than 60 years), male sex (P <.001), lower education (P <.001), hypertension (P <.001), and diabetes (P <.001).

The hazard ratio (HR) for earlier conversion from healthy to worse cognition among those with active epilepsy was 1.76 (95% CI, 1.38-2.24; P <.001), even after accounting for risk factors.

Kaplan-Meier curves showed that the median time to convert from healthy cognition to MCI among people with active epilepsy was about 5 years compared with about 9 years for those with resolved epilepsy and 10.5 years for those without epilepsy.

The story was similar for faster conversion from MCI to dementia. Compared with having no epilepsy, the HR for faster conversion for active epilepsy was 1.44 (95% CI, 1.20-1.73; P <.001).

In addition, the median time to conversion from MCI to dementia was about 3 years for those with active epilepsy compared with about 5 years for those with resolved epilepsy and about 5 years for those without epilepsy.

“It’s important for physicians to understand that uncontrolled epilepsy or active epilepsy is going to impact patients’ cognition adversely, which in itself is associated with increased comorbidity and mortality,” said Dr. Zawar.

The mechanism driving the acceleration to worse cognition in people with epilepsy is “complicated and involves a multitude of factors,” she said.

The researchers did not specifically investigate how use of antiseizure medications correlated with cognitive outcomes, but Dr. Zawar believes that “epilepsy in itself impacts cognition.”

The researchers also didn’t have EEG data for study participants who were recruited from Alzheimer’s disease centers where EEGs aren’t routinely carried out, so such data for many patients may not necessarily exist, said Dr. Zawar.
 

Important Research

Commenting for this news organization, Bruce Hermann, PhD, professor emeritus, Department of Neurology, University of Wisconsin School of Medicine and Public Health,  said that the study is important because of the, “tremendous interest and concern about aging with epilepsy.”

“We want to know how people with chronic epilepsy age cognitively and what’s the cognitive course of those who have late onset epilepsy, particularly those with unknown etiology,” he added. 

Dr. Hermann noted that much of the research in this area has been relatively small and single-center investigations. 

“These larger-scale investigations from outside the epilepsy community are so important because they have data on large numbers of subjects, they have cognitive data, and follow-ups over long periods of time, and they’re providing some really novel information,” Dr. Hermann said. 

He added that terms used in the dementia world such as MCI and frank dementia are somewhat foreign to epileptologists. In addition, interventions to delay, treat, or prevent cognitive decline such as exercise, diet, social activity, and mental stimulation that are regularly discussed by dementia experts are underrepresented in the epilepsy world.

“The things they talk about in memory clinics in the aging world almost routinely have not penetrated to the epilepsy clinics for aging individuals and for the epilepsy community in general.”

The study used the Montreal Cognitive Assessment to identify cognitive decline. “It would be nice to see how these people look with traditional neuropsychological tests,” said Dr. Hermann.

He added that information on the impact of epilepsy on different MCI phenotypes, for example, pure memory impairment subtype; pure nonmemory subtype; and multiple domain subtype, would also be useful.

The study was supported by the AES and the Alzheimer’s Association. 

Dr. Zawar and Dr. Hermann report no relevant disclosures.

A version of this article appeared on Medscape.com.

ORLANDO — People with epilepsy are more likely to decline cognitively compared with those without epilepsy, new research suggests.

Results of the large, longitudinal study show that seizures predicted earlier conversion time from normal cognition to mild cognitive impairment (MCI) but were not associated with conversion from MCI to dementia.

“Modifiable cardiovascular risk factors such as hypertension and diabetes need to be treated more aggressively because they can impact cognition, but epilepsy is another risk factor that needs to be treated in a timely fashion because it appears to be also associated with cognitive impairment,” said study investigator Ifrah Zawar MD, assistant professor, Department of Neurology, University of Virginia in Charlottesville.

The study (abstract #2.172) was presented on December 2 at the American Epilepsy Society annual meeting.
 

An Understudied Issue

Comorbid seizures occur in up to 64% of those with dementia, and patients with dementia and epilepsy have a more aggressive disease course, faster cognitive decline, and more severe neuronal loss, Dr. Zawar told Medscape Medical News.

But the impact of seizures on the conversion of cognitively healthy to MCI and from MCI to dementia, after accounting for cardiovascular risk factors, has not been well studied.

Researchers analyzed longitudinal data of 13,726 patients, mean age about 70 years, who were cognitively healthy or had mild cognitive impairment (MCI). Participants were recruited from 39 Alzheimer’s Disease (AD) centers in the United States from 2005 to 2021. 

Investigators categorized participants into three groups: active (having had seizures in the past year and/or requiring active treatment; N = 118), resolved (not on any treatment for the past year and not having seizures; N = 226), and no seizures (never having had seizures; N = 13,382).

The primary outcome was conversion from cognitively healthy to MCI/dementia and from MCI to dementia in those with and without active epilepsy and resolved epilepsy.

Factors associated with conversion from cognitively healthy to MCI among those with current or active epilepsy included older age (P <.001 for ages 60-80 years and P =.002 for age 80 years or older vs younger than 60 years), male sex (P <.001), lower education (P <.001), hypertension (P <.001), and diabetes (P <.001).

The hazard ratio (HR) for earlier conversion from healthy to worse cognition among those with active epilepsy was 1.76 (95% CI, 1.38-2.24; P <.001), even after accounting for risk factors.

Kaplan-Meier curves showed that the median time to convert from healthy cognition to MCI among people with active epilepsy was about 5 years compared with about 9 years for those with resolved epilepsy and 10.5 years for those without epilepsy.

The story was similar for faster conversion from MCI to dementia. Compared with having no epilepsy, the HR for faster conversion for active epilepsy was 1.44 (95% CI, 1.20-1.73; P <.001).

In addition, the median time to conversion from MCI to dementia was about 3 years for those with active epilepsy compared with about 5 years for those with resolved epilepsy and about 5 years for those without epilepsy.

“It’s important for physicians to understand that uncontrolled epilepsy or active epilepsy is going to impact patients’ cognition adversely, which in itself is associated with increased comorbidity and mortality,” said Dr. Zawar.

The mechanism driving the acceleration to worse cognition in people with epilepsy is “complicated and involves a multitude of factors,” she said.

The researchers did not specifically investigate how use of antiseizure medications correlated with cognitive outcomes, but Dr. Zawar believes that “epilepsy in itself impacts cognition.”

The researchers also didn’t have EEG data for study participants who were recruited from Alzheimer’s disease centers where EEGs aren’t routinely carried out, so such data for many patients may not necessarily exist, said Dr. Zawar.
 

Important Research

Commenting for this news organization, Bruce Hermann, PhD, professor emeritus, Department of Neurology, University of Wisconsin School of Medicine and Public Health,  said that the study is important because of the, “tremendous interest and concern about aging with epilepsy.”

“We want to know how people with chronic epilepsy age cognitively and what’s the cognitive course of those who have late onset epilepsy, particularly those with unknown etiology,” he added. 

Dr. Hermann noted that much of the research in this area has been relatively small and single-center investigations. 

“These larger-scale investigations from outside the epilepsy community are so important because they have data on large numbers of subjects, they have cognitive data, and follow-ups over long periods of time, and they’re providing some really novel information,” Dr. Hermann said. 

He added that terms used in the dementia world such as MCI and frank dementia are somewhat foreign to epileptologists. In addition, interventions to delay, treat, or prevent cognitive decline such as exercise, diet, social activity, and mental stimulation that are regularly discussed by dementia experts are underrepresented in the epilepsy world.

“The things they talk about in memory clinics in the aging world almost routinely have not penetrated to the epilepsy clinics for aging individuals and for the epilepsy community in general.”

The study used the Montreal Cognitive Assessment to identify cognitive decline. “It would be nice to see how these people look with traditional neuropsychological tests,” said Dr. Hermann.

He added that information on the impact of epilepsy on different MCI phenotypes, for example, pure memory impairment subtype; pure nonmemory subtype; and multiple domain subtype, would also be useful.

The study was supported by the AES and the Alzheimer’s Association. 

Dr. Zawar and Dr. Hermann report no relevant disclosures.

A version of this article appeared on Medscape.com.

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

ORLANDO — Combining an enzyme-inducing antiseizure medication with a direct-acting oral anticoagulant (DOAC) does not significantly increase the risk of thromboembolic events in patients with epilepsy, preliminary results of a new study show.

These new data are important, “particularly when we’re talking about a more global perspective, given the vital role of enzyme-inducing antiseizure medications in epilepsy care across many middle- and low-income countries where they may be the only readily available treatment options,” said study investigator Emily K. Acton, PhD candidate in epidemiology and a medical student, University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Illinois College of Medicine, Chicago. 

The findings also suggest that use of enzyme-inducing antiseizure medication with DOACs may be associated with a reduction in major bleeding events, although Ms. Acton stressed this requires more research.

The findings were presented at the American Epilepsy Society annual meeting.
 

Important Implications

Enzyme-inducing antiseizure medications may induce key drug metabolizing enzymes that result in wide-ranging interactions, Ms. Acton told this news organization. “But, in many cases, the clinical significance of these pharmacokinetic interactions is not completely understood.”

This has important implications for managing anticoagulation, said Ms. Acton. “The ease of DOAC use, and growing evidence of the drugs’ safety and efficacy compared to vitamin K antagonists, has led to widespread shifts in clinical practice towards DOACs.”

Due to the relative novelty of DOACs, their interaction profiles have been less than complete, she explained. Evidence that enzyme-inducing antiseizure medications may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk, comes mainly from in vitro and animal studies.

“Research in humans is lacking and complicated in interpretation by inconsistent findings and methodological limitations,” she said.

The investigators wanted to address the “clinical uncertainty” surrounding the real-world relevance of enzyme-inducing antiseizure medications and DOAC interactions but conducting a randomized trial “would be neither feasible nor ethical,” said Ms. Acton. 

Using healthcare claims data from October 2010 to September 2021, the researchers conducted an active comparator, new-user cohort study among a nationally representative sample of adults with epilepsy who had been co-prescribed these drugs. 

They compared thromboembolic and major bleeding event rates between exposure to DOACs with enzyme-inducing antiseizure medications vs exposure to DOACs with non-enzyme inducing antiseizure medications.

Enzyme-inducing antiseizure medications included in the study were carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate. Non-enzyme-inducing antiseizure medications included gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin.

The researchers used data-adaptive high-dimensional propensity score matching to control for “hundreds and hundreds” of observed confounders, and proxies for unobserved confounders, said Ms. Acton. They identified outcomes based on validated diagnostic coding algorithms for thromboembolic and major bleeding events and estimated adjusted hazard ratios (aHRs) using Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs.
 

Reduced Risk of Major Bleeding 

Outcomes were analyzed in three separate cohorts. These included patients on DOACs for any indication (indication-agnostic); those on DOACs for atrial fibrillation (AF); and those taking DOACs for deep vein thrombus/pulmonary embolism (DVT/PE).

In the indication-agnostic analysis, the investigators examined thromboembolic events among 5989 episodes in patients taking both DOACs and enzyme-inducing antiseizure medications, compared witha reference group of 14,671 episodes in patients taking DOACs and non-enzyme-inducing antiseizure medications.

The reference group was generally older and had a greater prevalence of a number of major comorbidities compared with the exposed group, noted Ms. Acton.

For the indication-agnostic analysis, the aHR was 1.11 (95% CI 0.89-1.39). Results were similar for the AF indication (aHR 1.10; 95% CI 0.82-1.46) and for the DVT/PE indication (aHR 1.11; 95% CI 0.81-1.51).

“This research provides large-scale, real-world evidence enzyme-inducing antiseizure medication use alongside DOACs does not significantly elevate risk of thromboembolic events among a nationally representative epilepsy population,” said Ms. Acton.

However, “it’s always important to consider risk factors for thromboembolic and bleeding events at the level of the individual patient,” she added.

With respect to major bleeding events, there was a slightly reduced risk in the exposed group, specifically in the analysis of subjects with atrial fibrillation, where the aHR was 0.63 (95% CI 0.44-0.89).

“A potential explanation may be pharmacokinetic interaction with enzyme-inducing antiseizure medications occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects,” said Ms. Acton.

However, she cautioned that more research is needed.

As for the differential potency among the various enzyme-inducing antiseizure medications studied, Ms. Acton said results from a secondary analysis in the atrial fibrillation assessment that removed the potentially less potent enzyme inducers, oxcarbazepine and topiramate, didn’t significantly change the study results.
 

‘Really Great News’

Commenting on the findings for this news organization, epilepsy expert Daniel M. Goldenholz, MD, PhD, assistant professor of Neurology, Harvard Beth Israel Deaconess Medical Center, Boston, Massachusetts, said the finding of no meaningful difference between DOAC plus enzyme-inducing medications vs DOACs plus non-enzyme-inducing medications is encouraging.

“This study asks a very important question at the population level and appropriately tries to control for present and hidden factors using a propensity matching approach,” he said.

The fact that the data support no difference in terms of thromboembolic events “is really great news” for patients taking an enzyme-inducing antiseizure medication who need to use a DOAC, he said.

While some patients or clinicians might consider transitioning off an enzyme-inducing antiseizure medication, this can lead to new side effects and potentially higher drug costs. “Knowing that a transition may be unnecessary is exciting,” said Dr. Goldenholz.

However, he’s concerned the 1.5-year observation period may not be long enough to see a true effect of these drug combinations.

He also noted that due to the “theoretical higher risk,” patients combining DOACs with enzyme-inducing drugs typically need extra monitoring, which may be less practical outside the US. This suggests “the result may not necessarily generalize outside high-income countries,” he said.

Dr. Goldenholz emphasized that the data are preliminary. “As always, I look forward to a full peer-reviewed study before forming final conclusions.”

The study was supported by the US Department of Health and Human Services’ National Institute of Neurological Disorders and Stroke.

Ms. Acton and Dr. Goldenholz report no relevant financial relationships.

A version of this article appeared on Medscape.com.

ORLANDO — A new review adds to growing evidence that the modified Atkins diet (MAD) significantly reduces seizures in adults with drug-resistant epilepsy.

The results of the small new review and meta-analysis suggest that “the MAD may be an effective adjuvant therapy for older patients who have failed anti-seizure medications,” study investigator Aiswarya Raj, MBBS, Aster Malabar Institute of Medical Sciences, Kerala, India, said in an interview.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Paucity of Adult Data 

The MAD is a less restrictive hybrid of the ketogenic diet that limits carbohydrate intake and encourages fat consumption. It does not restrict fluids, calories, or proteins and does not require fats to be weighed or measured.

The diet includes fewer carbohydrates than the traditional Atkins diet and places more emphasis on fat intake. Dr. Raj said that the research suggests that the MAD “is a promising therapy in pediatric populations, but there’s not a lot of data in adults.”

Dr. Raj noted that this diet type has not been that popular in patients who clinicians believe might be better treated with drug therapy, possibly because of concern about the cardiac impact of consuming high-fat foods.

After conducting a systematic literature review assessing the efficacy of MAD in adults, the researchers included three randomized controlled trials and four observational studies published from January 2000 to May 2023 in the analysis.

The randomized controlled trials in the review assessed the primary outcome, a greater than 50% seizure reduction, at the end of 2 months, 3 months, and 6 months. In the MAD group, 32.5% of participants had more than a 50% seizure reduction vs 3% in the control group (odds ratio [OR], 12.62; 95% CI, 4.05-39.29; P < .0001).

Four participants who followed the diet achieved complete seizure-freedom compared with no participants in the control group (OR, 16.20; 95% CI, 0.82-318.82; P = .07).

The prospective studies examined this outcome at the end of 1 month or 3 months. In these studies, 41.9% of individuals experienced more than a 50% seizure reduction after 1 month of following the MAD, and 34.2% experienced this reduction after 3 months (OR, 1.41; 95% CI, 0.79-2.52; P = .24), with zero heterogeneity across studies.

It’s difficult to interpret the difference in seizure reduction between 1 and 3 months of therapy, Dr. Raj noted, because “there’s always the issue of compliance when you put a patient on a long-term diet.”

Positive results for MAD in adults were shown in another recent systematic review and meta-analysis published in Seizure: European Journal of Epilepsy.

That analysis included six studies with 575 patients who were randomly assigned to MAD or usual diet (UD) plus standard drug therapy. After an average follow-up of 12 weeks, MAD was associated with a higher rate of 50% or greater reduction in seizure frequency (relative risk [RR], 6.28; 95% CI, 3.52-10.50; P < .001), both in adults with drug-resistant epilepsy (RR, 6.14; 95% CI, 1.15-32.66; P = .033) and children (RR, 6.28; 95% CI, 3.43-11.49; P < .001).

MAD was also associated with a higher seizure freedom rate compared with UD (RR, 5.94; 95% CI, 1.93-18.31; P = .002).
 

Cholesterol Concern

In Dr. Raj’s analysis, there was an increment in blood total cholesterol level after 3 months of MAD (standard mean difference, -0.82; 95% CI, -1.23 to -0.40; P = .0001).

Concern about elevated blood cholesterol affecting coronary artery disease risk may explain why doctors sometimes shy away from recommending the MAD to their adult patients. “Some may not want to take that risk; you don’t want patients to succumb to coronary artery disease,” said Dr. Raj.

She noted that 3 months “is a very short time period,” and studies looking at cholesterol levels at the end of at least 1 year are needed to determine whether levels return to normal.

“We’re seeing a lot of literature now that suggests dietary intake does not really have a link with cholesterol levels,” she said. If this can be proven, “then this is definitely a great therapy.” 

The evidence of cardiovascular safety of the MAD includes a study of 37 patients who showed that although total cholesterol and low-density lipoprotein (LDL) cholesterol increased over the first 3 months of MAD treatment, these values normalized within 1 year of treatment, including in patients treated with MAD for more than 3 years.
 

Primary Diet Recommendation

This news organization asked one of the authors of that study, Mackenzie C. Cervenka, MD, professor of neurology and medical director of the Adult Epilepsy Diet Center, Johns Hopkins Hospital, Baltimore, Maryland, to comment on the new research.

She said that she was “thrilled” to see more evidence showing that this diet therapy can be as effective for adults as for children. “This is a really important message to get out there.”

At her adult epilepsy diet center, the MAD is the “primary” diet recommended for patients who are resistant to seizure medication, not tube fed, and are keen to try diet therapy, said Dr. Cervenka.

In her experience, the likelihood of having a 50% or greater seizure reduction is about 40% among medication-resistant patients, “so very similar to what they reported in that review,” she said.

However, she noted that she emphasizes to patients that “diet therapy is not meant to be monotherapy.”

Dr. Cervenka’s team is examining LDL cholesterol levels as well as LDL particle size in adults who have been on the MAD for 2 years. LDL particle size, she noted, is a better predictor of long-term cardiovascular health. 

No conflicts of interest were reported.
 

A version of this article appeared on Medscape.com.

ORLANDO — A new review adds to growing evidence that the modified Atkins diet (MAD) significantly reduces seizures in adults with drug-resistant epilepsy.

The results of the small new review and meta-analysis suggest that “the MAD may be an effective adjuvant therapy for older patients who have failed anti-seizure medications,” study investigator Aiswarya Raj, MBBS, Aster Malabar Institute of Medical Sciences, Kerala, India, said in an interview.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Paucity of Adult Data 

The MAD is a less restrictive hybrid of the ketogenic diet that limits carbohydrate intake and encourages fat consumption. It does not restrict fluids, calories, or proteins and does not require fats to be weighed or measured.

The diet includes fewer carbohydrates than the traditional Atkins diet and places more emphasis on fat intake. Dr. Raj said that the research suggests that the MAD “is a promising therapy in pediatric populations, but there’s not a lot of data in adults.”

Dr. Raj noted that this diet type has not been that popular in patients who clinicians believe might be better treated with drug therapy, possibly because of concern about the cardiac impact of consuming high-fat foods.

After conducting a systematic literature review assessing the efficacy of MAD in adults, the researchers included three randomized controlled trials and four observational studies published from January 2000 to May 2023 in the analysis.

The randomized controlled trials in the review assessed the primary outcome, a greater than 50% seizure reduction, at the end of 2 months, 3 months, and 6 months. In the MAD group, 32.5% of participants had more than a 50% seizure reduction vs 3% in the control group (odds ratio [OR], 12.62; 95% CI, 4.05-39.29; P < .0001).

Four participants who followed the diet achieved complete seizure-freedom compared with no participants in the control group (OR, 16.20; 95% CI, 0.82-318.82; P = .07).

The prospective studies examined this outcome at the end of 1 month or 3 months. In these studies, 41.9% of individuals experienced more than a 50% seizure reduction after 1 month of following the MAD, and 34.2% experienced this reduction after 3 months (OR, 1.41; 95% CI, 0.79-2.52; P = .24), with zero heterogeneity across studies.

It’s difficult to interpret the difference in seizure reduction between 1 and 3 months of therapy, Dr. Raj noted, because “there’s always the issue of compliance when you put a patient on a long-term diet.”

Positive results for MAD in adults were shown in another recent systematic review and meta-analysis published in Seizure: European Journal of Epilepsy.

That analysis included six studies with 575 patients who were randomly assigned to MAD or usual diet (UD) plus standard drug therapy. After an average follow-up of 12 weeks, MAD was associated with a higher rate of 50% or greater reduction in seizure frequency (relative risk [RR], 6.28; 95% CI, 3.52-10.50; P < .001), both in adults with drug-resistant epilepsy (RR, 6.14; 95% CI, 1.15-32.66; P = .033) and children (RR, 6.28; 95% CI, 3.43-11.49; P < .001).

MAD was also associated with a higher seizure freedom rate compared with UD (RR, 5.94; 95% CI, 1.93-18.31; P = .002).
 

Cholesterol Concern

In Dr. Raj’s analysis, there was an increment in blood total cholesterol level after 3 months of MAD (standard mean difference, -0.82; 95% CI, -1.23 to -0.40; P = .0001).

Concern about elevated blood cholesterol affecting coronary artery disease risk may explain why doctors sometimes shy away from recommending the MAD to their adult patients. “Some may not want to take that risk; you don’t want patients to succumb to coronary artery disease,” said Dr. Raj.

She noted that 3 months “is a very short time period,” and studies looking at cholesterol levels at the end of at least 1 year are needed to determine whether levels return to normal.

“We’re seeing a lot of literature now that suggests dietary intake does not really have a link with cholesterol levels,” she said. If this can be proven, “then this is definitely a great therapy.” 

The evidence of cardiovascular safety of the MAD includes a study of 37 patients who showed that although total cholesterol and low-density lipoprotein (LDL) cholesterol increased over the first 3 months of MAD treatment, these values normalized within 1 year of treatment, including in patients treated with MAD for more than 3 years.
 

Primary Diet Recommendation

This news organization asked one of the authors of that study, Mackenzie C. Cervenka, MD, professor of neurology and medical director of the Adult Epilepsy Diet Center, Johns Hopkins Hospital, Baltimore, Maryland, to comment on the new research.

She said that she was “thrilled” to see more evidence showing that this diet therapy can be as effective for adults as for children. “This is a really important message to get out there.”

At her adult epilepsy diet center, the MAD is the “primary” diet recommended for patients who are resistant to seizure medication, not tube fed, and are keen to try diet therapy, said Dr. Cervenka.

In her experience, the likelihood of having a 50% or greater seizure reduction is about 40% among medication-resistant patients, “so very similar to what they reported in that review,” she said.

However, she noted that she emphasizes to patients that “diet therapy is not meant to be monotherapy.”

Dr. Cervenka’s team is examining LDL cholesterol levels as well as LDL particle size in adults who have been on the MAD for 2 years. LDL particle size, she noted, is a better predictor of long-term cardiovascular health. 

No conflicts of interest were reported.
 

A version of this article appeared on Medscape.com.

ORLANDO — A new review adds to growing evidence that the modified Atkins diet (MAD) significantly reduces seizures in adults with drug-resistant epilepsy.

The results of the small new review and meta-analysis suggest that “the MAD may be an effective adjuvant therapy for older patients who have failed anti-seizure medications,” study investigator Aiswarya Raj, MBBS, Aster Malabar Institute of Medical Sciences, Kerala, India, said in an interview.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Paucity of Adult Data 

The MAD is a less restrictive hybrid of the ketogenic diet that limits carbohydrate intake and encourages fat consumption. It does not restrict fluids, calories, or proteins and does not require fats to be weighed or measured.

The diet includes fewer carbohydrates than the traditional Atkins diet and places more emphasis on fat intake. Dr. Raj said that the research suggests that the MAD “is a promising therapy in pediatric populations, but there’s not a lot of data in adults.”

Dr. Raj noted that this diet type has not been that popular in patients who clinicians believe might be better treated with drug therapy, possibly because of concern about the cardiac impact of consuming high-fat foods.

After conducting a systematic literature review assessing the efficacy of MAD in adults, the researchers included three randomized controlled trials and four observational studies published from January 2000 to May 2023 in the analysis.

The randomized controlled trials in the review assessed the primary outcome, a greater than 50% seizure reduction, at the end of 2 months, 3 months, and 6 months. In the MAD group, 32.5% of participants had more than a 50% seizure reduction vs 3% in the control group (odds ratio [OR], 12.62; 95% CI, 4.05-39.29; P < .0001).

Four participants who followed the diet achieved complete seizure-freedom compared with no participants in the control group (OR, 16.20; 95% CI, 0.82-318.82; P = .07).

The prospective studies examined this outcome at the end of 1 month or 3 months. In these studies, 41.9% of individuals experienced more than a 50% seizure reduction after 1 month of following the MAD, and 34.2% experienced this reduction after 3 months (OR, 1.41; 95% CI, 0.79-2.52; P = .24), with zero heterogeneity across studies.

It’s difficult to interpret the difference in seizure reduction between 1 and 3 months of therapy, Dr. Raj noted, because “there’s always the issue of compliance when you put a patient on a long-term diet.”

Positive results for MAD in adults were shown in another recent systematic review and meta-analysis published in Seizure: European Journal of Epilepsy.

That analysis included six studies with 575 patients who were randomly assigned to MAD or usual diet (UD) plus standard drug therapy. After an average follow-up of 12 weeks, MAD was associated with a higher rate of 50% or greater reduction in seizure frequency (relative risk [RR], 6.28; 95% CI, 3.52-10.50; P < .001), both in adults with drug-resistant epilepsy (RR, 6.14; 95% CI, 1.15-32.66; P = .033) and children (RR, 6.28; 95% CI, 3.43-11.49; P < .001).

MAD was also associated with a higher seizure freedom rate compared with UD (RR, 5.94; 95% CI, 1.93-18.31; P = .002).
 

Cholesterol Concern

In Dr. Raj’s analysis, there was an increment in blood total cholesterol level after 3 months of MAD (standard mean difference, -0.82; 95% CI, -1.23 to -0.40; P = .0001).

Concern about elevated blood cholesterol affecting coronary artery disease risk may explain why doctors sometimes shy away from recommending the MAD to their adult patients. “Some may not want to take that risk; you don’t want patients to succumb to coronary artery disease,” said Dr. Raj.

She noted that 3 months “is a very short time period,” and studies looking at cholesterol levels at the end of at least 1 year are needed to determine whether levels return to normal.

“We’re seeing a lot of literature now that suggests dietary intake does not really have a link with cholesterol levels,” she said. If this can be proven, “then this is definitely a great therapy.” 

The evidence of cardiovascular safety of the MAD includes a study of 37 patients who showed that although total cholesterol and low-density lipoprotein (LDL) cholesterol increased over the first 3 months of MAD treatment, these values normalized within 1 year of treatment, including in patients treated with MAD for more than 3 years.
 

Primary Diet Recommendation

This news organization asked one of the authors of that study, Mackenzie C. Cervenka, MD, professor of neurology and medical director of the Adult Epilepsy Diet Center, Johns Hopkins Hospital, Baltimore, Maryland, to comment on the new research.

She said that she was “thrilled” to see more evidence showing that this diet therapy can be as effective for adults as for children. “This is a really important message to get out there.”

At her adult epilepsy diet center, the MAD is the “primary” diet recommended for patients who are resistant to seizure medication, not tube fed, and are keen to try diet therapy, said Dr. Cervenka.

In her experience, the likelihood of having a 50% or greater seizure reduction is about 40% among medication-resistant patients, “so very similar to what they reported in that review,” she said.

However, she noted that she emphasizes to patients that “diet therapy is not meant to be monotherapy.”

Dr. Cervenka’s team is examining LDL cholesterol levels as well as LDL particle size in adults who have been on the MAD for 2 years. LDL particle size, she noted, is a better predictor of long-term cardiovascular health. 

No conflicts of interest were reported.
 

A version of this article appeared on Medscape.com.

ORLANDO — Older people with epilepsy who live in deprived neighborhoods with lower socioeconomic status, fewer educational opportunities, and less access to health care have poorer memory, executive function, and processing speed than those living in more affluent areas, early research suggests.

Seniors with epilepsy present with multiple comorbidities, including, for example, hypertension and diabetes, and they are at increased risk of developing dementia, said study investigator Anny Reyes, PhD, a postdoctoral scholar at the University of California at San Diego.

Past research has shown neighborhood disadvantage is associated with numerous adverse health outcomes, including an increased risk for developing Alzheimer’s disease and related dementias (ADRD).

“We already know epilepsy on its own increases risks for dementia, and when you add disadvantaged to that, it’s going to increase the risk even more,” said Dr. Reyes.

Neurologists should ask their older patients with epilepsy, many of whom live alone, about food insecurity and access to resources “not just within the hospital system but also within their community,” she said.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Proxy Measure of Disadvantage

The incidence and prevalence of epilepsy increases with age. Older adults represent the fastest growing segment of individuals with epilepsy, said Dr. Reyes.

The new study included 40 patients with focal epilepsy, average age 67 years, from three areas: San Diego, California; Madison, Wisconsin; and Cleveland, Ohio.

Researchers collected clinical and sociodemographic information as well as vascular biomarkers. They also gathered individual-level data, including income, parental education levels, details on childhood upbringing, etc.

Using residential addresses, investigators determined the area deprivation index (ADI) value for study participants. The ADI is a proxy measure for neighborhood-level socioeconomic disadvantage that captures factors such a poverty, employment, housing, and education opportunities.

ADI values range from 1 to 10, with a higher number indicating greater neighborhood disadvantage. About 30% of the cohort had an ADI decile greater than 6.

Researchers divided subjects into Most Disadvantaged (ADI greater than 7) and Least Disadvantaged (AD 7 or less). The two groups were similar with regard to age, education level, and race/ethnicity.

But those from the most disadvantaged areas were younger, taking more antiseizure medications, had fewer years of education, lower levels of father’s education, less personal and family income, and were less likely to be diagnosed with hypertension.

Study subjects completed neuropsychological testing, including:

• Measures of learning (Rey Auditory Verbal Learning Test [RAVLT] Learning Over Trials; Wechsler Memory Scale 4th Edition [WMS-4] Logical Memory [LM] Story B immediate; and WMS-4 Visual Reproduction [VR] immediate)
• Memory (RAVLT delayed recall, WMS-4 LM delayed recall, and WMS-4 VR delayed recall)
• Language (Multilingual Naming Test, Auditory Naming Test, and animal fluency)
• Executive function/processing speed (Letter fluency and Trail-Making Test Parts A and B)

The study found a correlation between higher ADI (most disadvantaged) and poorer performance on learning (Spearman rho: -0.433; 95% CI -0.664 to -0.126; P = .006), memory (r = -0.496; 95% CI -0.707 to -0.205; P = .001), and executive function/processes speed (r = -0.315; 95% CI -0.577 to 0.006; P = .048), but no significant association with language.

Looking at individual-level data, the study found memory and processing speed “were driving the relationship, and again, patients had worse performance when they were coming from the most disadvantaged neighborhoods,” said Dr. Reyes.

The investigators also examined mood, including depression and anxiety, and subjective complaints of cognitive problems. “We found those patients residing in the most disadvantaged neighborhoods complained more about memory problems,” she said.

The results underscore the need for community-level interventions “that could provide resources in support of these older adults and their families and connect them to services we know are good for brain health,” said Dr. Reyes.

Alzheimer’s disease experts “have done a really good job of this, but this is new for epilepsy,” she added. “This gives us a great opportunity to kind of bridge the worlds of dementia and epilepsy.”
 

Novel Research

Commenting on the research, Rani Sarkis, MD, assistant professor of neurology, Brigham and Women’s Hospital, Boston, said the study is “very useful” as it ties social determinants of health to cognition.

“We have not been doing that” in people with epilepsy, he said.

The study, one of the first to look at the link between disadvantaged neighborhoods and cognitive impairment, “has very important” public health implications, including the need to consider access to activities that promote cognitive resilience and other brain health initiatives, said Dr. Sarkis.

Another larger study that looked at neighborhood deprivation and cognition in epilepsy was also presented at the AES meeting and published earlier this year in the journal Neurology.

That study included 800 patients with pharmaco-resistant temporal lobe epilepsy being evaluated for surgery at the Cleveland Clinic, mean age about 38 years. It examined numerous cognitive domains as well as depression and anxiety in relation to ADI generated by patient addresses and split into quintiles from least to most disadvantaged.

After controlling for covariants, the study found scores for all cognitive domains were significantly worse in the most disadvantaged quintile except for executive function, which was close to reaching significance (P = .052), said lead author Robyn M. Busch, PhD, a clinical neuropsychologist in the Epilepsy Center, Department of Neurology, Cleveland Clinic.

The study also found people in the most disadvantaged areas had more symptoms of depression and anxiety compared with people in the least disadvantaged areas, said Busch.
 

A Complex Issue

Although the exact mechanism tying disadvantaged areas to cognition in epilepsy isn’t fully understood, having less access to health care and educational opportunities, poor nutrition, and being under chronic stress “are all things that affect the brain,” said Dr. Busch.

“This is super complex and it’s going to be really difficult to tease apart, but we’d like to look at imaging data to see if it’s something structural, if there are functional changes in the brain or something that might help us understand this better.”

But it’s also possible that having epilepsy “might be pushing people into environments” that offer fewer employment and educational opportunities and less access to resources, she said.

The study authors and Dr. Sarkis report no relevant financial relationships.

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

ORLANDO — Older people with epilepsy who live in deprived neighborhoods with lower socioeconomic status, fewer educational opportunities, and less access to health care have poorer memory, executive function, and processing speed than those living in more affluent areas, early research suggests.

Seniors with epilepsy present with multiple comorbidities, including, for example, hypertension and diabetes, and they are at increased risk of developing dementia, said study investigator Anny Reyes, PhD, a postdoctoral scholar at the University of California at San Diego.

Past research has shown neighborhood disadvantage is associated with numerous adverse health outcomes, including an increased risk for developing Alzheimer’s disease and related dementias (ADRD).

“We already know epilepsy on its own increases risks for dementia, and when you add disadvantaged to that, it’s going to increase the risk even more,” said Dr. Reyes.

Neurologists should ask their older patients with epilepsy, many of whom live alone, about food insecurity and access to resources “not just within the hospital system but also within their community,” she said.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Proxy Measure of Disadvantage

The incidence and prevalence of epilepsy increases with age. Older adults represent the fastest growing segment of individuals with epilepsy, said Dr. Reyes.

The new study included 40 patients with focal epilepsy, average age 67 years, from three areas: San Diego, California; Madison, Wisconsin; and Cleveland, Ohio.

Researchers collected clinical and sociodemographic information as well as vascular biomarkers. They also gathered individual-level data, including income, parental education levels, details on childhood upbringing, etc.

Using residential addresses, investigators determined the area deprivation index (ADI) value for study participants. The ADI is a proxy measure for neighborhood-level socioeconomic disadvantage that captures factors such a poverty, employment, housing, and education opportunities.

ADI values range from 1 to 10, with a higher number indicating greater neighborhood disadvantage. About 30% of the cohort had an ADI decile greater than 6.

Researchers divided subjects into Most Disadvantaged (ADI greater than 7) and Least Disadvantaged (AD 7 or less). The two groups were similar with regard to age, education level, and race/ethnicity.

But those from the most disadvantaged areas were younger, taking more antiseizure medications, had fewer years of education, lower levels of father’s education, less personal and family income, and were less likely to be diagnosed with hypertension.

Study subjects completed neuropsychological testing, including:

• Measures of learning (Rey Auditory Verbal Learning Test [RAVLT] Learning Over Trials; Wechsler Memory Scale 4th Edition [WMS-4] Logical Memory [LM] Story B immediate; and WMS-4 Visual Reproduction [VR] immediate)
• Memory (RAVLT delayed recall, WMS-4 LM delayed recall, and WMS-4 VR delayed recall)
• Language (Multilingual Naming Test, Auditory Naming Test, and animal fluency)
• Executive function/processing speed (Letter fluency and Trail-Making Test Parts A and B)

The study found a correlation between higher ADI (most disadvantaged) and poorer performance on learning (Spearman rho: -0.433; 95% CI -0.664 to -0.126; P = .006), memory (r = -0.496; 95% CI -0.707 to -0.205; P = .001), and executive function/processes speed (r = -0.315; 95% CI -0.577 to 0.006; P = .048), but no significant association with language.

Looking at individual-level data, the study found memory and processing speed “were driving the relationship, and again, patients had worse performance when they were coming from the most disadvantaged neighborhoods,” said Dr. Reyes.

The investigators also examined mood, including depression and anxiety, and subjective complaints of cognitive problems. “We found those patients residing in the most disadvantaged neighborhoods complained more about memory problems,” she said.

The results underscore the need for community-level interventions “that could provide resources in support of these older adults and their families and connect them to services we know are good for brain health,” said Dr. Reyes.

Alzheimer’s disease experts “have done a really good job of this, but this is new for epilepsy,” she added. “This gives us a great opportunity to kind of bridge the worlds of dementia and epilepsy.”
 

Novel Research

Commenting on the research, Rani Sarkis, MD, assistant professor of neurology, Brigham and Women’s Hospital, Boston, said the study is “very useful” as it ties social determinants of health to cognition.

“We have not been doing that” in people with epilepsy, he said.

The study, one of the first to look at the link between disadvantaged neighborhoods and cognitive impairment, “has very important” public health implications, including the need to consider access to activities that promote cognitive resilience and other brain health initiatives, said Dr. Sarkis.

Another larger study that looked at neighborhood deprivation and cognition in epilepsy was also presented at the AES meeting and published earlier this year in the journal Neurology.

That study included 800 patients with pharmaco-resistant temporal lobe epilepsy being evaluated for surgery at the Cleveland Clinic, mean age about 38 years. It examined numerous cognitive domains as well as depression and anxiety in relation to ADI generated by patient addresses and split into quintiles from least to most disadvantaged.

After controlling for covariants, the study found scores for all cognitive domains were significantly worse in the most disadvantaged quintile except for executive function, which was close to reaching significance (P = .052), said lead author Robyn M. Busch, PhD, a clinical neuropsychologist in the Epilepsy Center, Department of Neurology, Cleveland Clinic.

The study also found people in the most disadvantaged areas had more symptoms of depression and anxiety compared with people in the least disadvantaged areas, said Busch.
 

A Complex Issue

Although the exact mechanism tying disadvantaged areas to cognition in epilepsy isn’t fully understood, having less access to health care and educational opportunities, poor nutrition, and being under chronic stress “are all things that affect the brain,” said Dr. Busch.

“This is super complex and it’s going to be really difficult to tease apart, but we’d like to look at imaging data to see if it’s something structural, if there are functional changes in the brain or something that might help us understand this better.”

But it’s also possible that having epilepsy “might be pushing people into environments” that offer fewer employment and educational opportunities and less access to resources, she said.

The study authors and Dr. Sarkis report no relevant financial relationships.

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

ORLANDO — Older people with epilepsy who live in deprived neighborhoods with lower socioeconomic status, fewer educational opportunities, and less access to health care have poorer memory, executive function, and processing speed than those living in more affluent areas, early research suggests.

Seniors with epilepsy present with multiple comorbidities, including, for example, hypertension and diabetes, and they are at increased risk of developing dementia, said study investigator Anny Reyes, PhD, a postdoctoral scholar at the University of California at San Diego.

Past research has shown neighborhood disadvantage is associated with numerous adverse health outcomes, including an increased risk for developing Alzheimer’s disease and related dementias (ADRD).

“We already know epilepsy on its own increases risks for dementia, and when you add disadvantaged to that, it’s going to increase the risk even more,” said Dr. Reyes.

Neurologists should ask their older patients with epilepsy, many of whom live alone, about food insecurity and access to resources “not just within the hospital system but also within their community,” she said.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Proxy Measure of Disadvantage

The incidence and prevalence of epilepsy increases with age. Older adults represent the fastest growing segment of individuals with epilepsy, said Dr. Reyes.

The new study included 40 patients with focal epilepsy, average age 67 years, from three areas: San Diego, California; Madison, Wisconsin; and Cleveland, Ohio.

Researchers collected clinical and sociodemographic information as well as vascular biomarkers. They also gathered individual-level data, including income, parental education levels, details on childhood upbringing, etc.

Using residential addresses, investigators determined the area deprivation index (ADI) value for study participants. The ADI is a proxy measure for neighborhood-level socioeconomic disadvantage that captures factors such a poverty, employment, housing, and education opportunities.

ADI values range from 1 to 10, with a higher number indicating greater neighborhood disadvantage. About 30% of the cohort had an ADI decile greater than 6.

Researchers divided subjects into Most Disadvantaged (ADI greater than 7) and Least Disadvantaged (AD 7 or less). The two groups were similar with regard to age, education level, and race/ethnicity.

But those from the most disadvantaged areas were younger, taking more antiseizure medications, had fewer years of education, lower levels of father’s education, less personal and family income, and were less likely to be diagnosed with hypertension.

Study subjects completed neuropsychological testing, including:

• Measures of learning (Rey Auditory Verbal Learning Test [RAVLT] Learning Over Trials; Wechsler Memory Scale 4th Edition [WMS-4] Logical Memory [LM] Story B immediate; and WMS-4 Visual Reproduction [VR] immediate)
• Memory (RAVLT delayed recall, WMS-4 LM delayed recall, and WMS-4 VR delayed recall)
• Language (Multilingual Naming Test, Auditory Naming Test, and animal fluency)
• Executive function/processing speed (Letter fluency and Trail-Making Test Parts A and B)

The study found a correlation between higher ADI (most disadvantaged) and poorer performance on learning (Spearman rho: -0.433; 95% CI -0.664 to -0.126; P = .006), memory (r = -0.496; 95% CI -0.707 to -0.205; P = .001), and executive function/processes speed (r = -0.315; 95% CI -0.577 to 0.006; P = .048), but no significant association with language.

Looking at individual-level data, the study found memory and processing speed “were driving the relationship, and again, patients had worse performance when they were coming from the most disadvantaged neighborhoods,” said Dr. Reyes.

The investigators also examined mood, including depression and anxiety, and subjective complaints of cognitive problems. “We found those patients residing in the most disadvantaged neighborhoods complained more about memory problems,” she said.

The results underscore the need for community-level interventions “that could provide resources in support of these older adults and their families and connect them to services we know are good for brain health,” said Dr. Reyes.

Alzheimer’s disease experts “have done a really good job of this, but this is new for epilepsy,” she added. “This gives us a great opportunity to kind of bridge the worlds of dementia and epilepsy.”
 

Novel Research

Commenting on the research, Rani Sarkis, MD, assistant professor of neurology, Brigham and Women’s Hospital, Boston, said the study is “very useful” as it ties social determinants of health to cognition.

“We have not been doing that” in people with epilepsy, he said.

The study, one of the first to look at the link between disadvantaged neighborhoods and cognitive impairment, “has very important” public health implications, including the need to consider access to activities that promote cognitive resilience and other brain health initiatives, said Dr. Sarkis.

Another larger study that looked at neighborhood deprivation and cognition in epilepsy was also presented at the AES meeting and published earlier this year in the journal Neurology.

That study included 800 patients with pharmaco-resistant temporal lobe epilepsy being evaluated for surgery at the Cleveland Clinic, mean age about 38 years. It examined numerous cognitive domains as well as depression and anxiety in relation to ADI generated by patient addresses and split into quintiles from least to most disadvantaged.

After controlling for covariants, the study found scores for all cognitive domains were significantly worse in the most disadvantaged quintile except for executive function, which was close to reaching significance (P = .052), said lead author Robyn M. Busch, PhD, a clinical neuropsychologist in the Epilepsy Center, Department of Neurology, Cleveland Clinic.

The study also found people in the most disadvantaged areas had more symptoms of depression and anxiety compared with people in the least disadvantaged areas, said Busch.
 

A Complex Issue

Although the exact mechanism tying disadvantaged areas to cognition in epilepsy isn’t fully understood, having less access to health care and educational opportunities, poor nutrition, and being under chronic stress “are all things that affect the brain,” said Dr. Busch.

“This is super complex and it’s going to be really difficult to tease apart, but we’d like to look at imaging data to see if it’s something structural, if there are functional changes in the brain or something that might help us understand this better.”

But it’s also possible that having epilepsy “might be pushing people into environments” that offer fewer employment and educational opportunities and less access to resources, she said.

The study authors and Dr. Sarkis report no relevant financial relationships.

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

ORLANDO — Genetic testing is warranted in patients with epilepsy of unknown origin, new research suggests. Investigators found that pathogenic genetic variants were identified in over 40% of patients with epilepsy of unknown cause who underwent genetic testing.

Such testing is particularly beneficial for those with early-onset epilepsy and those with comorbid developmental delay, said study investigator Yi Li, MD, PhD, clinical assistant professor, Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, California. 

But every patient with epilepsy of unknown etiology needs to consider genetic testing as part of their standard workup.

Dr. Li noted research showing that a diagnosis of a genetic epilepsy leads to alteration of treatment in about 20% of cases — for example, starting a specific antiseizure medication or avoiding a treatment such as a sodium channel blocker in patients diagnosed with Dravet syndrome. A genetic diagnosis also may make patients eligible for clinical trials investigating gene therapies. 

Genetic testing results may end a long and exhausting “diagnostic odyssey” that families have been on, she said. Patients often wait more than a decade to get genetic testing, the study found.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Major Delays

About 20%-30% of epilepsy is caused by acquired conditions such as stroke, tumor, or head injury. The remaining 70%-80% is believed to be due to one or more genetic factors.

Genetic testing has become standard for children with early-onset epilepsy, but it’s not common practice among adults with the condition — at least not yet.

The retrospective study involved a chart review of patient electronic health records from 2018-2023. Researchers used the Stanford electronic health record Cohort Discovery tool (STARR) database to identify 286 patients over age 16 years with epilepsy who had records of genetic testing.

Of the 286 patients, 148 were male and 138 female, and mean age was approximately 30 years. Among those with known epilepsy types, 53.6% had focal epilepsy and 28.8% had generalized epilpesy.

The mean age of seizure onset was 11.9 years, but the mean age at genetic testing was 25.1 years. “There’s a gap of about 13 or 14 years for genetic workup after a patient has a first seizure,” said Dr. Li.

Such a “huge delay” means patients may miss out on “potential precision treatment choices,” she said.

And having a diagnosis can connect patients to others with the same condition as well as to related organizations and communities that offer support, she added.

Types of genetic testing identified in the study included panel testing, which looks at the genes associated with epilepsy; whole exome sequencing (WES), which includes all 20,000 genes in one test; and microarray testing, which assesses missing sections of chromosomes. WES had the highest diagnostic yield (48%), followed by genetic panel testing (32.7%) and microarray testing (20.9%).

These tests collectively identified pathogenic variants in 40.9% of patients. In addition, test results showed that 53.10% of patients had variants of uncertain significance.

In the full cohort, the most commonly identified variants were mutations in TSC1 (which causes tuberous sclerosis, SCN1A (which causes Dravet syndrome), and MECP2. Among patients with seizure onset after age 1 year, MECP2 and DEPDC5 were the two most commonly identified pathogenic variants.

Researchers examined factors possibly associated with a higher risk for genetic epilepsy, including family history, comorbid developmental delay, febrile seizures, status epilepticus, perinatal injury, and seizure onset age. In an adjusted analysis, comorbid developmental delay (estimate 2.338; 95% confidence interval [CI], 1.402-3.900; P =.001) and seizure onset before 1 year (estimate 2.365; 95% CI, 1.282-4.366; P =.006) predicted higher yield of pathogenic variants related to epilepsy.

Dr. Li noted that study participants with a family history of epilepsy were not more likely to test positive for a genetic link, so doctors shouldn’t rule out testing in patients if there’s no family history.

Both the International League Against Epilepsy (ILAE) and the National Society of Genetic Counselors (NSGC) recommend genetic testing in adult epilepsy patients, with the AES endorsing the NSGC guideline.

Although testing is becoming increasingly accessible, insurance companies don’t always cover the cost.

Dr. Li said she hopes her research raises awareness among clinicians that there’s more they can do to improve care for epilepsy patients. “We should offer patients genetic testing if we don’t have a clear etiology.”
 

Valuable Evidence

Commenting on the research findings, Annapurna Poduri, MD, MPH, director, Epilepsy Genetics Program, Boston Children’s Hospital, Boston, Massachusetts, said this research “is incredibly important.”

“What’s really telling about this study and others that have come up over the last few years is they’re real-world retrospective studies, so they’re looking back at patients who have been seen over many, many years.”

The research provides clinicians, insurance companies, and others with evidence that genetic testing is “valuable and can actually improve outcomes,” said Dr. Poduri.

She noted that 20 years ago, there were only a handful of genes identified as being involved with epilepsy, most related to sodium or potassium channels. But since then, “the technology has just raced ahead” to the point where now “dozens of genes” have been identified.

Not only does knowing the genetic basis of epilepsy improve management, but it offers families some peace of mind. “They blame themselves” for their loved one’s condition, said Dr. Poduri. “They may worry it was something they did in pregnancy; for example, maybe it was because [they] didn’t take that vitamin one day.”

Diagnostic certainty also means that patients “don’t have to do more tests which might be invasive” and unnecessarily costly.

Drs. Li and Poduri report no relevant conflicts of interest.

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

ORLANDO — Genetic testing is warranted in patients with epilepsy of unknown origin, new research suggests. Investigators found that pathogenic genetic variants were identified in over 40% of patients with epilepsy of unknown cause who underwent genetic testing.

Such testing is particularly beneficial for those with early-onset epilepsy and those with comorbid developmental delay, said study investigator Yi Li, MD, PhD, clinical assistant professor, Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, California. 

But every patient with epilepsy of unknown etiology needs to consider genetic testing as part of their standard workup.

Dr. Li noted research showing that a diagnosis of a genetic epilepsy leads to alteration of treatment in about 20% of cases — for example, starting a specific antiseizure medication or avoiding a treatment such as a sodium channel blocker in patients diagnosed with Dravet syndrome. A genetic diagnosis also may make patients eligible for clinical trials investigating gene therapies. 

Genetic testing results may end a long and exhausting “diagnostic odyssey” that families have been on, she said. Patients often wait more than a decade to get genetic testing, the study found.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Major Delays

About 20%-30% of epilepsy is caused by acquired conditions such as stroke, tumor, or head injury. The remaining 70%-80% is believed to be due to one or more genetic factors.

Genetic testing has become standard for children with early-onset epilepsy, but it’s not common practice among adults with the condition — at least not yet.

The retrospective study involved a chart review of patient electronic health records from 2018-2023. Researchers used the Stanford electronic health record Cohort Discovery tool (STARR) database to identify 286 patients over age 16 years with epilepsy who had records of genetic testing.

Of the 286 patients, 148 were male and 138 female, and mean age was approximately 30 years. Among those with known epilepsy types, 53.6% had focal epilepsy and 28.8% had generalized epilpesy.

The mean age of seizure onset was 11.9 years, but the mean age at genetic testing was 25.1 years. “There’s a gap of about 13 or 14 years for genetic workup after a patient has a first seizure,” said Dr. Li.

Such a “huge delay” means patients may miss out on “potential precision treatment choices,” she said.

And having a diagnosis can connect patients to others with the same condition as well as to related organizations and communities that offer support, she added.

Types of genetic testing identified in the study included panel testing, which looks at the genes associated with epilepsy; whole exome sequencing (WES), which includes all 20,000 genes in one test; and microarray testing, which assesses missing sections of chromosomes. WES had the highest diagnostic yield (48%), followed by genetic panel testing (32.7%) and microarray testing (20.9%).

These tests collectively identified pathogenic variants in 40.9% of patients. In addition, test results showed that 53.10% of patients had variants of uncertain significance.

In the full cohort, the most commonly identified variants were mutations in TSC1 (which causes tuberous sclerosis, SCN1A (which causes Dravet syndrome), and MECP2. Among patients with seizure onset after age 1 year, MECP2 and DEPDC5 were the two most commonly identified pathogenic variants.

Researchers examined factors possibly associated with a higher risk for genetic epilepsy, including family history, comorbid developmental delay, febrile seizures, status epilepticus, perinatal injury, and seizure onset age. In an adjusted analysis, comorbid developmental delay (estimate 2.338; 95% confidence interval [CI], 1.402-3.900; P =.001) and seizure onset before 1 year (estimate 2.365; 95% CI, 1.282-4.366; P =.006) predicted higher yield of pathogenic variants related to epilepsy.

Dr. Li noted that study participants with a family history of epilepsy were not more likely to test positive for a genetic link, so doctors shouldn’t rule out testing in patients if there’s no family history.

Both the International League Against Epilepsy (ILAE) and the National Society of Genetic Counselors (NSGC) recommend genetic testing in adult epilepsy patients, with the AES endorsing the NSGC guideline.

Although testing is becoming increasingly accessible, insurance companies don’t always cover the cost.

Dr. Li said she hopes her research raises awareness among clinicians that there’s more they can do to improve care for epilepsy patients. “We should offer patients genetic testing if we don’t have a clear etiology.”
 

Valuable Evidence

Commenting on the research findings, Annapurna Poduri, MD, MPH, director, Epilepsy Genetics Program, Boston Children’s Hospital, Boston, Massachusetts, said this research “is incredibly important.”

“What’s really telling about this study and others that have come up over the last few years is they’re real-world retrospective studies, so they’re looking back at patients who have been seen over many, many years.”

The research provides clinicians, insurance companies, and others with evidence that genetic testing is “valuable and can actually improve outcomes,” said Dr. Poduri.

She noted that 20 years ago, there were only a handful of genes identified as being involved with epilepsy, most related to sodium or potassium channels. But since then, “the technology has just raced ahead” to the point where now “dozens of genes” have been identified.

Not only does knowing the genetic basis of epilepsy improve management, but it offers families some peace of mind. “They blame themselves” for their loved one’s condition, said Dr. Poduri. “They may worry it was something they did in pregnancy; for example, maybe it was because [they] didn’t take that vitamin one day.”

Diagnostic certainty also means that patients “don’t have to do more tests which might be invasive” and unnecessarily costly.

Drs. Li and Poduri report no relevant conflicts of interest.

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

ORLANDO — Genetic testing is warranted in patients with epilepsy of unknown origin, new research suggests. Investigators found that pathogenic genetic variants were identified in over 40% of patients with epilepsy of unknown cause who underwent genetic testing.

Such testing is particularly beneficial for those with early-onset epilepsy and those with comorbid developmental delay, said study investigator Yi Li, MD, PhD, clinical assistant professor, Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, California. 

But every patient with epilepsy of unknown etiology needs to consider genetic testing as part of their standard workup.

Dr. Li noted research showing that a diagnosis of a genetic epilepsy leads to alteration of treatment in about 20% of cases — for example, starting a specific antiseizure medication or avoiding a treatment such as a sodium channel blocker in patients diagnosed with Dravet syndrome. A genetic diagnosis also may make patients eligible for clinical trials investigating gene therapies. 

Genetic testing results may end a long and exhausting “diagnostic odyssey” that families have been on, she said. Patients often wait more than a decade to get genetic testing, the study found.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Major Delays

About 20%-30% of epilepsy is caused by acquired conditions such as stroke, tumor, or head injury. The remaining 70%-80% is believed to be due to one or more genetic factors.

Genetic testing has become standard for children with early-onset epilepsy, but it’s not common practice among adults with the condition — at least not yet.

The retrospective study involved a chart review of patient electronic health records from 2018-2023. Researchers used the Stanford electronic health record Cohort Discovery tool (STARR) database to identify 286 patients over age 16 years with epilepsy who had records of genetic testing.

Of the 286 patients, 148 were male and 138 female, and mean age was approximately 30 years. Among those with known epilepsy types, 53.6% had focal epilepsy and 28.8% had generalized epilpesy.

The mean age of seizure onset was 11.9 years, but the mean age at genetic testing was 25.1 years. “There’s a gap of about 13 or 14 years for genetic workup after a patient has a first seizure,” said Dr. Li.

Such a “huge delay” means patients may miss out on “potential precision treatment choices,” she said.

And having a diagnosis can connect patients to others with the same condition as well as to related organizations and communities that offer support, she added.

Types of genetic testing identified in the study included panel testing, which looks at the genes associated with epilepsy; whole exome sequencing (WES), which includes all 20,000 genes in one test; and microarray testing, which assesses missing sections of chromosomes. WES had the highest diagnostic yield (48%), followed by genetic panel testing (32.7%) and microarray testing (20.9%).

These tests collectively identified pathogenic variants in 40.9% of patients. In addition, test results showed that 53.10% of patients had variants of uncertain significance.

In the full cohort, the most commonly identified variants were mutations in TSC1 (which causes tuberous sclerosis, SCN1A (which causes Dravet syndrome), and MECP2. Among patients with seizure onset after age 1 year, MECP2 and DEPDC5 were the two most commonly identified pathogenic variants.

Researchers examined factors possibly associated with a higher risk for genetic epilepsy, including family history, comorbid developmental delay, febrile seizures, status epilepticus, perinatal injury, and seizure onset age. In an adjusted analysis, comorbid developmental delay (estimate 2.338; 95% confidence interval [CI], 1.402-3.900; P =.001) and seizure onset before 1 year (estimate 2.365; 95% CI, 1.282-4.366; P =.006) predicted higher yield of pathogenic variants related to epilepsy.

Dr. Li noted that study participants with a family history of epilepsy were not more likely to test positive for a genetic link, so doctors shouldn’t rule out testing in patients if there’s no family history.

Both the International League Against Epilepsy (ILAE) and the National Society of Genetic Counselors (NSGC) recommend genetic testing in adult epilepsy patients, with the AES endorsing the NSGC guideline.

Although testing is becoming increasingly accessible, insurance companies don’t always cover the cost.

Dr. Li said she hopes her research raises awareness among clinicians that there’s more they can do to improve care for epilepsy patients. “We should offer patients genetic testing if we don’t have a clear etiology.”
 

Valuable Evidence

Commenting on the research findings, Annapurna Poduri, MD, MPH, director, Epilepsy Genetics Program, Boston Children’s Hospital, Boston, Massachusetts, said this research “is incredibly important.”

“What’s really telling about this study and others that have come up over the last few years is they’re real-world retrospective studies, so they’re looking back at patients who have been seen over many, many years.”

The research provides clinicians, insurance companies, and others with evidence that genetic testing is “valuable and can actually improve outcomes,” said Dr. Poduri.

She noted that 20 years ago, there were only a handful of genes identified as being involved with epilepsy, most related to sodium or potassium channels. But since then, “the technology has just raced ahead” to the point where now “dozens of genes” have been identified.

Not only does knowing the genetic basis of epilepsy improve management, but it offers families some peace of mind. “They blame themselves” for their loved one’s condition, said Dr. Poduri. “They may worry it was something they did in pregnancy; for example, maybe it was because [they] didn’t take that vitamin one day.”

Diagnostic certainty also means that patients “don’t have to do more tests which might be invasive” and unnecessarily costly.

Drs. Li and Poduri report no relevant conflicts of interest.

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

ORLANDO — Sleep disorders in people with epilepsy are linked to a significantly higher risk for sudden unexplained death in epilepsy (SUDEP) and all-cause mortality, new research shows.

SUDEP is a major concern for patients with epilepsy, said study investigator Marion Lazaj, MSc, Center for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada, but she believes that SUDEP risk assessment is overly focused on seizure control.

“We want to push the idea that this mortality risk assessment needs to be widened to include sleep factors, and not just sleep disorders but even sleep disturbances,” said Ms. Lazaj.

She also believes physicians should routinely discuss SUDEP with their patients with epilepsy. Given that the incidence of SUDEP is only about 1%, many clinicians don’t want to unduly frighten their patients, she added.

The findings were presented at the annual meeting of the American Epilepsy Society (AES).

The retrospective study included chart data from 1,506 consecutive patients diagnosed with epilepsy at a single center over 4 years. The mean age of participants was about 37 years but there was a large age range, said Ms. Lazaj.

The cohort was divided into two groups. Group 1 included 1130 patients without a comorbid sleep disorder, and Group 2 had 376 patients with a primary comorbid sleep disorder, mostly obstructive sleep apnea (OSA) but also restless leg syndrome or insomnia.

They gathered demographic information including age, sex, employment status, education, and epilepsy-related data such as epilepsy type, duration, the number of anti-seizure medications and relevant information from hospital and emergency room (ER) records.
 

SUDEP Inventory

Researchers assessed SUDEP risk using the revised SUDEP-7 risk inventory. The first four items on this inventory focus on generalized tonic clonic seizure activity and occurrence while others assess the number of antiseizure medicines, epilepsy duration, and the presence of other developmental delays.

Investigators then stratified patients into high risk (score on the SUDEP-7 of 5 or greater) and low mortality risk (score less than 5).

Results showed a significant association between a high mortality risk and having a comorbid sleep disorder (P = .033). Researchers also looked at all-cause mortality, including drownings and suicides, and found a similar significant association (P = .026). There was also an association between high risk and accidents and trauma (P = .042).

The researchers had access to overnight diagnostic polysomnography data for a smaller group of patients. Here, they found decreased sleep efficiency (P =.0098), increased spontaneous arousal index (P = .034), and prolonged sleep onset latency (P = .0000052) were all significantly associated with high SUDEP risk.

From the polysomnographic data, researchers found high SUDEP risk was significantly associated with a diagnosis of OSA (P = .034).
 

Powerful Study

Commenting on the findings, Gordon F. Buchanan, MD, PhD, Beth L. Tross epilepsy associate professor, Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, said he was “very excited” by the research.

“That this study attempts to look through data in a retrospective way and see if there’s additional risk with having comorbid sleep disorders is really interesting and I think really powerful,” he said.

Sleep disorders “are potentially a really simple thing that we can screen for and test for,” he added. He also noted that additional research is needed to replicate the findings.

Dr. Buchanan acknowledged that the SUDEP-7 inventory is not a particularly good tool and said there is a need for a better means of assessment that includes sleep disorders and other factors like sleep states and circadian rhythm, which he said affect SUDEP risk.

Ms. Lazaj and Dr. Buchanan report no relevant financial relationships.

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

ORLANDO — Sleep disorders in people with epilepsy are linked to a significantly higher risk for sudden unexplained death in epilepsy (SUDEP) and all-cause mortality, new research shows.

SUDEP is a major concern for patients with epilepsy, said study investigator Marion Lazaj, MSc, Center for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada, but she believes that SUDEP risk assessment is overly focused on seizure control.

“We want to push the idea that this mortality risk assessment needs to be widened to include sleep factors, and not just sleep disorders but even sleep disturbances,” said Ms. Lazaj.

She also believes physicians should routinely discuss SUDEP with their patients with epilepsy. Given that the incidence of SUDEP is only about 1%, many clinicians don’t want to unduly frighten their patients, she added.

The findings were presented at the annual meeting of the American Epilepsy Society (AES).

The retrospective study included chart data from 1,506 consecutive patients diagnosed with epilepsy at a single center over 4 years. The mean age of participants was about 37 years but there was a large age range, said Ms. Lazaj.

The cohort was divided into two groups. Group 1 included 1130 patients without a comorbid sleep disorder, and Group 2 had 376 patients with a primary comorbid sleep disorder, mostly obstructive sleep apnea (OSA) but also restless leg syndrome or insomnia.

They gathered demographic information including age, sex, employment status, education, and epilepsy-related data such as epilepsy type, duration, the number of anti-seizure medications and relevant information from hospital and emergency room (ER) records.
 

SUDEP Inventory

Researchers assessed SUDEP risk using the revised SUDEP-7 risk inventory. The first four items on this inventory focus on generalized tonic clonic seizure activity and occurrence while others assess the number of antiseizure medicines, epilepsy duration, and the presence of other developmental delays.

Investigators then stratified patients into high risk (score on the SUDEP-7 of 5 or greater) and low mortality risk (score less than 5).

Results showed a significant association between a high mortality risk and having a comorbid sleep disorder (P = .033). Researchers also looked at all-cause mortality, including drownings and suicides, and found a similar significant association (P = .026). There was also an association between high risk and accidents and trauma (P = .042).

The researchers had access to overnight diagnostic polysomnography data for a smaller group of patients. Here, they found decreased sleep efficiency (P =.0098), increased spontaneous arousal index (P = .034), and prolonged sleep onset latency (P = .0000052) were all significantly associated with high SUDEP risk.

From the polysomnographic data, researchers found high SUDEP risk was significantly associated with a diagnosis of OSA (P = .034).
 

Powerful Study

Commenting on the findings, Gordon F. Buchanan, MD, PhD, Beth L. Tross epilepsy associate professor, Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, said he was “very excited” by the research.

“That this study attempts to look through data in a retrospective way and see if there’s additional risk with having comorbid sleep disorders is really interesting and I think really powerful,” he said.

Sleep disorders “are potentially a really simple thing that we can screen for and test for,” he added. He also noted that additional research is needed to replicate the findings.

Dr. Buchanan acknowledged that the SUDEP-7 inventory is not a particularly good tool and said there is a need for a better means of assessment that includes sleep disorders and other factors like sleep states and circadian rhythm, which he said affect SUDEP risk.

Ms. Lazaj and Dr. Buchanan report no relevant financial relationships.

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

ORLANDO — Sleep disorders in people with epilepsy are linked to a significantly higher risk for sudden unexplained death in epilepsy (SUDEP) and all-cause mortality, new research shows.

SUDEP is a major concern for patients with epilepsy, said study investigator Marion Lazaj, MSc, Center for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada, but she believes that SUDEP risk assessment is overly focused on seizure control.

“We want to push the idea that this mortality risk assessment needs to be widened to include sleep factors, and not just sleep disorders but even sleep disturbances,” said Ms. Lazaj.

She also believes physicians should routinely discuss SUDEP with their patients with epilepsy. Given that the incidence of SUDEP is only about 1%, many clinicians don’t want to unduly frighten their patients, she added.

The findings were presented at the annual meeting of the American Epilepsy Society (AES).

The retrospective study included chart data from 1,506 consecutive patients diagnosed with epilepsy at a single center over 4 years. The mean age of participants was about 37 years but there was a large age range, said Ms. Lazaj.

The cohort was divided into two groups. Group 1 included 1130 patients without a comorbid sleep disorder, and Group 2 had 376 patients with a primary comorbid sleep disorder, mostly obstructive sleep apnea (OSA) but also restless leg syndrome or insomnia.

They gathered demographic information including age, sex, employment status, education, and epilepsy-related data such as epilepsy type, duration, the number of anti-seizure medications and relevant information from hospital and emergency room (ER) records.
 

SUDEP Inventory

Researchers assessed SUDEP risk using the revised SUDEP-7 risk inventory. The first four items on this inventory focus on generalized tonic clonic seizure activity and occurrence while others assess the number of antiseizure medicines, epilepsy duration, and the presence of other developmental delays.

Investigators then stratified patients into high risk (score on the SUDEP-7 of 5 or greater) and low mortality risk (score less than 5).

Results showed a significant association between a high mortality risk and having a comorbid sleep disorder (P = .033). Researchers also looked at all-cause mortality, including drownings and suicides, and found a similar significant association (P = .026). There was also an association between high risk and accidents and trauma (P = .042).

The researchers had access to overnight diagnostic polysomnography data for a smaller group of patients. Here, they found decreased sleep efficiency (P =.0098), increased spontaneous arousal index (P = .034), and prolonged sleep onset latency (P = .0000052) were all significantly associated with high SUDEP risk.

From the polysomnographic data, researchers found high SUDEP risk was significantly associated with a diagnosis of OSA (P = .034).
 

Powerful Study

Commenting on the findings, Gordon F. Buchanan, MD, PhD, Beth L. Tross epilepsy associate professor, Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, said he was “very excited” by the research.

“That this study attempts to look through data in a retrospective way and see if there’s additional risk with having comorbid sleep disorders is really interesting and I think really powerful,” he said.

Sleep disorders “are potentially a really simple thing that we can screen for and test for,” he added. He also noted that additional research is needed to replicate the findings.

Dr. Buchanan acknowledged that the SUDEP-7 inventory is not a particularly good tool and said there is a need for a better means of assessment that includes sleep disorders and other factors like sleep states and circadian rhythm, which he said affect SUDEP risk.

Ms. Lazaj and Dr. Buchanan report no relevant financial relationships.

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