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With Proper Training, AI Can Be a Useful Tool in Epilepsy Management
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.
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.
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.
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.
FROM AES 2023
Genetic Testing Is Recommended for Adult Patients With Epilepsy
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.”
FROM AES 2023
Alzheimer’s and Epilepsy: Can Shared Molecular Mechanisms Reveal New Opportunities for Epilepsy?
ORLANDO — “,” 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 — “,” 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 — “,” 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.
FROM AES 2023
Despite Few CNS Gene Therapies for Epilepsy, New Research Offers Hope
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.
FROM AES 2023
Emerging therapies in Duchenne and facioscapulohumeral muscular dystrophy
“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”
DMD: Current and emerging therapies
DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.
FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.
AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.
The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.3 The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.
Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.
Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.
Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:
ENTR-601-44 is another exon 44–skipping therapy in the pipeline.
On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.
Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.
Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.
Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.
“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
FSHD: Emerging therapies
The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.1 An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.4 The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.
AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.5 The trial began in April 2023; estimated completion date is September 2025.
As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.
“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
Neonatal screening and early diagnosis: Imperative for improving outcomes
Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.
DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.
In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.
Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.
“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”
Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
DMD therapies carry a hefty price
Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.
Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.6,7
‘It takes a village’: Comprehensive care requires a multidisciplinary team
Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.
A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.
“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”
“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”
Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.
Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
References
1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.
2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.
3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.
4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.
5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.
6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.
7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.
“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”
DMD: Current and emerging therapies
DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.
FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.
AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.
The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.3 The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.
Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.
Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.
Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:
ENTR-601-44 is another exon 44–skipping therapy in the pipeline.
On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.
Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.
Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.
Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.
“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
FSHD: Emerging therapies
The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.1 An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.4 The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.
AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.5 The trial began in April 2023; estimated completion date is September 2025.
As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.
“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
Neonatal screening and early diagnosis: Imperative for improving outcomes
Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.
DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.
In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.
Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.
“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”
Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
DMD therapies carry a hefty price
Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.
Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.6,7
‘It takes a village’: Comprehensive care requires a multidisciplinary team
Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.
A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.
“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”
“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”
Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.
Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
References
1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.
2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.
3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.
4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.
5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.
6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.
7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.
“There have been so many breakthroughs recently on the side of genetically targeted treatment [for muscular dystrophy] that supports muscle better,” said John F. Brandsema, MD, a child neurologist and section head at Children’s Hospital of Philadelphia, in an interview with Neurology Reviews 2023 Rare Neurological Disease Special Report. “We’re starting to see clinical response to some things that have been in trials – after decades of banging our heads on the wall trying new therapies, only to see them fail. I think it’s about reframing Duchenne muscular dystrophy [DMD] and facioscapulohumeral muscular dystrophy [FSHD] as treatable by target therapy because previously, they were treated with supportive care.”
DMD: Current and emerging therapies
DMD is caused by a mutation in the dystrophin gene on the X chromosome that inhibits production of dystrophin, a protein that shields muscles from injury during contraction. Dystrophin deficiency prevents muscle recovery, resulting in muscle-cell death and, ultimately, loss of function due to muscle degeneration.
FDA-approved exon-skipping therapies. Treatment modalities for what has historically been an incurable, lifespan-shortening disease involved supportive care that addresses symptoms, not the underlying cause. Consequently, many patients with DMD live only into their 20s and 30s. The tide began to turn in 2016, however, when the U.S. Food and Drug Administration granted accelerated approval for eteplirsen, an exon 51–skipping treatment that was the first RNA-based therapy for DMD to target the underlying cause. Additional exon-skipping therapies followed, including casimersen, which skips exon 45, and golodirsen and viltolarsen, which skip exon 53.
AOC 1044: Novel exon-skipping. In April 2023, the FDA granted orphan-drug designation to the experimental drug antibody oligonucleotide conjugate (AOC) 1044 that skips exon 44. A small interfering RNA (siRNA), AOC 1044 works in patients who have a mutation amenable to exon 44 skipping (a disease type known as DMD44) by delivering phosphorodiamidate morpholino to skeletal muscle and heart tissue that skips exon 44. The process allows for dystrophin production, thereby preventing degradation of muscle tissue.
The orphan drug status of AOC 1044 made it available to the population of patients enrolled in the EXPLORE44 Phase 1/2 trial. However, studies demonstrating effectiveness of the drug – with the hope of, ultimately, providing widespread access to AOC 1044 – are still underway. In one of those studies, investigators expect to enroll approximately 40 healthy volunteers and 24 DMD44 patients 7-27 years of age.3 The study will evaluate the effects of exon skipping and dystrophin protein levels in participants who have DMD44.
Delandistrogene moxeparvovec. Oct. 27, 2021, marked the inception of the phase 3 Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Delivery Study to Evaluate the Safety and Efficacy of SRP-9001 in Subjects With Duchenne Muscular Dystrophy (EMBARK). The trial is evaluating the safety and efficacy of the gene-therapy agent delandistrogene moxeparvovec in ambulatory boys who were 4 to less than 8 years of age at randomization. The 126 boys enrolled in the trial met the criteria of (1) a diagnosis of DMD confirmed by documented clinical findings and previous genetic testing and (2) a pathogenic frameshift mutation stop codon located between exons 18 and 79 (inclusive), except for a mutation fully contained within exon 45.
Additional inclusion criteria were (1) the ability to cooperate with motor-assessment testing and (2) receiving a steady daily dose of oral corticosteroid for 12 weeks or longer prior to screening, and (3) the expectation of maintaining the study dosage throughout screening. Boys who had previously received gene therapy, investigational medication, or any treatment that could have amplified dystrophin expression within the time limit specified by the protocol were ineligible to participate. Boys were excluded from the study if they presented with any other illness, medical condition, or need for chronic drug treatment.
Exon-skipping therapies in trials. Various biotech and pharmaceutical companies have initiated clinical trials to explore the potential of additional exon-skipping therapies for the DMD population:
ENTR-601-44 is another exon 44–skipping therapy in the pipeline.
On Aug. 22, 2023, the FDA approved delandistrogene moxeparvovec-rokl, a recombinant gene therapy utilizing an adenovirus vector. The product is indicated for ambulatory patients with DMD 4-5 years of age who have a confirmed mutation of the dystrophin gene.
Dyne Therapeutics is actively recruiting participants to investigate Dyne 251, its exon 51–skipping therapy.
Trials are in the works by BioMarin Pharmaceutical for its next-generation peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) for skipping exon 51.
Despite the prospects of such therapy, therapeutic targeting of exon 44 addresses only patients with DMD44, who account for approximately 10% of the DMD population. Disease involving the most prevalent site of a dystrophin gene mutation, exon 51, affects 13% of the DMD population. This leaves the majority of patients with DMD without gene therapy. Yet Dr. Brandsema is optimistic nevertheless.
“We were just failing over and over again with DMD treatment, but there is some hope now,” Dr. Brandsema said. “Also, FSHD is right on the cusp of having new therapies approaching.”
FSHD: Emerging therapies
The third more common type of muscular dystrophy is not a life-threatening condition. FSHD affects approximately 4 of every 100,000 people.1 An autosomal-dominant condition, FSHD is ultimately caused by inappropriate expression of the DUX4 protein product – a consequence of a complex genetic activity involving DUX4, its chromosomal locus, and the number of repeats of a microsatellite called D4Z4.4 The disease usually starts in proximal regions of the face (that is, surrounding the eyes and mouth), before spreading to muscular groups of the limbs – most prominently, muscles of the scapulae and humeri. Symptoms usually appear in these places initially, but the condition can affect any part of the body. Fifty percent of FSHD patients experience loss of high-frequency hearing and present with retinovasculopathy. Like DMD, FSHD varies in severity, with some forms presenting at birth.
AOC 1020-CS1 is an example of a new FSHD treatment under investigation. The phase 1/2 FORTITUDE trial is a randomized, double-blind, placebo-controlled study exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy of single- and multiple-dose AOC 1020-CS1 therapy in FSHD.5 The trial began in April 2023; estimated completion date is September 2025.
As with many rare diseases, however, following patients and capturing data that fully narrate their story remains challenging in both DMD and FSHD. Although clinical trials undoubtedly offer hope of expanding treatment options and additional insights into disease-state management, the often insidious, complex nature of some rare diseases, such as DMD and FSHD, presents some limitations.
“Patients are hard to measure,” Dr. Brandsema explained, “because they’re so variable at baseline in history and progress in a different [slower] way than timelines are set up in our system to study drugs.”
Neonatal screening and early diagnosis: Imperative for improving outcomes
Neonatal screening helps with early detection and treatment. Prompt diagnosis does not necessarily prolong a DMD patient’s life, but it can enhance their quality of life.
DNA diagnostics. A critical component of the path to treatment is DNA diagnostics. According to Barry J. Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, the Human Genome Project conducted by the National Institutes of Health helped make DNA tests affordable; such tests run about $800 today. However, given continuous advancements in sequencing, Dr. Byrne said that whole-exome sequencing for $100 is within reach.
In terms of accessibility, some nations – Canada is an example – include testing as part of national health care services. In the United States, coverage for testing varies by health insurance plan. In addition, some plans have favored rapid diagnostic testing, and the overall cost is often individualized to the patient.
Early diagnosis and supportive care. Early diagnosis can certainly help improve DMD patients’ quality of life; supportive care provides some benefit. Dr. Byrne stressed the importance of managing extraskeletal clinical manifestations in this patient population. A critical area is initiating cardiovascular treatment immediately following diagnosis, even if the patient does not exhibit cardiovascular symptoms.
“Cardiac manifestations are actually the cause of mortality in DMD, and most boys with DMD should begin cardiovascular treatment shortly after diagnosis,” Dr. Byrne told Neurology Reviews 2023 Rare Neurological Disease Special Report. “The message to neurologists is that these patients can benefit from early cardiovascular treatment because we can prevent the complications of DMD-related heart failure until much later in life.”
Historically, clinicians used echocardiography as the mainstay tool to assess cardiovascular function; however, more and more clinicians are turning to magnetic resonance imaging for such investigation. Dr. Byrne, a cardiologist, explained that magnetic resonance imaging identifies cardiovascular dysfunction at earlier stages than echocardiography can. In addition, although DMD patients frequently experience fatigue, Dr. Byrne cautions neurologists that fatigue is usually related to muscle weakness, not necessarily heart failure.
DMD therapies carry a hefty price
Right now, the projected price range of AOC 1044 is $3.2 million to $3.4 million. Akin to the case with onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy, the world’s first gene therapy and first seven-figure drug, the manufacturer of AOC 1044 based pricing on the anticipated cost of treating a DMD44 patient throughout the lifespan, according to Dr. Byrne.
Delandistrogene moxeparvovec might come with an even higher price tag. A cost-effectiveness analysis study priced the therapy at $5 million. In a presentation to investors, the manufacturer projected the price in the range of $5 million to $13 million.6,7
‘It takes a village’: Comprehensive care requires a multidisciplinary team
Dr. Brandsema and Dr. Byrne agree: Optimizing outcomes requires ongoing coordinated and collaborative efforts of an interdisciplinary team of health care providers for the duration of DMD and FSHD patients’ lifespan.
A neurologist by training, Dr. Brandsema recognizes the importance of interdisciplinary collaboration in caring for patients with DMD, given the multiorgan manifestations of the disease.
“We have some hope with DMD, and FSHD is right on the cusp of having new therapies approaching ... It is important to recognize that interdisciplinary follow-up and optimized standard of care are important after dosing.”
“I think many patients living with neurological disorders have multiple providers they rely on for care,” Dr. Byrne said, “but cardiovascular and pulmonary care are important because both are affected in the case of DMD – not so much in FSHD.”
Ultimately, advancements in therapy and care give patients living with these disorders, and their caregivers, a renewed sense of hope – hope that their life will be improved by breakthrough therapies that have been approved or will arrive soon.
Dr. Brandsema discloses he is a consultant for Alexion, Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech/Roche, Janssen, Marathon, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is a speaker for AveXis and Biogen, a medical advisory council member for Cure SMA, and a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech/Roche, Ionis, Lilly, Janssen, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Dr. Byrne has no relevant financial disclosures.
References
1. Centers for Disease Control and Prevention. What is muscular dystrophy? Updated Nov. 21, 2022. Accessed Sept. 3, 2023. https://www.cdc.gov/ncbddd/musculardystrophy/facts.html.
2. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. U.S. Food and Drug Administration. Press release. June 22, 2023. Accessed Sept. 3, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy.
3. Study of AOC 1044 in healthy adult volunteers and participants with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (EXPLORE44). ClinicalTrials.gov Identifier: NCT05670730. Updated April 4, 2023. Accessed Sep. 3, 2023. https://www.clinicaltrials.gov/study/NCT05670730?cond=DMD&intr=AOC%201044&rank=1.
4. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap. Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1916-31. doi: 10.1212/CON.0000000000000399.
5. Phase 1/2 study of AOC 1020 in adults with facioscapulohumeral muscular dystrophy (FSHD) (FORTITUDE). ClinicalTrials.gov Identifier: NCT05747924. Updated Aug. 9, 2023. Accessed Sept. 3, 2023. https://clinicaltrials.gov/study/NCT05747924?term=fORTITUDE&cond=Facioscapulohumeral%20Muscular%20Dystrophy&rank=1.
6. Klimchak AC, Sedita LE, Rodino-Klapac LR, et al. Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States. J Mark Access Health Policy. 2023;11(1):2216518. doi: 10.1080/20016689.2023.2216518.
7. Ingram D. [Investor relations presentation.] Sarepta Therapeutics website. June 22, 2023. Accessed Sept. 3, 2023. https://investorrelations.sarepta.com/static-files/7216948c-f688-4024-922e-39761bc7a984.
Mediterranean diet improves cognition in MS
due to a potential neuroprotective mechanism, according to findings of a study that was released early, ahead of presentation at the annual meting of the American Academy of Neurology.
“We were most surprised by the magnitude of the results,” said Ilana Katz Sand, MD, associate professor of neurology at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai in New York. “We hypothesized a significant association between Mediterranean diet and cognition in MS, but we did not anticipate the 20% absolute difference, particularly because we rigorously controlled the demographic and health-related factors, like socioeconomic status, body mass index, and exercise habits.”
The Mediterranean diet consists of predominately vegetables, fruits, legumes, fish, and healthy fats while minimizing the consumption of dairy products, meats, and saturated acids. Previous literature has drawn an association between diet and MS symptomology, notably with regard to the Mediterranean diet. These studies indicated a connection between thalamic volume in patients with early MS as well as objectively captured MS-related disability. In this study, researchers have continued their investigation by exploring how the Mediterranean diet affects cognition.
In this cross-sectional observational study, investigators evaluated 563 people with MS ranging in age from 18 to 65 years (n = 563; 71% women; aged 44.2 ± 11.3 years). To accomplish this task, researchers conducted a retrospective chart review capturing data from patients with MS who had undergone neurobehavioral screenings. Qualifying subjects completed the Mediterranean Diet Adherence Screener (MEDAS) to determine the extent to which they adhered to the Mediterranean diet. A 14-item questionnaire, MEDAS assess a person’s usual intake of healthful foods such as vegetables and olive oil, as well as minimization of unhealthy foods such as butter and red meat. They also completed an analogue of the CICMAS cognitive battery comprised of a composite of Symbol Digit Modalities Test, Hopkins Verbal Learning Test, Revised, and CANTAB Paired Associate Learning.
Researchers evaluated patient-reported outcomes adjusted based on demographics (i.e., age, sex, race, ethnicity, and socioeconomic status) and health-related factors. These elements included body mass index, exercise, sleep disturbance, hypertension, diabetes, hyperlipidemia, and smoking.
The study excluded patients who had another primary neurological condition in addition to MS (n = 24), serious psychiatric illness such as schizophrenia (n = 5) or clinical relapse within 6 weeks (n = 2), or missing data (n = 13).
Based on the diet scores, investigators stratified participants into four groups. Those with the scores ranging from 0 to 4 were classified into the lowest group, while scores of 9 or greater qualified participants for the high group.
Investigators observed a significant association between a higher Mediterranean diet score and condition in the population sampled. They found a mean z-score of –0.67 (0.95). In addition, a higher MEDAS proved an independent indicator of better cognition (B = 0.08 [95% confidence interval (CI), 0.05, 0.11], beta = 0.20, P < .001). In fact, a high MEDAS independently correlated to a 20% lower risk for cognitive impairment (odds ratio [OR] = .80 {95% CI, 0.73, 0.89}, P < .001). Ultimately, the study’s findings demonstrated MEDAS served as the strongest health-related indicator of z-score and cognitive impairment. Moreover, dietary modification based on effect suggested stronger associations between diet and cognition with progressive disease as opposed to relapsing disease, as noted by the relationship between the z-score and cognition.
“Further research is needed,” Dr. Katz Sand said. “But because the progressive phenotype reflects more prominent neurodegeneration, the greater observed effect size in those with progressive MS suggests a potential neuroprotective mechanism.”
This study was funded in part by an Irma T. Hirschl/Monique Weill-Caulier Research Award to Dr. Katz Sand. Dr. Katz Sand and coauthors also received funding from the National Multiple Sclerosis Society.
due to a potential neuroprotective mechanism, according to findings of a study that was released early, ahead of presentation at the annual meting of the American Academy of Neurology.
“We were most surprised by the magnitude of the results,” said Ilana Katz Sand, MD, associate professor of neurology at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai in New York. “We hypothesized a significant association between Mediterranean diet and cognition in MS, but we did not anticipate the 20% absolute difference, particularly because we rigorously controlled the demographic and health-related factors, like socioeconomic status, body mass index, and exercise habits.”
The Mediterranean diet consists of predominately vegetables, fruits, legumes, fish, and healthy fats while minimizing the consumption of dairy products, meats, and saturated acids. Previous literature has drawn an association between diet and MS symptomology, notably with regard to the Mediterranean diet. These studies indicated a connection between thalamic volume in patients with early MS as well as objectively captured MS-related disability. In this study, researchers have continued their investigation by exploring how the Mediterranean diet affects cognition.
In this cross-sectional observational study, investigators evaluated 563 people with MS ranging in age from 18 to 65 years (n = 563; 71% women; aged 44.2 ± 11.3 years). To accomplish this task, researchers conducted a retrospective chart review capturing data from patients with MS who had undergone neurobehavioral screenings. Qualifying subjects completed the Mediterranean Diet Adherence Screener (MEDAS) to determine the extent to which they adhered to the Mediterranean diet. A 14-item questionnaire, MEDAS assess a person’s usual intake of healthful foods such as vegetables and olive oil, as well as minimization of unhealthy foods such as butter and red meat. They also completed an analogue of the CICMAS cognitive battery comprised of a composite of Symbol Digit Modalities Test, Hopkins Verbal Learning Test, Revised, and CANTAB Paired Associate Learning.
Researchers evaluated patient-reported outcomes adjusted based on demographics (i.e., age, sex, race, ethnicity, and socioeconomic status) and health-related factors. These elements included body mass index, exercise, sleep disturbance, hypertension, diabetes, hyperlipidemia, and smoking.
The study excluded patients who had another primary neurological condition in addition to MS (n = 24), serious psychiatric illness such as schizophrenia (n = 5) or clinical relapse within 6 weeks (n = 2), or missing data (n = 13).
Based on the diet scores, investigators stratified participants into four groups. Those with the scores ranging from 0 to 4 were classified into the lowest group, while scores of 9 or greater qualified participants for the high group.
Investigators observed a significant association between a higher Mediterranean diet score and condition in the population sampled. They found a mean z-score of –0.67 (0.95). In addition, a higher MEDAS proved an independent indicator of better cognition (B = 0.08 [95% confidence interval (CI), 0.05, 0.11], beta = 0.20, P < .001). In fact, a high MEDAS independently correlated to a 20% lower risk for cognitive impairment (odds ratio [OR] = .80 {95% CI, 0.73, 0.89}, P < .001). Ultimately, the study’s findings demonstrated MEDAS served as the strongest health-related indicator of z-score and cognitive impairment. Moreover, dietary modification based on effect suggested stronger associations between diet and cognition with progressive disease as opposed to relapsing disease, as noted by the relationship between the z-score and cognition.
“Further research is needed,” Dr. Katz Sand said. “But because the progressive phenotype reflects more prominent neurodegeneration, the greater observed effect size in those with progressive MS suggests a potential neuroprotective mechanism.”
This study was funded in part by an Irma T. Hirschl/Monique Weill-Caulier Research Award to Dr. Katz Sand. Dr. Katz Sand and coauthors also received funding from the National Multiple Sclerosis Society.
due to a potential neuroprotective mechanism, according to findings of a study that was released early, ahead of presentation at the annual meting of the American Academy of Neurology.
“We were most surprised by the magnitude of the results,” said Ilana Katz Sand, MD, associate professor of neurology at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai in New York. “We hypothesized a significant association between Mediterranean diet and cognition in MS, but we did not anticipate the 20% absolute difference, particularly because we rigorously controlled the demographic and health-related factors, like socioeconomic status, body mass index, and exercise habits.”
The Mediterranean diet consists of predominately vegetables, fruits, legumes, fish, and healthy fats while minimizing the consumption of dairy products, meats, and saturated acids. Previous literature has drawn an association between diet and MS symptomology, notably with regard to the Mediterranean diet. These studies indicated a connection between thalamic volume in patients with early MS as well as objectively captured MS-related disability. In this study, researchers have continued their investigation by exploring how the Mediterranean diet affects cognition.
In this cross-sectional observational study, investigators evaluated 563 people with MS ranging in age from 18 to 65 years (n = 563; 71% women; aged 44.2 ± 11.3 years). To accomplish this task, researchers conducted a retrospective chart review capturing data from patients with MS who had undergone neurobehavioral screenings. Qualifying subjects completed the Mediterranean Diet Adherence Screener (MEDAS) to determine the extent to which they adhered to the Mediterranean diet. A 14-item questionnaire, MEDAS assess a person’s usual intake of healthful foods such as vegetables and olive oil, as well as minimization of unhealthy foods such as butter and red meat. They also completed an analogue of the CICMAS cognitive battery comprised of a composite of Symbol Digit Modalities Test, Hopkins Verbal Learning Test, Revised, and CANTAB Paired Associate Learning.
Researchers evaluated patient-reported outcomes adjusted based on demographics (i.e., age, sex, race, ethnicity, and socioeconomic status) and health-related factors. These elements included body mass index, exercise, sleep disturbance, hypertension, diabetes, hyperlipidemia, and smoking.
The study excluded patients who had another primary neurological condition in addition to MS (n = 24), serious psychiatric illness such as schizophrenia (n = 5) or clinical relapse within 6 weeks (n = 2), or missing data (n = 13).
Based on the diet scores, investigators stratified participants into four groups. Those with the scores ranging from 0 to 4 were classified into the lowest group, while scores of 9 or greater qualified participants for the high group.
Investigators observed a significant association between a higher Mediterranean diet score and condition in the population sampled. They found a mean z-score of –0.67 (0.95). In addition, a higher MEDAS proved an independent indicator of better cognition (B = 0.08 [95% confidence interval (CI), 0.05, 0.11], beta = 0.20, P < .001). In fact, a high MEDAS independently correlated to a 20% lower risk for cognitive impairment (odds ratio [OR] = .80 {95% CI, 0.73, 0.89}, P < .001). Ultimately, the study’s findings demonstrated MEDAS served as the strongest health-related indicator of z-score and cognitive impairment. Moreover, dietary modification based on effect suggested stronger associations between diet and cognition with progressive disease as opposed to relapsing disease, as noted by the relationship between the z-score and cognition.
“Further research is needed,” Dr. Katz Sand said. “But because the progressive phenotype reflects more prominent neurodegeneration, the greater observed effect size in those with progressive MS suggests a potential neuroprotective mechanism.”
This study was funded in part by an Irma T. Hirschl/Monique Weill-Caulier Research Award to Dr. Katz Sand. Dr. Katz Sand and coauthors also received funding from the National Multiple Sclerosis Society.
FROM AAN 2023
MS bears no effect on certain pregnancy complications, stillbirth, or congenital deformation
, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.
“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”
MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
Assessing pregnancy outcomes
This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.
Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.
“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
Comprehensive data
Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.
A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.
Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.
, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.
“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”
MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
Assessing pregnancy outcomes
This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.
Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.
“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
Comprehensive data
Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.
A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.
Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.
, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.
“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”
MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
Assessing pregnancy outcomes
This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.
Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.
“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
Comprehensive data
Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.
A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.
Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.
FROM NEUROLOGY CLINICAL PRACTICE
EULAR recommendations define strategies to improve adherence in RMDs
Clinicians who care for patients with rheumatic and musculoskeletal diseases (RMDs) can now refer to a new set of strategies and points to consider from a European League Against Rheumatism (EULAR) task force in building a patient-centered approach to improve adherence to treatments.
Nonadherence to treatments is concerning given that 30%-80% of patients who have RMDs are thought to not follow a recommended treatment plan according to their physicians’ instructions, according to first author Valentin Ritschl of the Medical University of Vienna and colleagues.
“The problem of poor adherence is addressed in some EULAR recommendations/points to consider on the management of specific health conditions or on the role of professionals,” Mr. Ritschl said in an interview. “However, all these recommendations focus on limited aspects of nonadherence and do not cover the multifaceted nature of this phenomenon.”
Mr. Ritschl and colleagues conducted an extensive systematic literature review, the results of which they presented to a task force consisting of a panel of international experts hailing from 12 different countries. The task force included rheumatologists and other health professionals in rheumatology, as well as patient representatives.
The collaboration resulted in investigators crafting a definition of adherence in addition to drafting four overarching principles and nine points to consider, which were published Dec. 18 in Annals of the Rheumatic Diseases.
They defined adherence as “the extent to which a person’s behavior corresponds with the agreed prescription, of pharmacological or nonpharmacological treatments, by a health care provider.”
The four overarching principles emphasize the following concepts: that adherence affects outcomes in people who have RMDs; the importance of shared decision-making, with the understanding that the adherence describes the patient’s behavior “following an agreed prescription”; that numerous factors can affect adherence; and the notion of adherence being a dynamic process that, consequently, requires continuous evaluation.
Among the nine points to consider, Mr. Ritschl and coauthors encouraged all health care providers involved in caring for RMD patients to assume responsibility for promoting adherence. Practitioners should also strive to create an ongoing, open dialogue to discuss adherence, especially in cases in which the patient’s RMD is not well controlled. The patient-centered recommendations include taking into account the patient’s goals and preferences because these greatly contribute to the patient’s ability to adhere to any medication regimen. Another arm of that exploration also requires the medical professional to evaluate any circumstances that could bear a negative effect on the patient’s adherence – whether it be medication access issues related to cost or availability, or functional challenges such as memory, motivation, or complexity of the medication regimen.
Mr. Ritschl believed the task force’s recommendations will add value and help improve overall outcomes in RMD population management.
“Until today, there are no recommendations or points to consider developed in order to support our patients to be adherent to the agreed treatment plan,” he said. “In our project/initiative, we therefore developed for the first time points to consider to detect, assess, and manage nonadherence in people with RMDs.”
Additionally, the recommendations offer some strategic insights to help improve clinical trials because the deleterious effects of nonadherence also affect study results.
Looking ahead, Mr. Ritschl said randomized, controlled trials are necessary to test strategies that might improve adherence. He strongly emphasized the importance of designing future research studies that are heavily patient centered and effective for shared decision-making.
The project was funded by EULAR. Mr. Ritschl reported having no disclosures, but many of his coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Ritschl V et al. Ann Rheum Dis. 2020 Dec 18. doi: 10.1136/annrheumdis-2020-218986.
Clinicians who care for patients with rheumatic and musculoskeletal diseases (RMDs) can now refer to a new set of strategies and points to consider from a European League Against Rheumatism (EULAR) task force in building a patient-centered approach to improve adherence to treatments.
Nonadherence to treatments is concerning given that 30%-80% of patients who have RMDs are thought to not follow a recommended treatment plan according to their physicians’ instructions, according to first author Valentin Ritschl of the Medical University of Vienna and colleagues.
“The problem of poor adherence is addressed in some EULAR recommendations/points to consider on the management of specific health conditions or on the role of professionals,” Mr. Ritschl said in an interview. “However, all these recommendations focus on limited aspects of nonadherence and do not cover the multifaceted nature of this phenomenon.”
Mr. Ritschl and colleagues conducted an extensive systematic literature review, the results of which they presented to a task force consisting of a panel of international experts hailing from 12 different countries. The task force included rheumatologists and other health professionals in rheumatology, as well as patient representatives.
The collaboration resulted in investigators crafting a definition of adherence in addition to drafting four overarching principles and nine points to consider, which were published Dec. 18 in Annals of the Rheumatic Diseases.
They defined adherence as “the extent to which a person’s behavior corresponds with the agreed prescription, of pharmacological or nonpharmacological treatments, by a health care provider.”
The four overarching principles emphasize the following concepts: that adherence affects outcomes in people who have RMDs; the importance of shared decision-making, with the understanding that the adherence describes the patient’s behavior “following an agreed prescription”; that numerous factors can affect adherence; and the notion of adherence being a dynamic process that, consequently, requires continuous evaluation.
Among the nine points to consider, Mr. Ritschl and coauthors encouraged all health care providers involved in caring for RMD patients to assume responsibility for promoting adherence. Practitioners should also strive to create an ongoing, open dialogue to discuss adherence, especially in cases in which the patient’s RMD is not well controlled. The patient-centered recommendations include taking into account the patient’s goals and preferences because these greatly contribute to the patient’s ability to adhere to any medication regimen. Another arm of that exploration also requires the medical professional to evaluate any circumstances that could bear a negative effect on the patient’s adherence – whether it be medication access issues related to cost or availability, or functional challenges such as memory, motivation, or complexity of the medication regimen.
Mr. Ritschl believed the task force’s recommendations will add value and help improve overall outcomes in RMD population management.
“Until today, there are no recommendations or points to consider developed in order to support our patients to be adherent to the agreed treatment plan,” he said. “In our project/initiative, we therefore developed for the first time points to consider to detect, assess, and manage nonadherence in people with RMDs.”
Additionally, the recommendations offer some strategic insights to help improve clinical trials because the deleterious effects of nonadherence also affect study results.
Looking ahead, Mr. Ritschl said randomized, controlled trials are necessary to test strategies that might improve adherence. He strongly emphasized the importance of designing future research studies that are heavily patient centered and effective for shared decision-making.
The project was funded by EULAR. Mr. Ritschl reported having no disclosures, but many of his coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Ritschl V et al. Ann Rheum Dis. 2020 Dec 18. doi: 10.1136/annrheumdis-2020-218986.
Clinicians who care for patients with rheumatic and musculoskeletal diseases (RMDs) can now refer to a new set of strategies and points to consider from a European League Against Rheumatism (EULAR) task force in building a patient-centered approach to improve adherence to treatments.
Nonadherence to treatments is concerning given that 30%-80% of patients who have RMDs are thought to not follow a recommended treatment plan according to their physicians’ instructions, according to first author Valentin Ritschl of the Medical University of Vienna and colleagues.
“The problem of poor adherence is addressed in some EULAR recommendations/points to consider on the management of specific health conditions or on the role of professionals,” Mr. Ritschl said in an interview. “However, all these recommendations focus on limited aspects of nonadherence and do not cover the multifaceted nature of this phenomenon.”
Mr. Ritschl and colleagues conducted an extensive systematic literature review, the results of which they presented to a task force consisting of a panel of international experts hailing from 12 different countries. The task force included rheumatologists and other health professionals in rheumatology, as well as patient representatives.
The collaboration resulted in investigators crafting a definition of adherence in addition to drafting four overarching principles and nine points to consider, which were published Dec. 18 in Annals of the Rheumatic Diseases.
They defined adherence as “the extent to which a person’s behavior corresponds with the agreed prescription, of pharmacological or nonpharmacological treatments, by a health care provider.”
The four overarching principles emphasize the following concepts: that adherence affects outcomes in people who have RMDs; the importance of shared decision-making, with the understanding that the adherence describes the patient’s behavior “following an agreed prescription”; that numerous factors can affect adherence; and the notion of adherence being a dynamic process that, consequently, requires continuous evaluation.
Among the nine points to consider, Mr. Ritschl and coauthors encouraged all health care providers involved in caring for RMD patients to assume responsibility for promoting adherence. Practitioners should also strive to create an ongoing, open dialogue to discuss adherence, especially in cases in which the patient’s RMD is not well controlled. The patient-centered recommendations include taking into account the patient’s goals and preferences because these greatly contribute to the patient’s ability to adhere to any medication regimen. Another arm of that exploration also requires the medical professional to evaluate any circumstances that could bear a negative effect on the patient’s adherence – whether it be medication access issues related to cost or availability, or functional challenges such as memory, motivation, or complexity of the medication regimen.
Mr. Ritschl believed the task force’s recommendations will add value and help improve overall outcomes in RMD population management.
“Until today, there are no recommendations or points to consider developed in order to support our patients to be adherent to the agreed treatment plan,” he said. “In our project/initiative, we therefore developed for the first time points to consider to detect, assess, and manage nonadherence in people with RMDs.”
Additionally, the recommendations offer some strategic insights to help improve clinical trials because the deleterious effects of nonadherence also affect study results.
Looking ahead, Mr. Ritschl said randomized, controlled trials are necessary to test strategies that might improve adherence. He strongly emphasized the importance of designing future research studies that are heavily patient centered and effective for shared decision-making.
The project was funded by EULAR. Mr. Ritschl reported having no disclosures, but many of his coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Ritschl V et al. Ann Rheum Dis. 2020 Dec 18. doi: 10.1136/annrheumdis-2020-218986.
FROM ANNALS OF THE RHEUMATIC DISEASES
Are patients with epilepsy at increased risk of COVID-19 infection?
Chronic conditions such as lung disease, diabetes, and heart disease frequently receive attention for increasing the risk of complications for people who contract the coronavirus. Meanwhile, many members of the epilepsy community continue to wonder how the virus affects them. To address these concerns, the Epilepsy Foundation has released information that answers many common questions that people with epilepsy have about how COVID-19 can impact their health.
Perhaps the most pressing of these questions is: Does epilepsy increase the risk or severity of the coronavirus?
“The most common thing we’re hearing from patients in my practice is their proactive concern for being at increased risk for getting the coronavirus,” confirmed Selim Benbadis, MD, division director, epilepsy, EEG, and sleep medicine at the University of South Florida in Tampa. “Epilepsy patients are not at increased risk for complications from the coronavirus because epilepsy does not affect the immune system.”
In other words, people who have epilepsy face the same health challenges as people who do not have the condition and are otherwise healthy. For this reason, people who have epilepsy should exercise the same habits and preventative measures that healthy people would typically take, such as social distancing; avoiding contact with sick people; washing hands regularly; disinfecting surfaces regularly; and avoiding touching hands, eyes, nose and mouth.
However, as Dr. Benbadis explained, the high fever associated with coronavirus can trigger seizures. The increased risk is another reason people who have epilepsy should do their best to avoid getting sick.
Seizure medications do not increase COVID-19 risk but other conditions can
Similarly, epilepsy medications do not increase the risk of contracting the disease.
“The medications patients take to treat their epilepsy do not affect their immune system,” said Andrew Wilner, MD, associate professor of neurology at the University of Tennessee Health Science Center, Memphis. There are a few exceptions – such as adrenocorticotropic hormone and everolimus – but doctors rarely use these drugs to treat epilepsy.
However, there are some situations and conditions that may pose a risk for people who contact the coronavirus. For instance, people who have problems swallowing their food and tend to suck food down their windpipes are more likely to develop pneumonia. Also, much like the general population, having diabetes, heart disease, or lung problems increase the chances of developing complications from the virus.
The best ways to avoid additional risks in epilepsy
Because of the pandemic, people who have epilepsy may have found that many of their doctors’ appointments have been canceled. Many clinics and medical practices have done this in order minimize exposing people who have acute illnesses to the virus. By focusing more on patients with acute conditions, doctors and nurses can better tend to patients with acute problems. As a result, practices have shifted to providing patient care using telemedicine as much as possible.
“Telemedicine services have surged, and I’ve been saying for years that telemedicine was going to grow,” Dr. Benbadis said. “It’s more convenient, and I believe that we’re going to see increased use of telemedicine long after the coronavirus pandemic is over.”
Aside from communicating with their doctors, the Epilepsy Foundation and Dr. Wilner stress that the best way for people who have epilepsy to stay healthy is by taking their medications on a regular basis exactly as prescribed.
“Taking mediation correctly and regularly is the best strategy for epilepsy patients to avoid unnecessary hospitalizations,” Dr. Wilner said. “If they have breakthrough seizures and get sent to the emergency room, then they risk being exposed to the virus in the ER.”
Also, because ERs are more crowded than usual, the Epilepsy Foundation encourages people who suspect they have the coronavirus to call their doctor’s office first. The goal is to try to make sure that people who have severe or life-threatening symptoms have access to treatment in the ER.
As with the general population, the first thing that epilepsy patients who suspect they have the coronavirus should do is call his or her doctor’s office. The health care professional taking the call will ask the patient a series of questions to determine whether the patient has COVID-19 or another condition or needs to seek emergency medical attention.
Fever, cough, and trouble breathing fall among the most commonly reported symptoms of the coronavirus. In many cases, health care providers recommend that people with mild versions of these symptoms stay at home.
Helpful tips
The Epilepsy Foundation offers tips on signs to look for when trying to figure out when a seizure requires an ER visit. These are:
- Seizures in which awareness is lost for more than 5 minutes and no reversal medications are available.
- Seizures with an unusual pattern or duration.
- Seizures that cannot be treated safely at home or are not responding to rescue medication even after the medication has had enough time to work.
- Seizures that occur after a severe blow to the head.
Additionally, while COVID-19 can cause death and sudden death in patients, the virus does not cause sudden unexpected death in epilepsy (SUDEP). Because SUDEP is extremely rare, Dr. Benbadis said that there is no information to suggest that contracting the coronavirus will increase the risk,
Finally, no shortages of seizures medications have been reported as a result of COVID-19. However, there were shortages of generic levetiracetam immediate-release and levetiracetam extended-release medications prior to and during COVID-19. Experts expect the shortage to continue.
Overall, people who have epilepsy should be able to stay healthy – provided they exercise healthy and preventative habits.
“The majority of epilepsy patients should be reassured that if they continue their usual care, take their meds as directed, get adequate sleep, nutritious diet, they’re not at any increased risk compared to the general population,” said Dr. Wilner.
Dr. Benbadis reported the following disclosures: consultant for Bioserenity (DigiTrace), Brain Sentinel, Cavion, Ceribell, Eisai, Greenwich, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion; speakers bureau for Eisai, Greenwich, LivaNova, Sunovion; Florida Medical Director of Stratus/Alliance; Member: Epilepsy Study Consortium; grant support from Cavion, LivaNova, Greenwich, SK biopharmaceuticals, Sunovion, Takeda, UCB, Xenon; royalties as an author or editor for Emedicine-Medscape-WebMD, UpToDate; editorial board for the Epilepsy.com (Epilepsy Foundation) controversy section, Emedicine-Medscape-WebMD, Epileptic Disorders, Epilepsy and Behavior, and Expert Review of Neurotherapeutics. Dr. Wilner reports Medical Advisory Board of Accordant Health Services, Greensboro, S.C., and book royalties: “The Locum Life: A Physician’s Guide to Locum Tenens,” Lulu Press.
Chronic conditions such as lung disease, diabetes, and heart disease frequently receive attention for increasing the risk of complications for people who contract the coronavirus. Meanwhile, many members of the epilepsy community continue to wonder how the virus affects them. To address these concerns, the Epilepsy Foundation has released information that answers many common questions that people with epilepsy have about how COVID-19 can impact their health.
Perhaps the most pressing of these questions is: Does epilepsy increase the risk or severity of the coronavirus?
“The most common thing we’re hearing from patients in my practice is their proactive concern for being at increased risk for getting the coronavirus,” confirmed Selim Benbadis, MD, division director, epilepsy, EEG, and sleep medicine at the University of South Florida in Tampa. “Epilepsy patients are not at increased risk for complications from the coronavirus because epilepsy does not affect the immune system.”
In other words, people who have epilepsy face the same health challenges as people who do not have the condition and are otherwise healthy. For this reason, people who have epilepsy should exercise the same habits and preventative measures that healthy people would typically take, such as social distancing; avoiding contact with sick people; washing hands regularly; disinfecting surfaces regularly; and avoiding touching hands, eyes, nose and mouth.
However, as Dr. Benbadis explained, the high fever associated with coronavirus can trigger seizures. The increased risk is another reason people who have epilepsy should do their best to avoid getting sick.
Seizure medications do not increase COVID-19 risk but other conditions can
Similarly, epilepsy medications do not increase the risk of contracting the disease.
“The medications patients take to treat their epilepsy do not affect their immune system,” said Andrew Wilner, MD, associate professor of neurology at the University of Tennessee Health Science Center, Memphis. There are a few exceptions – such as adrenocorticotropic hormone and everolimus – but doctors rarely use these drugs to treat epilepsy.
However, there are some situations and conditions that may pose a risk for people who contact the coronavirus. For instance, people who have problems swallowing their food and tend to suck food down their windpipes are more likely to develop pneumonia. Also, much like the general population, having diabetes, heart disease, or lung problems increase the chances of developing complications from the virus.
The best ways to avoid additional risks in epilepsy
Because of the pandemic, people who have epilepsy may have found that many of their doctors’ appointments have been canceled. Many clinics and medical practices have done this in order minimize exposing people who have acute illnesses to the virus. By focusing more on patients with acute conditions, doctors and nurses can better tend to patients with acute problems. As a result, practices have shifted to providing patient care using telemedicine as much as possible.
“Telemedicine services have surged, and I’ve been saying for years that telemedicine was going to grow,” Dr. Benbadis said. “It’s more convenient, and I believe that we’re going to see increased use of telemedicine long after the coronavirus pandemic is over.”
Aside from communicating with their doctors, the Epilepsy Foundation and Dr. Wilner stress that the best way for people who have epilepsy to stay healthy is by taking their medications on a regular basis exactly as prescribed.
“Taking mediation correctly and regularly is the best strategy for epilepsy patients to avoid unnecessary hospitalizations,” Dr. Wilner said. “If they have breakthrough seizures and get sent to the emergency room, then they risk being exposed to the virus in the ER.”
Also, because ERs are more crowded than usual, the Epilepsy Foundation encourages people who suspect they have the coronavirus to call their doctor’s office first. The goal is to try to make sure that people who have severe or life-threatening symptoms have access to treatment in the ER.
As with the general population, the first thing that epilepsy patients who suspect they have the coronavirus should do is call his or her doctor’s office. The health care professional taking the call will ask the patient a series of questions to determine whether the patient has COVID-19 or another condition or needs to seek emergency medical attention.
Fever, cough, and trouble breathing fall among the most commonly reported symptoms of the coronavirus. In many cases, health care providers recommend that people with mild versions of these symptoms stay at home.
Helpful tips
The Epilepsy Foundation offers tips on signs to look for when trying to figure out when a seizure requires an ER visit. These are:
- Seizures in which awareness is lost for more than 5 minutes and no reversal medications are available.
- Seizures with an unusual pattern or duration.
- Seizures that cannot be treated safely at home or are not responding to rescue medication even after the medication has had enough time to work.
- Seizures that occur after a severe blow to the head.
Additionally, while COVID-19 can cause death and sudden death in patients, the virus does not cause sudden unexpected death in epilepsy (SUDEP). Because SUDEP is extremely rare, Dr. Benbadis said that there is no information to suggest that contracting the coronavirus will increase the risk,
Finally, no shortages of seizures medications have been reported as a result of COVID-19. However, there were shortages of generic levetiracetam immediate-release and levetiracetam extended-release medications prior to and during COVID-19. Experts expect the shortage to continue.
Overall, people who have epilepsy should be able to stay healthy – provided they exercise healthy and preventative habits.
“The majority of epilepsy patients should be reassured that if they continue their usual care, take their meds as directed, get adequate sleep, nutritious diet, they’re not at any increased risk compared to the general population,” said Dr. Wilner.
Dr. Benbadis reported the following disclosures: consultant for Bioserenity (DigiTrace), Brain Sentinel, Cavion, Ceribell, Eisai, Greenwich, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion; speakers bureau for Eisai, Greenwich, LivaNova, Sunovion; Florida Medical Director of Stratus/Alliance; Member: Epilepsy Study Consortium; grant support from Cavion, LivaNova, Greenwich, SK biopharmaceuticals, Sunovion, Takeda, UCB, Xenon; royalties as an author or editor for Emedicine-Medscape-WebMD, UpToDate; editorial board for the Epilepsy.com (Epilepsy Foundation) controversy section, Emedicine-Medscape-WebMD, Epileptic Disorders, Epilepsy and Behavior, and Expert Review of Neurotherapeutics. Dr. Wilner reports Medical Advisory Board of Accordant Health Services, Greensboro, S.C., and book royalties: “The Locum Life: A Physician’s Guide to Locum Tenens,” Lulu Press.
Chronic conditions such as lung disease, diabetes, and heart disease frequently receive attention for increasing the risk of complications for people who contract the coronavirus. Meanwhile, many members of the epilepsy community continue to wonder how the virus affects them. To address these concerns, the Epilepsy Foundation has released information that answers many common questions that people with epilepsy have about how COVID-19 can impact their health.
Perhaps the most pressing of these questions is: Does epilepsy increase the risk or severity of the coronavirus?
“The most common thing we’re hearing from patients in my practice is their proactive concern for being at increased risk for getting the coronavirus,” confirmed Selim Benbadis, MD, division director, epilepsy, EEG, and sleep medicine at the University of South Florida in Tampa. “Epilepsy patients are not at increased risk for complications from the coronavirus because epilepsy does not affect the immune system.”
In other words, people who have epilepsy face the same health challenges as people who do not have the condition and are otherwise healthy. For this reason, people who have epilepsy should exercise the same habits and preventative measures that healthy people would typically take, such as social distancing; avoiding contact with sick people; washing hands regularly; disinfecting surfaces regularly; and avoiding touching hands, eyes, nose and mouth.
However, as Dr. Benbadis explained, the high fever associated with coronavirus can trigger seizures. The increased risk is another reason people who have epilepsy should do their best to avoid getting sick.
Seizure medications do not increase COVID-19 risk but other conditions can
Similarly, epilepsy medications do not increase the risk of contracting the disease.
“The medications patients take to treat their epilepsy do not affect their immune system,” said Andrew Wilner, MD, associate professor of neurology at the University of Tennessee Health Science Center, Memphis. There are a few exceptions – such as adrenocorticotropic hormone and everolimus – but doctors rarely use these drugs to treat epilepsy.
However, there are some situations and conditions that may pose a risk for people who contact the coronavirus. For instance, people who have problems swallowing their food and tend to suck food down their windpipes are more likely to develop pneumonia. Also, much like the general population, having diabetes, heart disease, or lung problems increase the chances of developing complications from the virus.
The best ways to avoid additional risks in epilepsy
Because of the pandemic, people who have epilepsy may have found that many of their doctors’ appointments have been canceled. Many clinics and medical practices have done this in order minimize exposing people who have acute illnesses to the virus. By focusing more on patients with acute conditions, doctors and nurses can better tend to patients with acute problems. As a result, practices have shifted to providing patient care using telemedicine as much as possible.
“Telemedicine services have surged, and I’ve been saying for years that telemedicine was going to grow,” Dr. Benbadis said. “It’s more convenient, and I believe that we’re going to see increased use of telemedicine long after the coronavirus pandemic is over.”
Aside from communicating with their doctors, the Epilepsy Foundation and Dr. Wilner stress that the best way for people who have epilepsy to stay healthy is by taking their medications on a regular basis exactly as prescribed.
“Taking mediation correctly and regularly is the best strategy for epilepsy patients to avoid unnecessary hospitalizations,” Dr. Wilner said. “If they have breakthrough seizures and get sent to the emergency room, then they risk being exposed to the virus in the ER.”
Also, because ERs are more crowded than usual, the Epilepsy Foundation encourages people who suspect they have the coronavirus to call their doctor’s office first. The goal is to try to make sure that people who have severe or life-threatening symptoms have access to treatment in the ER.
As with the general population, the first thing that epilepsy patients who suspect they have the coronavirus should do is call his or her doctor’s office. The health care professional taking the call will ask the patient a series of questions to determine whether the patient has COVID-19 or another condition or needs to seek emergency medical attention.
Fever, cough, and trouble breathing fall among the most commonly reported symptoms of the coronavirus. In many cases, health care providers recommend that people with mild versions of these symptoms stay at home.
Helpful tips
The Epilepsy Foundation offers tips on signs to look for when trying to figure out when a seizure requires an ER visit. These are:
- Seizures in which awareness is lost for more than 5 minutes and no reversal medications are available.
- Seizures with an unusual pattern or duration.
- Seizures that cannot be treated safely at home or are not responding to rescue medication even after the medication has had enough time to work.
- Seizures that occur after a severe blow to the head.
Additionally, while COVID-19 can cause death and sudden death in patients, the virus does not cause sudden unexpected death in epilepsy (SUDEP). Because SUDEP is extremely rare, Dr. Benbadis said that there is no information to suggest that contracting the coronavirus will increase the risk,
Finally, no shortages of seizures medications have been reported as a result of COVID-19. However, there were shortages of generic levetiracetam immediate-release and levetiracetam extended-release medications prior to and during COVID-19. Experts expect the shortage to continue.
Overall, people who have epilepsy should be able to stay healthy – provided they exercise healthy and preventative habits.
“The majority of epilepsy patients should be reassured that if they continue their usual care, take their meds as directed, get adequate sleep, nutritious diet, they’re not at any increased risk compared to the general population,” said Dr. Wilner.
Dr. Benbadis reported the following disclosures: consultant for Bioserenity (DigiTrace), Brain Sentinel, Cavion, Ceribell, Eisai, Greenwich, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion; speakers bureau for Eisai, Greenwich, LivaNova, Sunovion; Florida Medical Director of Stratus/Alliance; Member: Epilepsy Study Consortium; grant support from Cavion, LivaNova, Greenwich, SK biopharmaceuticals, Sunovion, Takeda, UCB, Xenon; royalties as an author or editor for Emedicine-Medscape-WebMD, UpToDate; editorial board for the Epilepsy.com (Epilepsy Foundation) controversy section, Emedicine-Medscape-WebMD, Epileptic Disorders, Epilepsy and Behavior, and Expert Review of Neurotherapeutics. Dr. Wilner reports Medical Advisory Board of Accordant Health Services, Greensboro, S.C., and book royalties: “The Locum Life: A Physician’s Guide to Locum Tenens,” Lulu Press.