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Don’t panic over lamotrigine, but beware of cardiac risks
New York University neurologist Jacqueline A. French, MD, told colleagues at the annual meeting of the American Epilepsy Society. But it’s now crucial to take special precautions in high-risk groups such as older people and heart patients.
“We need to plan more carefully when we use it, which we hate to do, as we know. But we’ve still got to do it,” said Dr. French, former president of the AES. “The risks are very small, but keep in mind that they’re not zero.”
In October 2020, the Food and Drug Administration added a warning to the lamotrigine label that said the drug “could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in patients with structural heart disease or myocardial ischemia.”
The FDA recommended avoiding the sodium channel blocker’s use “in patients who have cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies). Concomitant use of other sodium channel blockers may increase the risk of proarrhythmia.”
Later, in March 2021, the FDA announced that a review of in vitro findings “showed a potential increased risk of heart rhythm problems.”
As Dr. French noted, lamotrigine remains widely prescribed even though there’s “no pharmaceutical company out there pushing [it].” It’s an especially beneficial drug for certain groups such as the elderly and women of child-bearing age, she said.
But older people are also at higher risk of drug-related heart complications because of the fact that many already have cardiac disease, Dr. French said. She highlighted a 2005 trial of lamotrigine that found 48% of 593 patients aged 60 years and older had cardiac disease.
Special precautions
So what should neurologists know about prescribing lamotrigine in light of the new warning? Dr. French recommended guidelines that she cowrote with the AES and International League Against Epilepsy.
- Prescribe as normal in patients under 60 with no cardiac risk factors. In patients older than 60, or younger with risk factors, consider an EKG before prescribing lamotrigine.
- “Nonspecific EKG abnormalities (e.g., nonspecific ST and T wave abnormalities) are not concerning, and should not preclude these individuals from being prescribed lamotrigine.”
- Beware of higher risk and consider consulting a cardiologist before starting treatment in patients with second- or third-degree heart block, Brugada syndrome, arrhythmogenic ventricular cardiomyopathy, left bundle branch block, and right bundle branch block with left anterior or posterior fascicular block.
- “In most cases the initial EKG can be obtained while titrating, mainly when the individual is at the first dose of 25 mg/day because lamotrigine must be titrated slowly, and because cardiac adverse events are dose related.”
- “Clinicians should consider obtaining an EKG and/or cardiology consultation in people on lamotrigine with sudden-onset syncope or presyncope with loss of muscular tone without a clear vasovagal or orthostatic cause.”
Dr. French cautioned colleagues that they shouldn’t assume that lamotrigine stands alone among sodium channel blockers in terms of cardiac risk. As she noted, the FDA is asking manufacturers of other drugs in that class to provide data. “At some point, maybe sometime in the near future, we are going to hear in this particular in vitro sense how the other sodium channel blockers do stack up, compared with lamotrigine. At presence, in the absence of the availability of all of the rest of the data, it would be incorrect to presume that lamotrigine has more cardiac effects than other sodium channel blocking antiseizure medicines or all antiseizure medicines.”
For now, she said, although the guidelines are for lamotrigine, it’s “prudent” to follow them for all sodium channel blockers.
Dr. French reported no disclosures.
New York University neurologist Jacqueline A. French, MD, told colleagues at the annual meeting of the American Epilepsy Society. But it’s now crucial to take special precautions in high-risk groups such as older people and heart patients.
“We need to plan more carefully when we use it, which we hate to do, as we know. But we’ve still got to do it,” said Dr. French, former president of the AES. “The risks are very small, but keep in mind that they’re not zero.”
In October 2020, the Food and Drug Administration added a warning to the lamotrigine label that said the drug “could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in patients with structural heart disease or myocardial ischemia.”
The FDA recommended avoiding the sodium channel blocker’s use “in patients who have cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies). Concomitant use of other sodium channel blockers may increase the risk of proarrhythmia.”
Later, in March 2021, the FDA announced that a review of in vitro findings “showed a potential increased risk of heart rhythm problems.”
As Dr. French noted, lamotrigine remains widely prescribed even though there’s “no pharmaceutical company out there pushing [it].” It’s an especially beneficial drug for certain groups such as the elderly and women of child-bearing age, she said.
But older people are also at higher risk of drug-related heart complications because of the fact that many already have cardiac disease, Dr. French said. She highlighted a 2005 trial of lamotrigine that found 48% of 593 patients aged 60 years and older had cardiac disease.
Special precautions
So what should neurologists know about prescribing lamotrigine in light of the new warning? Dr. French recommended guidelines that she cowrote with the AES and International League Against Epilepsy.
- Prescribe as normal in patients under 60 with no cardiac risk factors. In patients older than 60, or younger with risk factors, consider an EKG before prescribing lamotrigine.
- “Nonspecific EKG abnormalities (e.g., nonspecific ST and T wave abnormalities) are not concerning, and should not preclude these individuals from being prescribed lamotrigine.”
- Beware of higher risk and consider consulting a cardiologist before starting treatment in patients with second- or third-degree heart block, Brugada syndrome, arrhythmogenic ventricular cardiomyopathy, left bundle branch block, and right bundle branch block with left anterior or posterior fascicular block.
- “In most cases the initial EKG can be obtained while titrating, mainly when the individual is at the first dose of 25 mg/day because lamotrigine must be titrated slowly, and because cardiac adverse events are dose related.”
- “Clinicians should consider obtaining an EKG and/or cardiology consultation in people on lamotrigine with sudden-onset syncope or presyncope with loss of muscular tone without a clear vasovagal or orthostatic cause.”
Dr. French cautioned colleagues that they shouldn’t assume that lamotrigine stands alone among sodium channel blockers in terms of cardiac risk. As she noted, the FDA is asking manufacturers of other drugs in that class to provide data. “At some point, maybe sometime in the near future, we are going to hear in this particular in vitro sense how the other sodium channel blockers do stack up, compared with lamotrigine. At presence, in the absence of the availability of all of the rest of the data, it would be incorrect to presume that lamotrigine has more cardiac effects than other sodium channel blocking antiseizure medicines or all antiseizure medicines.”
For now, she said, although the guidelines are for lamotrigine, it’s “prudent” to follow them for all sodium channel blockers.
Dr. French reported no disclosures.
New York University neurologist Jacqueline A. French, MD, told colleagues at the annual meeting of the American Epilepsy Society. But it’s now crucial to take special precautions in high-risk groups such as older people and heart patients.
“We need to plan more carefully when we use it, which we hate to do, as we know. But we’ve still got to do it,” said Dr. French, former president of the AES. “The risks are very small, but keep in mind that they’re not zero.”
In October 2020, the Food and Drug Administration added a warning to the lamotrigine label that said the drug “could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in patients with structural heart disease or myocardial ischemia.”
The FDA recommended avoiding the sodium channel blocker’s use “in patients who have cardiac conduction disorders (e.g., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (e.g., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies). Concomitant use of other sodium channel blockers may increase the risk of proarrhythmia.”
Later, in March 2021, the FDA announced that a review of in vitro findings “showed a potential increased risk of heart rhythm problems.”
As Dr. French noted, lamotrigine remains widely prescribed even though there’s “no pharmaceutical company out there pushing [it].” It’s an especially beneficial drug for certain groups such as the elderly and women of child-bearing age, she said.
But older people are also at higher risk of drug-related heart complications because of the fact that many already have cardiac disease, Dr. French said. She highlighted a 2005 trial of lamotrigine that found 48% of 593 patients aged 60 years and older had cardiac disease.
Special precautions
So what should neurologists know about prescribing lamotrigine in light of the new warning? Dr. French recommended guidelines that she cowrote with the AES and International League Against Epilepsy.
- Prescribe as normal in patients under 60 with no cardiac risk factors. In patients older than 60, or younger with risk factors, consider an EKG before prescribing lamotrigine.
- “Nonspecific EKG abnormalities (e.g., nonspecific ST and T wave abnormalities) are not concerning, and should not preclude these individuals from being prescribed lamotrigine.”
- Beware of higher risk and consider consulting a cardiologist before starting treatment in patients with second- or third-degree heart block, Brugada syndrome, arrhythmogenic ventricular cardiomyopathy, left bundle branch block, and right bundle branch block with left anterior or posterior fascicular block.
- “In most cases the initial EKG can be obtained while titrating, mainly when the individual is at the first dose of 25 mg/day because lamotrigine must be titrated slowly, and because cardiac adverse events are dose related.”
- “Clinicians should consider obtaining an EKG and/or cardiology consultation in people on lamotrigine with sudden-onset syncope or presyncope with loss of muscular tone without a clear vasovagal or orthostatic cause.”
Dr. French cautioned colleagues that they shouldn’t assume that lamotrigine stands alone among sodium channel blockers in terms of cardiac risk. As she noted, the FDA is asking manufacturers of other drugs in that class to provide data. “At some point, maybe sometime in the near future, we are going to hear in this particular in vitro sense how the other sodium channel blockers do stack up, compared with lamotrigine. At presence, in the absence of the availability of all of the rest of the data, it would be incorrect to presume that lamotrigine has more cardiac effects than other sodium channel blocking antiseizure medicines or all antiseizure medicines.”
For now, she said, although the guidelines are for lamotrigine, it’s “prudent” to follow them for all sodium channel blockers.
Dr. French reported no disclosures.
FROM AES 2021
Genetic tests prompt therapy adjustments in children with epilepsy
Physicians at a Boston hospital adjusted medical management for nearly three-quarters of patients with infantile- or childhood-onset epilepsy who were diagnosed with genetic epilepsy, researchers reported at the annual meeting of the American Epilepsy Society. The findings provide new insight into the usefulness of genetic tests in children with epilepsy of unknown cause.
“. Genetic testing should be included as part of the standard evaluation of individuals with unexplained pediatric epilepsy as a means of achieving diagnostic precision and informing clinical management,” study lead author Isabel Haviland, MD, a neurologist with Boston Children’s Hospital/Harvard Medical School, said in an interview.
According to Dr. Haviland, the causes of epilepsy are unexplained in an estimated two-thirds of pediatric epilepsy cases. “Increasingly, when genetic testing is available, previously unexplained cases of pediatric epilepsy are being found to have single-gene etiologies,” she said. “Though a genetic diagnosis in this population has implications for medical care, the direct impact on medical management in a clinical setting has not been measured. We aimed to describe the impact of genetic diagnosis on medical management in a cohort of individuals with pediatric epilepsy.”
Researchers tracked 602 patients at Boston Children’s Hospital who received next-generation gene sequencing testing from 2012 to 2019. Of those, Dr. Haviland said, 152 (25%) had a positive result that indicated genetic epilepsy (46% female, median age of onset = 6 months [2-15 months]). These patients were included in the study.
“We documented an impact on medical management in nearly three-fourths of participants (72%),” Dr. Haviland said. “A genetic diagnosis affected at least one of four categories of medical management, including care coordination (48%), treatment (45%), counseling about a change in prognosis (28%), and change in diagnosis for a few individuals who had a prior established diagnosis (1%).”
As examples, she mentioned three cases:
- Testing revealed that a subject has a disease-causing genetic variant in a gene called PRRT2. “This gene is involved in the release of neurotransmitters in the brain,” Dr. Haviland said. “Thanks to his diagnosis, he was treated with the antiseizure medication oxcarbazepine, which is often effective for epilepsy caused by variants in this gene. He had excellent response to the medication and later became seizure free.”
- A subject had a variation in the SCN1A gene that causes types of epilepsy. “At the time of his diagnosis, there was a trial for a medication called fenfluramine being offered for individuals with SCN1A variants, and his family elected to participate,” she said. “This medication was later approved by the [Food and Drug Administration] for SCN1A-related epilepsy.”
- Testing identified disease-causing variant in the GRIN2A gene in another subject. “This gene is involved in brain cell communication,” Dr. Haviland said. “This individual was treated with memantine, which acts on the specific biological pathway affected by the gene. This treatment would not have been considered without the genetic diagnosis as it is currently only approved for Alzheimer’s disease.”
In addition, Dr. Haviland said, researchers found that “there was impact on medical management both in those with earlier age of epilepsy onset (under 2 years) and those with later age of onset, as well as both in those with developmental disorders (such as autism spectrum disorder, intellectual disability and developmental delay) and those with normal development.
As for the cost of genetic tests, Dr. Haviland pointed to a 2019 study that she said estimated epilepsy panel testing runs from $1,500 to $7,500, and the whole exome sequencing from $4,500 to $7,000. “Insurers sometimes cover testing, but not always,” she said. “In some cases, insurance will only cover testing if it is documented that results will directly alter medical management, which highlights the importance of our findings.”
No study funding was reported. Dr. Haviland and several other authors report no disclosures. One author reports consulting fees from Takeda, Zogenix, Marinus, and FOXG1 Research Foundation. Another author reports research support from the International Foundation for CDKL5 Research.
Physicians at a Boston hospital adjusted medical management for nearly three-quarters of patients with infantile- or childhood-onset epilepsy who were diagnosed with genetic epilepsy, researchers reported at the annual meeting of the American Epilepsy Society. The findings provide new insight into the usefulness of genetic tests in children with epilepsy of unknown cause.
“. Genetic testing should be included as part of the standard evaluation of individuals with unexplained pediatric epilepsy as a means of achieving diagnostic precision and informing clinical management,” study lead author Isabel Haviland, MD, a neurologist with Boston Children’s Hospital/Harvard Medical School, said in an interview.
According to Dr. Haviland, the causes of epilepsy are unexplained in an estimated two-thirds of pediatric epilepsy cases. “Increasingly, when genetic testing is available, previously unexplained cases of pediatric epilepsy are being found to have single-gene etiologies,” she said. “Though a genetic diagnosis in this population has implications for medical care, the direct impact on medical management in a clinical setting has not been measured. We aimed to describe the impact of genetic diagnosis on medical management in a cohort of individuals with pediatric epilepsy.”
Researchers tracked 602 patients at Boston Children’s Hospital who received next-generation gene sequencing testing from 2012 to 2019. Of those, Dr. Haviland said, 152 (25%) had a positive result that indicated genetic epilepsy (46% female, median age of onset = 6 months [2-15 months]). These patients were included in the study.
“We documented an impact on medical management in nearly three-fourths of participants (72%),” Dr. Haviland said. “A genetic diagnosis affected at least one of four categories of medical management, including care coordination (48%), treatment (45%), counseling about a change in prognosis (28%), and change in diagnosis for a few individuals who had a prior established diagnosis (1%).”
As examples, she mentioned three cases:
- Testing revealed that a subject has a disease-causing genetic variant in a gene called PRRT2. “This gene is involved in the release of neurotransmitters in the brain,” Dr. Haviland said. “Thanks to his diagnosis, he was treated with the antiseizure medication oxcarbazepine, which is often effective for epilepsy caused by variants in this gene. He had excellent response to the medication and later became seizure free.”
- A subject had a variation in the SCN1A gene that causes types of epilepsy. “At the time of his diagnosis, there was a trial for a medication called fenfluramine being offered for individuals with SCN1A variants, and his family elected to participate,” she said. “This medication was later approved by the [Food and Drug Administration] for SCN1A-related epilepsy.”
- Testing identified disease-causing variant in the GRIN2A gene in another subject. “This gene is involved in brain cell communication,” Dr. Haviland said. “This individual was treated with memantine, which acts on the specific biological pathway affected by the gene. This treatment would not have been considered without the genetic diagnosis as it is currently only approved for Alzheimer’s disease.”
In addition, Dr. Haviland said, researchers found that “there was impact on medical management both in those with earlier age of epilepsy onset (under 2 years) and those with later age of onset, as well as both in those with developmental disorders (such as autism spectrum disorder, intellectual disability and developmental delay) and those with normal development.
As for the cost of genetic tests, Dr. Haviland pointed to a 2019 study that she said estimated epilepsy panel testing runs from $1,500 to $7,500, and the whole exome sequencing from $4,500 to $7,000. “Insurers sometimes cover testing, but not always,” she said. “In some cases, insurance will only cover testing if it is documented that results will directly alter medical management, which highlights the importance of our findings.”
No study funding was reported. Dr. Haviland and several other authors report no disclosures. One author reports consulting fees from Takeda, Zogenix, Marinus, and FOXG1 Research Foundation. Another author reports research support from the International Foundation for CDKL5 Research.
Physicians at a Boston hospital adjusted medical management for nearly three-quarters of patients with infantile- or childhood-onset epilepsy who were diagnosed with genetic epilepsy, researchers reported at the annual meeting of the American Epilepsy Society. The findings provide new insight into the usefulness of genetic tests in children with epilepsy of unknown cause.
“. Genetic testing should be included as part of the standard evaluation of individuals with unexplained pediatric epilepsy as a means of achieving diagnostic precision and informing clinical management,” study lead author Isabel Haviland, MD, a neurologist with Boston Children’s Hospital/Harvard Medical School, said in an interview.
According to Dr. Haviland, the causes of epilepsy are unexplained in an estimated two-thirds of pediatric epilepsy cases. “Increasingly, when genetic testing is available, previously unexplained cases of pediatric epilepsy are being found to have single-gene etiologies,” she said. “Though a genetic diagnosis in this population has implications for medical care, the direct impact on medical management in a clinical setting has not been measured. We aimed to describe the impact of genetic diagnosis on medical management in a cohort of individuals with pediatric epilepsy.”
Researchers tracked 602 patients at Boston Children’s Hospital who received next-generation gene sequencing testing from 2012 to 2019. Of those, Dr. Haviland said, 152 (25%) had a positive result that indicated genetic epilepsy (46% female, median age of onset = 6 months [2-15 months]). These patients were included in the study.
“We documented an impact on medical management in nearly three-fourths of participants (72%),” Dr. Haviland said. “A genetic diagnosis affected at least one of four categories of medical management, including care coordination (48%), treatment (45%), counseling about a change in prognosis (28%), and change in diagnosis for a few individuals who had a prior established diagnosis (1%).”
As examples, she mentioned three cases:
- Testing revealed that a subject has a disease-causing genetic variant in a gene called PRRT2. “This gene is involved in the release of neurotransmitters in the brain,” Dr. Haviland said. “Thanks to his diagnosis, he was treated with the antiseizure medication oxcarbazepine, which is often effective for epilepsy caused by variants in this gene. He had excellent response to the medication and later became seizure free.”
- A subject had a variation in the SCN1A gene that causes types of epilepsy. “At the time of his diagnosis, there was a trial for a medication called fenfluramine being offered for individuals with SCN1A variants, and his family elected to participate,” she said. “This medication was later approved by the [Food and Drug Administration] for SCN1A-related epilepsy.”
- Testing identified disease-causing variant in the GRIN2A gene in another subject. “This gene is involved in brain cell communication,” Dr. Haviland said. “This individual was treated with memantine, which acts on the specific biological pathway affected by the gene. This treatment would not have been considered without the genetic diagnosis as it is currently only approved for Alzheimer’s disease.”
In addition, Dr. Haviland said, researchers found that “there was impact on medical management both in those with earlier age of epilepsy onset (under 2 years) and those with later age of onset, as well as both in those with developmental disorders (such as autism spectrum disorder, intellectual disability and developmental delay) and those with normal development.
As for the cost of genetic tests, Dr. Haviland pointed to a 2019 study that she said estimated epilepsy panel testing runs from $1,500 to $7,500, and the whole exome sequencing from $4,500 to $7,000. “Insurers sometimes cover testing, but not always,” she said. “In some cases, insurance will only cover testing if it is documented that results will directly alter medical management, which highlights the importance of our findings.”
No study funding was reported. Dr. Haviland and several other authors report no disclosures. One author reports consulting fees from Takeda, Zogenix, Marinus, and FOXG1 Research Foundation. Another author reports research support from the International Foundation for CDKL5 Research.
FROM AES 2021
COVID-19 hospital data: New-onset seizures more common than breakthrough seizures
An analysis of hospitalized patients with COVID-19 finds that those with no history of epilepsy had more than 3 times the odds of suffering a new-onset seizure than patients with epilepsy were to have breakthrough seizures (odds radio [OR] 3.15, P < .0001), researchers reported at the annual meeting of the American Epilepsy Society.
study lead author Neeraj Singh, MD, a neurologist at the New York-based Northwell Health system, said in an interview. “That’s new. We don’t normally see that when someone has a bacterial or viral infection. It’s demonstrating that this infection is having direct effect on the brain and brain signals.”
According to Dr. Singh, there’s little data about seizures in patients with COVID-19 because doctors have focused on other symptoms. A 2021 multicenter study found that electrographic seizures were detected in 9.6% of 197 patients with COVID-19 who were referred for cEEG.
For the new study, Dr. Singh and a colleague tracked 917 patients with COVID-19 in the Northwell Health system who were treated from Feb. 14 to June 14, 2020, with antiepileptic medication. Of the patients, 451 had a history of epilepsy, and 466 did not.
According to Dr. Singh, 27.6% of the patients without a history of epilepsy had new-onset seizures, while 10.1% of the patients with history of epilepsy had breakthrough seizures. The difference in odds was more than threefold after adjustment. (Among all COVID-19 patients, he said, perhaps 8%-16% had seizures).
The researchers also found that patients with new-onset seizures stayed in the hospital much longer (average, 26.9 days) than any patients with a known history of epilepsy (12.8 days, P < .0001, for those who had breakthrough seizures and 10.9 days, P < .0001, for those who didn’t).
In addition, the researchers found that having any seizures – new-onset or breakthrough – was linked to higher risk of death (OR 1.41, P = .03).
Antiseizure medications are key treatments for these patients, Dr. Singh said. As for the patients with new-onset seizures who recover from COVID-19, Dr. Singh said, “it’s suspected that these people are going to have a new diagnosis of epilepsy, not just a one-time seizure.”
The findings suggest that some patients with epilepsy are protected against COVID-19-related seizures because they take antiepileptic medications that “protect the brain from getting a trigger for an abnormal signal that leads to a seizure,” he said. “That’s one possibility.”
What can neurologists learn from the study? Dr. Singh recommends a “lower threshold” to recommend or approve EEGs in patients with COVID-19 who are confused/altered when they come in, especially if this is not normal. “They may actually be having silent seizures that no one’s noticing,” he said.
No study funding was reported. The authors reported no relevant disclosures.
An analysis of hospitalized patients with COVID-19 finds that those with no history of epilepsy had more than 3 times the odds of suffering a new-onset seizure than patients with epilepsy were to have breakthrough seizures (odds radio [OR] 3.15, P < .0001), researchers reported at the annual meeting of the American Epilepsy Society.
study lead author Neeraj Singh, MD, a neurologist at the New York-based Northwell Health system, said in an interview. “That’s new. We don’t normally see that when someone has a bacterial or viral infection. It’s demonstrating that this infection is having direct effect on the brain and brain signals.”
According to Dr. Singh, there’s little data about seizures in patients with COVID-19 because doctors have focused on other symptoms. A 2021 multicenter study found that electrographic seizures were detected in 9.6% of 197 patients with COVID-19 who were referred for cEEG.
For the new study, Dr. Singh and a colleague tracked 917 patients with COVID-19 in the Northwell Health system who were treated from Feb. 14 to June 14, 2020, with antiepileptic medication. Of the patients, 451 had a history of epilepsy, and 466 did not.
According to Dr. Singh, 27.6% of the patients without a history of epilepsy had new-onset seizures, while 10.1% of the patients with history of epilepsy had breakthrough seizures. The difference in odds was more than threefold after adjustment. (Among all COVID-19 patients, he said, perhaps 8%-16% had seizures).
The researchers also found that patients with new-onset seizures stayed in the hospital much longer (average, 26.9 days) than any patients with a known history of epilepsy (12.8 days, P < .0001, for those who had breakthrough seizures and 10.9 days, P < .0001, for those who didn’t).
In addition, the researchers found that having any seizures – new-onset or breakthrough – was linked to higher risk of death (OR 1.41, P = .03).
Antiseizure medications are key treatments for these patients, Dr. Singh said. As for the patients with new-onset seizures who recover from COVID-19, Dr. Singh said, “it’s suspected that these people are going to have a new diagnosis of epilepsy, not just a one-time seizure.”
The findings suggest that some patients with epilepsy are protected against COVID-19-related seizures because they take antiepileptic medications that “protect the brain from getting a trigger for an abnormal signal that leads to a seizure,” he said. “That’s one possibility.”
What can neurologists learn from the study? Dr. Singh recommends a “lower threshold” to recommend or approve EEGs in patients with COVID-19 who are confused/altered when they come in, especially if this is not normal. “They may actually be having silent seizures that no one’s noticing,” he said.
No study funding was reported. The authors reported no relevant disclosures.
An analysis of hospitalized patients with COVID-19 finds that those with no history of epilepsy had more than 3 times the odds of suffering a new-onset seizure than patients with epilepsy were to have breakthrough seizures (odds radio [OR] 3.15, P < .0001), researchers reported at the annual meeting of the American Epilepsy Society.
study lead author Neeraj Singh, MD, a neurologist at the New York-based Northwell Health system, said in an interview. “That’s new. We don’t normally see that when someone has a bacterial or viral infection. It’s demonstrating that this infection is having direct effect on the brain and brain signals.”
According to Dr. Singh, there’s little data about seizures in patients with COVID-19 because doctors have focused on other symptoms. A 2021 multicenter study found that electrographic seizures were detected in 9.6% of 197 patients with COVID-19 who were referred for cEEG.
For the new study, Dr. Singh and a colleague tracked 917 patients with COVID-19 in the Northwell Health system who were treated from Feb. 14 to June 14, 2020, with antiepileptic medication. Of the patients, 451 had a history of epilepsy, and 466 did not.
According to Dr. Singh, 27.6% of the patients without a history of epilepsy had new-onset seizures, while 10.1% of the patients with history of epilepsy had breakthrough seizures. The difference in odds was more than threefold after adjustment. (Among all COVID-19 patients, he said, perhaps 8%-16% had seizures).
The researchers also found that patients with new-onset seizures stayed in the hospital much longer (average, 26.9 days) than any patients with a known history of epilepsy (12.8 days, P < .0001, for those who had breakthrough seizures and 10.9 days, P < .0001, for those who didn’t).
In addition, the researchers found that having any seizures – new-onset or breakthrough – was linked to higher risk of death (OR 1.41, P = .03).
Antiseizure medications are key treatments for these patients, Dr. Singh said. As for the patients with new-onset seizures who recover from COVID-19, Dr. Singh said, “it’s suspected that these people are going to have a new diagnosis of epilepsy, not just a one-time seizure.”
The findings suggest that some patients with epilepsy are protected against COVID-19-related seizures because they take antiepileptic medications that “protect the brain from getting a trigger for an abnormal signal that leads to a seizure,” he said. “That’s one possibility.”
What can neurologists learn from the study? Dr. Singh recommends a “lower threshold” to recommend or approve EEGs in patients with COVID-19 who are confused/altered when they come in, especially if this is not normal. “They may actually be having silent seizures that no one’s noticing,” he said.
No study funding was reported. The authors reported no relevant disclosures.
FROM AES 2021
Metastatic uveal melanoma: New drugs in pipeline, but prognoses remain grim
No one’s quite sure what causes uveal melanoma (UM). Unlike skin cancers, UM doesn’t seem to have any link to exposure to ultraviolet rays, although it’s most likely to strike people who are vulnerable to sun damage, like Caucasians and people with lighter eyes and lighter skin (but not lighter hair), and an inability to tan. Up to half of those affected by the disease will recover after treatment. In the other half, the cancer spreads from the eye – typically to the liver – and patient prognoses remain extremely poor despite extensive efforts to develop effective treatments.
“The median survival is probably about 2 years, and there are a number of papers out there that talk about life expectancy as short as 6 months,” said Marlana Orloff, MD, an associate professor of medical oncology at Thomas Jefferson University Hospital, Philadelphia.
But there is hope on the horizon, even if it’s not as near as patients would prefer. “Just over the last 5-10 years, we’ve gained a lot more knowledge about this disease as we try to understand how distinctly different it is, how mutations drive it, and how we can approach it using immunotherapy,” Dr. Orloff said. “I hope we’ll come up with better options for prolonging survival.”
Tracking uveal melanoma’s dangerous course
All melanomas, including UM, strike the melanocytes (cells) that provide pigment. According to a 2017 report1 in the journal Eye, “uveal melanoma is the most common primary intraocular tumor in adults with a mean age-adjusted incidence of 5.1 cases per million per year. Tumors are located either in the iris (4%), ciliary body (6%), or choroid (90%) . … As in many other cancer indications, both early detection and early treatment could be critical for a positive long-term survival outcome in uveal melanoma.”
The median age of diagnosis is 59-62 years, the report says, although non-Whites seem to develop the disease earlier.
The vast majority of patients receive treatment by plaque brachytherapy via radioactive seeds. “It’s like brachytherapy of the prostate,” said medical oncologist Rino S. Seedor, MD, of Thomas Jefferson University Hospital. “If the eye tumor is too big or invasive, they’ll cut out the eye.”
As many as 50% of patients will develop metastasis, sometimes within 2-3 years in those who have large tumors and high genetic risk, said ophthalmologist and radiation oncologist Miguel Materin, MD, of Duke University Eye Center, Durham, N.C. “There’s probably micrometastasis early in the development of the tumor,” he said. “The metastasis might develop before we or the patient knows there’s a tumor.”
Some physicians question the value of prognostic testing in patients who don’t yet show signs of metastasis, Dr. Materin said, because the findings can be grim.
Unlike his more cautious colleagues, Dr. Materin prefers to pursue testing, he said. Most patients agree to it. “It’s up to them to decide if they want to know if they have a bad prognosis,” he said, and the findings can be helpful to physicians because they provide useful genetic information about tumors.
Monitoring for liver metastasis is key
UM metastases are most likely to strike the liver, and prognoses are especially poor when they do. According to a 2019 analysis of 175 patients with metastatic UM in the Netherlands, “the presence of liver metastases is negatively associated with survival (hazard ratio = 2.09; 95% confidence interval, 1.07-4.08). … In 154 (88%) patients, the liver was affected, and only 3 patients were reported to have brain metastases.”2
As a result, physicians recommend close monitoring in patients with UM. Thomas Jefferson University’s Dr. Orloff uses tumor stages and genetic risk profiles to guide surveillance. “Very large tumors and/or monosomy 3 and 8q amplification or a Class 2 gene signature would suggest a higher-risk tumor,” she said. “For these patients we recommend MRI of the abdomen every 3 months for 2 years, CT of the chest every 6 months for 2 years, labs every 3 months for 2 years, then MRI every 6 months until year 5 with chest imaging yearly, then at 5 years everything yearly. For lower- or intermediate-risk patients we recommend MRI of the abdomen every 6 months for 5 years, chest imaging yearly, labs every 6 months, then at 5 years everything yearly.”
In the United States, patients with metastatic disease are typically sent to referral centers at institutions such as Duke, Yale (New Haven, Conn.), and Thomas Jefferson universities.
Metastasis treatments offer limited relief
There are no FDA-approved treatments for metastatic MU, and the treatments that physicians do use don’t seem to have much of an effect on life span. A 2019 study examined 73 patients with MU metastasis to the liver who were treated from 2004 to 2011 and 2012 to 2016. Among both cohorts, those who had no treatment lived nearly as long (median of 15 months) as those treated with local therapy (median of 18.7 months). Median survival for the entire population was 15 months (95% CI: 11–18 months). There was no statistically significant difference between the periods.3
However, there are signs that a move away from first-line chemotherapy in recent decades has led to longer life spans. Dr. Seedor led a 2018 study4 that compared two cohorts of MU patients with liver metastasis at her university: 98 patients from 1971 to 1993 (81% received systemic chemotherapy as their initial therapy) and 574 from 2000 to 2017 (they received various liver-directed initial treatments such as chemoembolization, drug-eluting beads, immunoembolization, and radioembolization).
The patients in the second group lived longer after treatment of initial UM than the first group (5.1 years vs. 3.3 years, P < .001) and after the development of liver metastasis (16.4 months vs. 4.8 months, P < .001). A 2020 follow-up study reported similar findings and noted that a “combination of liver-directed and newly developed systemic treatments may further improve the survival of these patients.”5
At Thomas Jefferson Medical Center, liver-directed therapy includes radioembolization, chemomobilization, and microwave ablation, Dr. Seedor said. “Which one we choose is based on how big the tumors are.”
Treatments in development could make advances
Physicians are working on several fronts to develop new treatments. A 2021 review of clinical trials found numerous trials regarding checkpoint inhibition, one devoted to a vaccine, and several involving checkpoint inhibitors. The review author notes that “the low mutational burden and poor immunogenicity of UM tumors may underlie poor responses and resistance to [immune checkpoint inhibitors] alone.”6
Earlier this year, grant-funded researchers reported encouraging news on the G protein inhibitor front. Their study found that FR900359, a selective inhibitor of the Gq/11/14 subfamily of heterotrimeric G proteins, could hold promise for “treating UM and potentially other diseases caused by constitutively active Gq/11.”7
In another 2021 study, this one with no reported funding, researchers explored the tumor microenvironment of UM and reported that their findings “provided a robust gene-based prognostic signature for predicting prognosis of UM patients and proposed a potential targeted therapy for preventing UM metastasis.”8
Experimental drug may add months of life
Physicians often recommend that patients take part in clinical trials. Earlier this year, researchers reported that a drug called tebentafusp – a bispecific fusion protein – slightly boosted metastatic UM survival in an open-label, phase 3 clinical trial when used as a first-line treatment. Patients were randomly assigned to tebentafusp, 1 of 2 immunotherapy drugs (ipilimumab or pembrolizumab), or the chemotherapy drug dacarbazine. Those who took tebentafusp vs. the other options lived longer with an estimated 1-year overall rate of 73.2% (95% CI: 66.3-78.9) vs. 57.5% (95% CI: 47.0-66.6), respectively. Fewer than 4% of those on tebentafusp needed to stop it because of adverse effects, and no treatment-related deaths occurred.9
Dr. Orloff is one of the coauthors of this study.
The National Cancer Institute provided more details about the industry-funded research and noted that median overall survival for patients who received the drug was 21.7 months vs. 16 months for the control group.
Not every patient is eligible for this treatment, however. A coauthor told the American Association for Cancer Research that “the major limitation of tebentafusp is that it can only be used in patients who have a specific HLA [human leukocyte antigen] type.” Patients must be HLA-A*0201-positive.10
In August 2021, the FDA granted priority review for tebentafusp.11 And in September 2021, a company called TriSalus announced the first patient enrollment in a “clinical study evaluating the administration of SD-101, an investigational toll-like receptor 9 (TLR9) agonist in adults with metastatic uveal melanoma.”12
According to the company, the research “is designed to evaluate the intravascular administration of SD-101 into uveal melanoma liver metastasis lesions in combination with checkpoint inhibitors using the novel Pressure-Enabled Drug Delivery (PEDD) approach.” This strategy is “designed to overcome the inherent intratumoral pressure of solid tumors,” the company said.
Dr. Materin serves on a scientific advisory board for Castle Biosciences. Dr. Orloff is a consultant for Immunocore, which funded the tebentafusp study, and serves on a scientific advisory board for TriSalus. Dr. Seedor reports no disclosures.
References
1.Kaliki S and Shields C. Eye. 2017 Feb;31:241-57.
2.Jochems A et al. Cancers. 2019 July;11(7):1007.
3.Xu LT et al. Ocul Oncol Pathol. 2019;5:323-32.
4.Seedor RS et al. J Clin Oncol. 2018 May;36(15_suppl):9592.
5.Seedor RS et al. Cancers (Basel). 2020 Jan 1;12(1):117.
6.Orloff M. Ocul Oncol Pathol. 2021 July;7:168-76.
7.Onken MD et al. J Biol Chem. 2021;296:100403.
8.Lei S and Zhang Y. Int Immunopharmacol. 2021 July;96:107816.
9.Piperno-Neumann S et al. Proceedings of the 112th Annual Meeting of the American Association for Cancer Research; 2021 April 10-15. Philadelphia (Pa.): AACR; 2021. Abstract nr 5133.
10.National Cancer Institute: https://www.cancer.gov/news-events/cancer-currents-blog/2021/tebentafusp-uveal-melanoma-improves-survival
11.Immunocore press release: https://ir.immunocore.com/news-releases/news-release-details/immunocore-announces-us-food-and-drug-administration-and
12.Trisalus announcement: https://finance.yahoo.com/news/trisalus-life-sciences-announces-first-130000215.html?guccounter=1
No one’s quite sure what causes uveal melanoma (UM). Unlike skin cancers, UM doesn’t seem to have any link to exposure to ultraviolet rays, although it’s most likely to strike people who are vulnerable to sun damage, like Caucasians and people with lighter eyes and lighter skin (but not lighter hair), and an inability to tan. Up to half of those affected by the disease will recover after treatment. In the other half, the cancer spreads from the eye – typically to the liver – and patient prognoses remain extremely poor despite extensive efforts to develop effective treatments.
“The median survival is probably about 2 years, and there are a number of papers out there that talk about life expectancy as short as 6 months,” said Marlana Orloff, MD, an associate professor of medical oncology at Thomas Jefferson University Hospital, Philadelphia.
But there is hope on the horizon, even if it’s not as near as patients would prefer. “Just over the last 5-10 years, we’ve gained a lot more knowledge about this disease as we try to understand how distinctly different it is, how mutations drive it, and how we can approach it using immunotherapy,” Dr. Orloff said. “I hope we’ll come up with better options for prolonging survival.”
Tracking uveal melanoma’s dangerous course
All melanomas, including UM, strike the melanocytes (cells) that provide pigment. According to a 2017 report1 in the journal Eye, “uveal melanoma is the most common primary intraocular tumor in adults with a mean age-adjusted incidence of 5.1 cases per million per year. Tumors are located either in the iris (4%), ciliary body (6%), or choroid (90%) . … As in many other cancer indications, both early detection and early treatment could be critical for a positive long-term survival outcome in uveal melanoma.”
The median age of diagnosis is 59-62 years, the report says, although non-Whites seem to develop the disease earlier.
The vast majority of patients receive treatment by plaque brachytherapy via radioactive seeds. “It’s like brachytherapy of the prostate,” said medical oncologist Rino S. Seedor, MD, of Thomas Jefferson University Hospital. “If the eye tumor is too big or invasive, they’ll cut out the eye.”
As many as 50% of patients will develop metastasis, sometimes within 2-3 years in those who have large tumors and high genetic risk, said ophthalmologist and radiation oncologist Miguel Materin, MD, of Duke University Eye Center, Durham, N.C. “There’s probably micrometastasis early in the development of the tumor,” he said. “The metastasis might develop before we or the patient knows there’s a tumor.”
Some physicians question the value of prognostic testing in patients who don’t yet show signs of metastasis, Dr. Materin said, because the findings can be grim.
Unlike his more cautious colleagues, Dr. Materin prefers to pursue testing, he said. Most patients agree to it. “It’s up to them to decide if they want to know if they have a bad prognosis,” he said, and the findings can be helpful to physicians because they provide useful genetic information about tumors.
Monitoring for liver metastasis is key
UM metastases are most likely to strike the liver, and prognoses are especially poor when they do. According to a 2019 analysis of 175 patients with metastatic UM in the Netherlands, “the presence of liver metastases is negatively associated with survival (hazard ratio = 2.09; 95% confidence interval, 1.07-4.08). … In 154 (88%) patients, the liver was affected, and only 3 patients were reported to have brain metastases.”2
As a result, physicians recommend close monitoring in patients with UM. Thomas Jefferson University’s Dr. Orloff uses tumor stages and genetic risk profiles to guide surveillance. “Very large tumors and/or monosomy 3 and 8q amplification or a Class 2 gene signature would suggest a higher-risk tumor,” she said. “For these patients we recommend MRI of the abdomen every 3 months for 2 years, CT of the chest every 6 months for 2 years, labs every 3 months for 2 years, then MRI every 6 months until year 5 with chest imaging yearly, then at 5 years everything yearly. For lower- or intermediate-risk patients we recommend MRI of the abdomen every 6 months for 5 years, chest imaging yearly, labs every 6 months, then at 5 years everything yearly.”
In the United States, patients with metastatic disease are typically sent to referral centers at institutions such as Duke, Yale (New Haven, Conn.), and Thomas Jefferson universities.
Metastasis treatments offer limited relief
There are no FDA-approved treatments for metastatic MU, and the treatments that physicians do use don’t seem to have much of an effect on life span. A 2019 study examined 73 patients with MU metastasis to the liver who were treated from 2004 to 2011 and 2012 to 2016. Among both cohorts, those who had no treatment lived nearly as long (median of 15 months) as those treated with local therapy (median of 18.7 months). Median survival for the entire population was 15 months (95% CI: 11–18 months). There was no statistically significant difference between the periods.3
However, there are signs that a move away from first-line chemotherapy in recent decades has led to longer life spans. Dr. Seedor led a 2018 study4 that compared two cohorts of MU patients with liver metastasis at her university: 98 patients from 1971 to 1993 (81% received systemic chemotherapy as their initial therapy) and 574 from 2000 to 2017 (they received various liver-directed initial treatments such as chemoembolization, drug-eluting beads, immunoembolization, and radioembolization).
The patients in the second group lived longer after treatment of initial UM than the first group (5.1 years vs. 3.3 years, P < .001) and after the development of liver metastasis (16.4 months vs. 4.8 months, P < .001). A 2020 follow-up study reported similar findings and noted that a “combination of liver-directed and newly developed systemic treatments may further improve the survival of these patients.”5
At Thomas Jefferson Medical Center, liver-directed therapy includes radioembolization, chemomobilization, and microwave ablation, Dr. Seedor said. “Which one we choose is based on how big the tumors are.”
Treatments in development could make advances
Physicians are working on several fronts to develop new treatments. A 2021 review of clinical trials found numerous trials regarding checkpoint inhibition, one devoted to a vaccine, and several involving checkpoint inhibitors. The review author notes that “the low mutational burden and poor immunogenicity of UM tumors may underlie poor responses and resistance to [immune checkpoint inhibitors] alone.”6
Earlier this year, grant-funded researchers reported encouraging news on the G protein inhibitor front. Their study found that FR900359, a selective inhibitor of the Gq/11/14 subfamily of heterotrimeric G proteins, could hold promise for “treating UM and potentially other diseases caused by constitutively active Gq/11.”7
In another 2021 study, this one with no reported funding, researchers explored the tumor microenvironment of UM and reported that their findings “provided a robust gene-based prognostic signature for predicting prognosis of UM patients and proposed a potential targeted therapy for preventing UM metastasis.”8
Experimental drug may add months of life
Physicians often recommend that patients take part in clinical trials. Earlier this year, researchers reported that a drug called tebentafusp – a bispecific fusion protein – slightly boosted metastatic UM survival in an open-label, phase 3 clinical trial when used as a first-line treatment. Patients were randomly assigned to tebentafusp, 1 of 2 immunotherapy drugs (ipilimumab or pembrolizumab), or the chemotherapy drug dacarbazine. Those who took tebentafusp vs. the other options lived longer with an estimated 1-year overall rate of 73.2% (95% CI: 66.3-78.9) vs. 57.5% (95% CI: 47.0-66.6), respectively. Fewer than 4% of those on tebentafusp needed to stop it because of adverse effects, and no treatment-related deaths occurred.9
Dr. Orloff is one of the coauthors of this study.
The National Cancer Institute provided more details about the industry-funded research and noted that median overall survival for patients who received the drug was 21.7 months vs. 16 months for the control group.
Not every patient is eligible for this treatment, however. A coauthor told the American Association for Cancer Research that “the major limitation of tebentafusp is that it can only be used in patients who have a specific HLA [human leukocyte antigen] type.” Patients must be HLA-A*0201-positive.10
In August 2021, the FDA granted priority review for tebentafusp.11 And in September 2021, a company called TriSalus announced the first patient enrollment in a “clinical study evaluating the administration of SD-101, an investigational toll-like receptor 9 (TLR9) agonist in adults with metastatic uveal melanoma.”12
According to the company, the research “is designed to evaluate the intravascular administration of SD-101 into uveal melanoma liver metastasis lesions in combination with checkpoint inhibitors using the novel Pressure-Enabled Drug Delivery (PEDD) approach.” This strategy is “designed to overcome the inherent intratumoral pressure of solid tumors,” the company said.
Dr. Materin serves on a scientific advisory board for Castle Biosciences. Dr. Orloff is a consultant for Immunocore, which funded the tebentafusp study, and serves on a scientific advisory board for TriSalus. Dr. Seedor reports no disclosures.
References
1.Kaliki S and Shields C. Eye. 2017 Feb;31:241-57.
2.Jochems A et al. Cancers. 2019 July;11(7):1007.
3.Xu LT et al. Ocul Oncol Pathol. 2019;5:323-32.
4.Seedor RS et al. J Clin Oncol. 2018 May;36(15_suppl):9592.
5.Seedor RS et al. Cancers (Basel). 2020 Jan 1;12(1):117.
6.Orloff M. Ocul Oncol Pathol. 2021 July;7:168-76.
7.Onken MD et al. J Biol Chem. 2021;296:100403.
8.Lei S and Zhang Y. Int Immunopharmacol. 2021 July;96:107816.
9.Piperno-Neumann S et al. Proceedings of the 112th Annual Meeting of the American Association for Cancer Research; 2021 April 10-15. Philadelphia (Pa.): AACR; 2021. Abstract nr 5133.
10.National Cancer Institute: https://www.cancer.gov/news-events/cancer-currents-blog/2021/tebentafusp-uveal-melanoma-improves-survival
11.Immunocore press release: https://ir.immunocore.com/news-releases/news-release-details/immunocore-announces-us-food-and-drug-administration-and
12.Trisalus announcement: https://finance.yahoo.com/news/trisalus-life-sciences-announces-first-130000215.html?guccounter=1
No one’s quite sure what causes uveal melanoma (UM). Unlike skin cancers, UM doesn’t seem to have any link to exposure to ultraviolet rays, although it’s most likely to strike people who are vulnerable to sun damage, like Caucasians and people with lighter eyes and lighter skin (but not lighter hair), and an inability to tan. Up to half of those affected by the disease will recover after treatment. In the other half, the cancer spreads from the eye – typically to the liver – and patient prognoses remain extremely poor despite extensive efforts to develop effective treatments.
“The median survival is probably about 2 years, and there are a number of papers out there that talk about life expectancy as short as 6 months,” said Marlana Orloff, MD, an associate professor of medical oncology at Thomas Jefferson University Hospital, Philadelphia.
But there is hope on the horizon, even if it’s not as near as patients would prefer. “Just over the last 5-10 years, we’ve gained a lot more knowledge about this disease as we try to understand how distinctly different it is, how mutations drive it, and how we can approach it using immunotherapy,” Dr. Orloff said. “I hope we’ll come up with better options for prolonging survival.”
Tracking uveal melanoma’s dangerous course
All melanomas, including UM, strike the melanocytes (cells) that provide pigment. According to a 2017 report1 in the journal Eye, “uveal melanoma is the most common primary intraocular tumor in adults with a mean age-adjusted incidence of 5.1 cases per million per year. Tumors are located either in the iris (4%), ciliary body (6%), or choroid (90%) . … As in many other cancer indications, both early detection and early treatment could be critical for a positive long-term survival outcome in uveal melanoma.”
The median age of diagnosis is 59-62 years, the report says, although non-Whites seem to develop the disease earlier.
The vast majority of patients receive treatment by plaque brachytherapy via radioactive seeds. “It’s like brachytherapy of the prostate,” said medical oncologist Rino S. Seedor, MD, of Thomas Jefferson University Hospital. “If the eye tumor is too big or invasive, they’ll cut out the eye.”
As many as 50% of patients will develop metastasis, sometimes within 2-3 years in those who have large tumors and high genetic risk, said ophthalmologist and radiation oncologist Miguel Materin, MD, of Duke University Eye Center, Durham, N.C. “There’s probably micrometastasis early in the development of the tumor,” he said. “The metastasis might develop before we or the patient knows there’s a tumor.”
Some physicians question the value of prognostic testing in patients who don’t yet show signs of metastasis, Dr. Materin said, because the findings can be grim.
Unlike his more cautious colleagues, Dr. Materin prefers to pursue testing, he said. Most patients agree to it. “It’s up to them to decide if they want to know if they have a bad prognosis,” he said, and the findings can be helpful to physicians because they provide useful genetic information about tumors.
Monitoring for liver metastasis is key
UM metastases are most likely to strike the liver, and prognoses are especially poor when they do. According to a 2019 analysis of 175 patients with metastatic UM in the Netherlands, “the presence of liver metastases is negatively associated with survival (hazard ratio = 2.09; 95% confidence interval, 1.07-4.08). … In 154 (88%) patients, the liver was affected, and only 3 patients were reported to have brain metastases.”2
As a result, physicians recommend close monitoring in patients with UM. Thomas Jefferson University’s Dr. Orloff uses tumor stages and genetic risk profiles to guide surveillance. “Very large tumors and/or monosomy 3 and 8q amplification or a Class 2 gene signature would suggest a higher-risk tumor,” she said. “For these patients we recommend MRI of the abdomen every 3 months for 2 years, CT of the chest every 6 months for 2 years, labs every 3 months for 2 years, then MRI every 6 months until year 5 with chest imaging yearly, then at 5 years everything yearly. For lower- or intermediate-risk patients we recommend MRI of the abdomen every 6 months for 5 years, chest imaging yearly, labs every 6 months, then at 5 years everything yearly.”
In the United States, patients with metastatic disease are typically sent to referral centers at institutions such as Duke, Yale (New Haven, Conn.), and Thomas Jefferson universities.
Metastasis treatments offer limited relief
There are no FDA-approved treatments for metastatic MU, and the treatments that physicians do use don’t seem to have much of an effect on life span. A 2019 study examined 73 patients with MU metastasis to the liver who were treated from 2004 to 2011 and 2012 to 2016. Among both cohorts, those who had no treatment lived nearly as long (median of 15 months) as those treated with local therapy (median of 18.7 months). Median survival for the entire population was 15 months (95% CI: 11–18 months). There was no statistically significant difference between the periods.3
However, there are signs that a move away from first-line chemotherapy in recent decades has led to longer life spans. Dr. Seedor led a 2018 study4 that compared two cohorts of MU patients with liver metastasis at her university: 98 patients from 1971 to 1993 (81% received systemic chemotherapy as their initial therapy) and 574 from 2000 to 2017 (they received various liver-directed initial treatments such as chemoembolization, drug-eluting beads, immunoembolization, and radioembolization).
The patients in the second group lived longer after treatment of initial UM than the first group (5.1 years vs. 3.3 years, P < .001) and after the development of liver metastasis (16.4 months vs. 4.8 months, P < .001). A 2020 follow-up study reported similar findings and noted that a “combination of liver-directed and newly developed systemic treatments may further improve the survival of these patients.”5
At Thomas Jefferson Medical Center, liver-directed therapy includes radioembolization, chemomobilization, and microwave ablation, Dr. Seedor said. “Which one we choose is based on how big the tumors are.”
Treatments in development could make advances
Physicians are working on several fronts to develop new treatments. A 2021 review of clinical trials found numerous trials regarding checkpoint inhibition, one devoted to a vaccine, and several involving checkpoint inhibitors. The review author notes that “the low mutational burden and poor immunogenicity of UM tumors may underlie poor responses and resistance to [immune checkpoint inhibitors] alone.”6
Earlier this year, grant-funded researchers reported encouraging news on the G protein inhibitor front. Their study found that FR900359, a selective inhibitor of the Gq/11/14 subfamily of heterotrimeric G proteins, could hold promise for “treating UM and potentially other diseases caused by constitutively active Gq/11.”7
In another 2021 study, this one with no reported funding, researchers explored the tumor microenvironment of UM and reported that their findings “provided a robust gene-based prognostic signature for predicting prognosis of UM patients and proposed a potential targeted therapy for preventing UM metastasis.”8
Experimental drug may add months of life
Physicians often recommend that patients take part in clinical trials. Earlier this year, researchers reported that a drug called tebentafusp – a bispecific fusion protein – slightly boosted metastatic UM survival in an open-label, phase 3 clinical trial when used as a first-line treatment. Patients were randomly assigned to tebentafusp, 1 of 2 immunotherapy drugs (ipilimumab or pembrolizumab), or the chemotherapy drug dacarbazine. Those who took tebentafusp vs. the other options lived longer with an estimated 1-year overall rate of 73.2% (95% CI: 66.3-78.9) vs. 57.5% (95% CI: 47.0-66.6), respectively. Fewer than 4% of those on tebentafusp needed to stop it because of adverse effects, and no treatment-related deaths occurred.9
Dr. Orloff is one of the coauthors of this study.
The National Cancer Institute provided more details about the industry-funded research and noted that median overall survival for patients who received the drug was 21.7 months vs. 16 months for the control group.
Not every patient is eligible for this treatment, however. A coauthor told the American Association for Cancer Research that “the major limitation of tebentafusp is that it can only be used in patients who have a specific HLA [human leukocyte antigen] type.” Patients must be HLA-A*0201-positive.10
In August 2021, the FDA granted priority review for tebentafusp.11 And in September 2021, a company called TriSalus announced the first patient enrollment in a “clinical study evaluating the administration of SD-101, an investigational toll-like receptor 9 (TLR9) agonist in adults with metastatic uveal melanoma.”12
According to the company, the research “is designed to evaluate the intravascular administration of SD-101 into uveal melanoma liver metastasis lesions in combination with checkpoint inhibitors using the novel Pressure-Enabled Drug Delivery (PEDD) approach.” This strategy is “designed to overcome the inherent intratumoral pressure of solid tumors,” the company said.
Dr. Materin serves on a scientific advisory board for Castle Biosciences. Dr. Orloff is a consultant for Immunocore, which funded the tebentafusp study, and serves on a scientific advisory board for TriSalus. Dr. Seedor reports no disclosures.
References
1.Kaliki S and Shields C. Eye. 2017 Feb;31:241-57.
2.Jochems A et al. Cancers. 2019 July;11(7):1007.
3.Xu LT et al. Ocul Oncol Pathol. 2019;5:323-32.
4.Seedor RS et al. J Clin Oncol. 2018 May;36(15_suppl):9592.
5.Seedor RS et al. Cancers (Basel). 2020 Jan 1;12(1):117.
6.Orloff M. Ocul Oncol Pathol. 2021 July;7:168-76.
7.Onken MD et al. J Biol Chem. 2021;296:100403.
8.Lei S and Zhang Y. Int Immunopharmacol. 2021 July;96:107816.
9.Piperno-Neumann S et al. Proceedings of the 112th Annual Meeting of the American Association for Cancer Research; 2021 April 10-15. Philadelphia (Pa.): AACR; 2021. Abstract nr 5133.
10.National Cancer Institute: https://www.cancer.gov/news-events/cancer-currents-blog/2021/tebentafusp-uveal-melanoma-improves-survival
11.Immunocore press release: https://ir.immunocore.com/news-releases/news-release-details/immunocore-announces-us-food-and-drug-administration-and
12.Trisalus announcement: https://finance.yahoo.com/news/trisalus-life-sciences-announces-first-130000215.html?guccounter=1
Epilepsy linked to 1.5-fold higher COVID-19 mortality in hospital
according to a new study presented at the annual meeting of the American Epilepsy Society. While the findings are preliminary and not yet adjusted for various confounders, the authors say they are a warning sign that patients with epilepsy may face higher risks.
“These findings suggest that epilepsy may be a pre-existing condition that places patients at increased risk for death if hospitalized with a COVID-19 infection. It may offer neurologists guidance when counseling patients on critical preventative measures such as masking, social distancing, and most importantly, vaccination,” lead author Claire Ufongene, a student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.
According to Ms. Ufongene, there’s sparse data about COVID-19 outcomes in patients with epilepsy, although she highlighted a 2021 meta-analysis of 13 studies that found a higher risk of severity (odds ratio, 1.69; 95% confidence interval, 1.11-2.59, P = .010) and mortality (OR, 1.71; 95% CI, 1.14-2.56, P = .010).
For the new study, researchers retrospectively tracked identified 334 patients with epilepsy and COVID-19 and 9,499 other patients with COVID-19 from March 15, 2020, to May 17, 2021. All were treated at hospitals within the New York–based Icahn School of Medicine at Mount Sinai.
The groups of patients with and without epilepsy were similar in some ways: 45% and 46%, respectively, were female (P = .674), and their ages were similar (average, 62 years and 65 years, respectively; P = .02). Racial makeup was also similar (non-Hispanic groups made up 27.8% of those with epilepsy and 24.5% of those without; the difference was not statistically significant).
“In addition, more of those with epilepsy were English speaking [83.2% vs. 77.9%] and had Medicaid insurance [50.9% vs. 38.9%], while fewer of those with epilepsy had private insurance [16.2% vs. 25.5%] or were Spanish speaking [14.0% vs. 9.3%],” study coauthor Nathalie Jette, MD, MSc, a neurologist at Icahn School of Medicine at Mount Sinai, said in an interview.
In terms of outcomes, patients with epilepsy were much more likely to need ventilator support (37.7% vs. 14.3%; P < .001), to be admitted to the ICU (39.2% vs. 17.7%; P < .001), and to die in the hospital (29.6% vs. 19.9%; P < .001).
“Most patients we follow in our practices with epilepsy who experienced COVID-19 in general have had symptoms similar to the general population,” Dr. Jette said. “There are rare instances where COVID-19 can result in an exacerbation of seizures in some with pre-existing epilepsy. This is not surprising as infections in particular can decrease the seizure threshold and result in breakthrough seizures in people living with epilepsy.”
Loss of seizure control
How might epilepsy be related to worse outcomes in COVID-19? Andrew Wilner, MD, a neurologist and internist at University of Tennessee Health Science Center, Memphis, who’s familiar with the study findings, said COVID-19 itself may not worsen epilepsy. “Evidence to suggest that COVID-19 directly affects the central nervous system is extremely limited. As such, one would not expect that a COVID-19 infection would cause epilepsy or exacerbate epilepsy,” he said. “However, patients with epilepsy who suffer from infections may be predisposed to decreased seizure control. Consequently, it would not be surprising if patients with epilepsy who also had COVID-19 had loss of seizure control and even status epilepticus, which could adversely affect their hospital course. However, there are no data on this potential phenomenon.”
Dr. Wilner suspected that comorbidities explain the higher mortality in patients with epilepsy. “The findings are probably most useful in that they call attention to the fact that epilepsy patients are more vulnerable to a host of comorbidities and resultant poorer outcomes due to any acute illness.”
As for treatment, Dr. Wilner urged colleagues to make sure that hospitalized patients with epilepsy “continue to receive their antiepileptic medications, which they may no longer be able to take orally. They may need to be switched temporarily to an intravenous formulation.”
In an interview, Selim Benbadis, MD, a neurologist from the University of South Florida, Tampa, suggested that antiseizure medications may play a role in the COVID-19 disease course because they can reduce the efficacy of other medications, although he noted that drug treatments for COVID-19 were limited early on. He recommended that neurologists “avoid old enzyme-inducing seizure medications, as is generally recommended.”
No study funding is reported. The study authors and Dr. Benbadis reported no relevant disclosures. Dr. Wilner is a medical adviser for the epilepsy disease management program for CVS/Health.
according to a new study presented at the annual meeting of the American Epilepsy Society. While the findings are preliminary and not yet adjusted for various confounders, the authors say they are a warning sign that patients with epilepsy may face higher risks.
“These findings suggest that epilepsy may be a pre-existing condition that places patients at increased risk for death if hospitalized with a COVID-19 infection. It may offer neurologists guidance when counseling patients on critical preventative measures such as masking, social distancing, and most importantly, vaccination,” lead author Claire Ufongene, a student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.
According to Ms. Ufongene, there’s sparse data about COVID-19 outcomes in patients with epilepsy, although she highlighted a 2021 meta-analysis of 13 studies that found a higher risk of severity (odds ratio, 1.69; 95% confidence interval, 1.11-2.59, P = .010) and mortality (OR, 1.71; 95% CI, 1.14-2.56, P = .010).
For the new study, researchers retrospectively tracked identified 334 patients with epilepsy and COVID-19 and 9,499 other patients with COVID-19 from March 15, 2020, to May 17, 2021. All were treated at hospitals within the New York–based Icahn School of Medicine at Mount Sinai.
The groups of patients with and without epilepsy were similar in some ways: 45% and 46%, respectively, were female (P = .674), and their ages were similar (average, 62 years and 65 years, respectively; P = .02). Racial makeup was also similar (non-Hispanic groups made up 27.8% of those with epilepsy and 24.5% of those without; the difference was not statistically significant).
“In addition, more of those with epilepsy were English speaking [83.2% vs. 77.9%] and had Medicaid insurance [50.9% vs. 38.9%], while fewer of those with epilepsy had private insurance [16.2% vs. 25.5%] or were Spanish speaking [14.0% vs. 9.3%],” study coauthor Nathalie Jette, MD, MSc, a neurologist at Icahn School of Medicine at Mount Sinai, said in an interview.
In terms of outcomes, patients with epilepsy were much more likely to need ventilator support (37.7% vs. 14.3%; P < .001), to be admitted to the ICU (39.2% vs. 17.7%; P < .001), and to die in the hospital (29.6% vs. 19.9%; P < .001).
“Most patients we follow in our practices with epilepsy who experienced COVID-19 in general have had symptoms similar to the general population,” Dr. Jette said. “There are rare instances where COVID-19 can result in an exacerbation of seizures in some with pre-existing epilepsy. This is not surprising as infections in particular can decrease the seizure threshold and result in breakthrough seizures in people living with epilepsy.”
Loss of seizure control
How might epilepsy be related to worse outcomes in COVID-19? Andrew Wilner, MD, a neurologist and internist at University of Tennessee Health Science Center, Memphis, who’s familiar with the study findings, said COVID-19 itself may not worsen epilepsy. “Evidence to suggest that COVID-19 directly affects the central nervous system is extremely limited. As such, one would not expect that a COVID-19 infection would cause epilepsy or exacerbate epilepsy,” he said. “However, patients with epilepsy who suffer from infections may be predisposed to decreased seizure control. Consequently, it would not be surprising if patients with epilepsy who also had COVID-19 had loss of seizure control and even status epilepticus, which could adversely affect their hospital course. However, there are no data on this potential phenomenon.”
Dr. Wilner suspected that comorbidities explain the higher mortality in patients with epilepsy. “The findings are probably most useful in that they call attention to the fact that epilepsy patients are more vulnerable to a host of comorbidities and resultant poorer outcomes due to any acute illness.”
As for treatment, Dr. Wilner urged colleagues to make sure that hospitalized patients with epilepsy “continue to receive their antiepileptic medications, which they may no longer be able to take orally. They may need to be switched temporarily to an intravenous formulation.”
In an interview, Selim Benbadis, MD, a neurologist from the University of South Florida, Tampa, suggested that antiseizure medications may play a role in the COVID-19 disease course because they can reduce the efficacy of other medications, although he noted that drug treatments for COVID-19 were limited early on. He recommended that neurologists “avoid old enzyme-inducing seizure medications, as is generally recommended.”
No study funding is reported. The study authors and Dr. Benbadis reported no relevant disclosures. Dr. Wilner is a medical adviser for the epilepsy disease management program for CVS/Health.
according to a new study presented at the annual meeting of the American Epilepsy Society. While the findings are preliminary and not yet adjusted for various confounders, the authors say they are a warning sign that patients with epilepsy may face higher risks.
“These findings suggest that epilepsy may be a pre-existing condition that places patients at increased risk for death if hospitalized with a COVID-19 infection. It may offer neurologists guidance when counseling patients on critical preventative measures such as masking, social distancing, and most importantly, vaccination,” lead author Claire Ufongene, a student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.
According to Ms. Ufongene, there’s sparse data about COVID-19 outcomes in patients with epilepsy, although she highlighted a 2021 meta-analysis of 13 studies that found a higher risk of severity (odds ratio, 1.69; 95% confidence interval, 1.11-2.59, P = .010) and mortality (OR, 1.71; 95% CI, 1.14-2.56, P = .010).
For the new study, researchers retrospectively tracked identified 334 patients with epilepsy and COVID-19 and 9,499 other patients with COVID-19 from March 15, 2020, to May 17, 2021. All were treated at hospitals within the New York–based Icahn School of Medicine at Mount Sinai.
The groups of patients with and without epilepsy were similar in some ways: 45% and 46%, respectively, were female (P = .674), and their ages were similar (average, 62 years and 65 years, respectively; P = .02). Racial makeup was also similar (non-Hispanic groups made up 27.8% of those with epilepsy and 24.5% of those without; the difference was not statistically significant).
“In addition, more of those with epilepsy were English speaking [83.2% vs. 77.9%] and had Medicaid insurance [50.9% vs. 38.9%], while fewer of those with epilepsy had private insurance [16.2% vs. 25.5%] or were Spanish speaking [14.0% vs. 9.3%],” study coauthor Nathalie Jette, MD, MSc, a neurologist at Icahn School of Medicine at Mount Sinai, said in an interview.
In terms of outcomes, patients with epilepsy were much more likely to need ventilator support (37.7% vs. 14.3%; P < .001), to be admitted to the ICU (39.2% vs. 17.7%; P < .001), and to die in the hospital (29.6% vs. 19.9%; P < .001).
“Most patients we follow in our practices with epilepsy who experienced COVID-19 in general have had symptoms similar to the general population,” Dr. Jette said. “There are rare instances where COVID-19 can result in an exacerbation of seizures in some with pre-existing epilepsy. This is not surprising as infections in particular can decrease the seizure threshold and result in breakthrough seizures in people living with epilepsy.”
Loss of seizure control
How might epilepsy be related to worse outcomes in COVID-19? Andrew Wilner, MD, a neurologist and internist at University of Tennessee Health Science Center, Memphis, who’s familiar with the study findings, said COVID-19 itself may not worsen epilepsy. “Evidence to suggest that COVID-19 directly affects the central nervous system is extremely limited. As such, one would not expect that a COVID-19 infection would cause epilepsy or exacerbate epilepsy,” he said. “However, patients with epilepsy who suffer from infections may be predisposed to decreased seizure control. Consequently, it would not be surprising if patients with epilepsy who also had COVID-19 had loss of seizure control and even status epilepticus, which could adversely affect their hospital course. However, there are no data on this potential phenomenon.”
Dr. Wilner suspected that comorbidities explain the higher mortality in patients with epilepsy. “The findings are probably most useful in that they call attention to the fact that epilepsy patients are more vulnerable to a host of comorbidities and resultant poorer outcomes due to any acute illness.”
As for treatment, Dr. Wilner urged colleagues to make sure that hospitalized patients with epilepsy “continue to receive their antiepileptic medications, which they may no longer be able to take orally. They may need to be switched temporarily to an intravenous formulation.”
In an interview, Selim Benbadis, MD, a neurologist from the University of South Florida, Tampa, suggested that antiseizure medications may play a role in the COVID-19 disease course because they can reduce the efficacy of other medications, although he noted that drug treatments for COVID-19 were limited early on. He recommended that neurologists “avoid old enzyme-inducing seizure medications, as is generally recommended.”
No study funding is reported. The study authors and Dr. Benbadis reported no relevant disclosures. Dr. Wilner is a medical adviser for the epilepsy disease management program for CVS/Health.
FROM AES 2021
More brain aging observed in older patients with child-onset epilepsy
While the meaning of the findings aren’t entirely clear, new research offers insight into the aging brains of people who developed child-onset epilepsy: A cohort with an average age of 63 appears to be more likely than controls to show signs of brain deterioration, according to a study presented at the annual meeting of the American Epilepsy Society.
“,” lead author Matti Sillanpää, MD, PhD, a researcher and former child neurologist based at the University of Turko in Finland, said in an interview.
The study began 60 years ago when Finnish researchers started to track 99 subjects who were under 16 and had developed uncomplicated epilepsy. In 2012, 51 participants returned for assessments (9 of the original cohort had died, 2 didn’t speak Finnish as a mother tongue, and 15 had left the country or couldn’t be found).
In 2017, 41 participants agreed to take part in follow-up assessments (1 of the 2012 cohort could not be traced, and 9 declined to participate.)
Researchers launched the follow-up assessments to provide more insight into aging and epilepsy, Dr. Sillanpää said. “While we are in the early stages of understanding the brain and cognitive aging processes of people with epilepsy, there are enough worrisome signs from neuroimaging and cognitive studies to suggest that much more clinical and research attention is warranted. Especially important are population-based investigations that include persons with both remitted as well as active epilepsy in order to obtain a clearer understanding of the overall aging risks involved.”
The average age of the 41 subjects in the second assessment was 63.2 (4.1), and 58% were female. Just over half (52%) had focal epilepsy, and 48% had generalized epilepsy. In 74%, epilepsy had remitted, and it remained active in the rest (26%).
For the study, researchers compared the subjects with a control group of 46 subjects, 50% of whom were female, with an average age of 63.0 (4.13). The original control group had 99 participants, and 52 took part in 2012. Of those, 6 declined to participate in the 2017 assessments.
The researchers report these findings:
- Patients with active epilepsy were more likely to have neurologic signs than were those with remitted epilepsy (P = .015), especially the most common signs – cerebellar signs (P < .001). There was a trend toward cerebellar atrophy but it wasn’t statistically significant (P = .06).
- Patients with focal epilepsies were more likely to have neurologic signs (P = .008) and, specifically, cerebellar signs (P = .018) than were those with generalized epilepsies.
- The study authors calculated the lifetime usage of four drugs: carbamazepine, diphenylhydantoin, phenobarbital, and valproate. They found that patients with higher usage had more peripheral neuropathy, especially those with high levels of diphenylhydantoin, and phenobarbital usage.
- Overall, patients with epilepsy versus controls and those with active epilepsy versus remitting epilepsy were more likely to show adjusted declines in “cognitive trajectories” (both P < .05)
The researchers also estimated beta-amyloid levels via Pittsburgh Compound B positron emission tomography (PIB-PET); some specialists consider PIB-positive levels to be a sign of more beta amyloid.
From 2012 to 2017, the percentage of patients with epilepsy who were PIB positive grew from 22% to 33% (P = .03), while the percentage grew from 7% to 11% in the controls (P = .04). “The presence of amyloid and increasing positivity is cause for concern, and further research into the course of the participants is critical,” Dr. Sillanpää said.
It’s not clear if higher levels of brain aging are affecting the lives of participants, he said. “No one in the cohort has a diagnosed dementia at present, but going forward it will be important to pay close attention to the day-to-day functional status of participants.”
The mechanisms that may cause more brain aging in epilepsy aren’t known. However, “the CDC has shown through population-based investigations that people with epilepsy as a group may be more socially isolated, more physically inactive, and may harbor other lifestyle issues that we now know to be counterproductive to successful cognitive and brain aging in the general population,” Dr. Sillanpää said. “These factors need to be examined in depth in aging persons with epilepsy to gain a sound understanding of the risk and resilience factors that are most important so that people with epilepsy can act accordingly.”
The researchers also report that in patients with epilepsy, there’s evidence of a link between hypertension and hippocampal atrophy. They reported trends toward links between obesity and ischemic disease and between type 2 diabetes and hippocampal atrophy.
Going forward, “the findings may be helpful in the treatment and counseling of patients with epilepsy and especially advocating for those health and lifestyle practices that may be beneficial to long-term courses,” Dr. Sillanpää said. As for the study cohort, he said, researchers plan to continue monitoring them to track their long-term outcomes and any development of neurological disorders such as Alzheimer’s disease.
This work was funded by CURE Epilepsy, the National Governmental Research Grant, and the Pro Humanitate Foundation Grant. The study authors report no disclosures.
While the meaning of the findings aren’t entirely clear, new research offers insight into the aging brains of people who developed child-onset epilepsy: A cohort with an average age of 63 appears to be more likely than controls to show signs of brain deterioration, according to a study presented at the annual meeting of the American Epilepsy Society.
“,” lead author Matti Sillanpää, MD, PhD, a researcher and former child neurologist based at the University of Turko in Finland, said in an interview.
The study began 60 years ago when Finnish researchers started to track 99 subjects who were under 16 and had developed uncomplicated epilepsy. In 2012, 51 participants returned for assessments (9 of the original cohort had died, 2 didn’t speak Finnish as a mother tongue, and 15 had left the country or couldn’t be found).
In 2017, 41 participants agreed to take part in follow-up assessments (1 of the 2012 cohort could not be traced, and 9 declined to participate.)
Researchers launched the follow-up assessments to provide more insight into aging and epilepsy, Dr. Sillanpää said. “While we are in the early stages of understanding the brain and cognitive aging processes of people with epilepsy, there are enough worrisome signs from neuroimaging and cognitive studies to suggest that much more clinical and research attention is warranted. Especially important are population-based investigations that include persons with both remitted as well as active epilepsy in order to obtain a clearer understanding of the overall aging risks involved.”
The average age of the 41 subjects in the second assessment was 63.2 (4.1), and 58% were female. Just over half (52%) had focal epilepsy, and 48% had generalized epilepsy. In 74%, epilepsy had remitted, and it remained active in the rest (26%).
For the study, researchers compared the subjects with a control group of 46 subjects, 50% of whom were female, with an average age of 63.0 (4.13). The original control group had 99 participants, and 52 took part in 2012. Of those, 6 declined to participate in the 2017 assessments.
The researchers report these findings:
- Patients with active epilepsy were more likely to have neurologic signs than were those with remitted epilepsy (P = .015), especially the most common signs – cerebellar signs (P < .001). There was a trend toward cerebellar atrophy but it wasn’t statistically significant (P = .06).
- Patients with focal epilepsies were more likely to have neurologic signs (P = .008) and, specifically, cerebellar signs (P = .018) than were those with generalized epilepsies.
- The study authors calculated the lifetime usage of four drugs: carbamazepine, diphenylhydantoin, phenobarbital, and valproate. They found that patients with higher usage had more peripheral neuropathy, especially those with high levels of diphenylhydantoin, and phenobarbital usage.
- Overall, patients with epilepsy versus controls and those with active epilepsy versus remitting epilepsy were more likely to show adjusted declines in “cognitive trajectories” (both P < .05)
The researchers also estimated beta-amyloid levels via Pittsburgh Compound B positron emission tomography (PIB-PET); some specialists consider PIB-positive levels to be a sign of more beta amyloid.
From 2012 to 2017, the percentage of patients with epilepsy who were PIB positive grew from 22% to 33% (P = .03), while the percentage grew from 7% to 11% in the controls (P = .04). “The presence of amyloid and increasing positivity is cause for concern, and further research into the course of the participants is critical,” Dr. Sillanpää said.
It’s not clear if higher levels of brain aging are affecting the lives of participants, he said. “No one in the cohort has a diagnosed dementia at present, but going forward it will be important to pay close attention to the day-to-day functional status of participants.”
The mechanisms that may cause more brain aging in epilepsy aren’t known. However, “the CDC has shown through population-based investigations that people with epilepsy as a group may be more socially isolated, more physically inactive, and may harbor other lifestyle issues that we now know to be counterproductive to successful cognitive and brain aging in the general population,” Dr. Sillanpää said. “These factors need to be examined in depth in aging persons with epilepsy to gain a sound understanding of the risk and resilience factors that are most important so that people with epilepsy can act accordingly.”
The researchers also report that in patients with epilepsy, there’s evidence of a link between hypertension and hippocampal atrophy. They reported trends toward links between obesity and ischemic disease and between type 2 diabetes and hippocampal atrophy.
Going forward, “the findings may be helpful in the treatment and counseling of patients with epilepsy and especially advocating for those health and lifestyle practices that may be beneficial to long-term courses,” Dr. Sillanpää said. As for the study cohort, he said, researchers plan to continue monitoring them to track their long-term outcomes and any development of neurological disorders such as Alzheimer’s disease.
This work was funded by CURE Epilepsy, the National Governmental Research Grant, and the Pro Humanitate Foundation Grant. The study authors report no disclosures.
While the meaning of the findings aren’t entirely clear, new research offers insight into the aging brains of people who developed child-onset epilepsy: A cohort with an average age of 63 appears to be more likely than controls to show signs of brain deterioration, according to a study presented at the annual meeting of the American Epilepsy Society.
“,” lead author Matti Sillanpää, MD, PhD, a researcher and former child neurologist based at the University of Turko in Finland, said in an interview.
The study began 60 years ago when Finnish researchers started to track 99 subjects who were under 16 and had developed uncomplicated epilepsy. In 2012, 51 participants returned for assessments (9 of the original cohort had died, 2 didn’t speak Finnish as a mother tongue, and 15 had left the country or couldn’t be found).
In 2017, 41 participants agreed to take part in follow-up assessments (1 of the 2012 cohort could not be traced, and 9 declined to participate.)
Researchers launched the follow-up assessments to provide more insight into aging and epilepsy, Dr. Sillanpää said. “While we are in the early stages of understanding the brain and cognitive aging processes of people with epilepsy, there are enough worrisome signs from neuroimaging and cognitive studies to suggest that much more clinical and research attention is warranted. Especially important are population-based investigations that include persons with both remitted as well as active epilepsy in order to obtain a clearer understanding of the overall aging risks involved.”
The average age of the 41 subjects in the second assessment was 63.2 (4.1), and 58% were female. Just over half (52%) had focal epilepsy, and 48% had generalized epilepsy. In 74%, epilepsy had remitted, and it remained active in the rest (26%).
For the study, researchers compared the subjects with a control group of 46 subjects, 50% of whom were female, with an average age of 63.0 (4.13). The original control group had 99 participants, and 52 took part in 2012. Of those, 6 declined to participate in the 2017 assessments.
The researchers report these findings:
- Patients with active epilepsy were more likely to have neurologic signs than were those with remitted epilepsy (P = .015), especially the most common signs – cerebellar signs (P < .001). There was a trend toward cerebellar atrophy but it wasn’t statistically significant (P = .06).
- Patients with focal epilepsies were more likely to have neurologic signs (P = .008) and, specifically, cerebellar signs (P = .018) than were those with generalized epilepsies.
- The study authors calculated the lifetime usage of four drugs: carbamazepine, diphenylhydantoin, phenobarbital, and valproate. They found that patients with higher usage had more peripheral neuropathy, especially those with high levels of diphenylhydantoin, and phenobarbital usage.
- Overall, patients with epilepsy versus controls and those with active epilepsy versus remitting epilepsy were more likely to show adjusted declines in “cognitive trajectories” (both P < .05)
The researchers also estimated beta-amyloid levels via Pittsburgh Compound B positron emission tomography (PIB-PET); some specialists consider PIB-positive levels to be a sign of more beta amyloid.
From 2012 to 2017, the percentage of patients with epilepsy who were PIB positive grew from 22% to 33% (P = .03), while the percentage grew from 7% to 11% in the controls (P = .04). “The presence of amyloid and increasing positivity is cause for concern, and further research into the course of the participants is critical,” Dr. Sillanpää said.
It’s not clear if higher levels of brain aging are affecting the lives of participants, he said. “No one in the cohort has a diagnosed dementia at present, but going forward it will be important to pay close attention to the day-to-day functional status of participants.”
The mechanisms that may cause more brain aging in epilepsy aren’t known. However, “the CDC has shown through population-based investigations that people with epilepsy as a group may be more socially isolated, more physically inactive, and may harbor other lifestyle issues that we now know to be counterproductive to successful cognitive and brain aging in the general population,” Dr. Sillanpää said. “These factors need to be examined in depth in aging persons with epilepsy to gain a sound understanding of the risk and resilience factors that are most important so that people with epilepsy can act accordingly.”
The researchers also report that in patients with epilepsy, there’s evidence of a link between hypertension and hippocampal atrophy. They reported trends toward links between obesity and ischemic disease and between type 2 diabetes and hippocampal atrophy.
Going forward, “the findings may be helpful in the treatment and counseling of patients with epilepsy and especially advocating for those health and lifestyle practices that may be beneficial to long-term courses,” Dr. Sillanpää said. As for the study cohort, he said, researchers plan to continue monitoring them to track their long-term outcomes and any development of neurological disorders such as Alzheimer’s disease.
This work was funded by CURE Epilepsy, the National Governmental Research Grant, and the Pro Humanitate Foundation Grant. The study authors report no disclosures.
FROM AES 2021
Multiple DMTs linked to alopecia, especially in women
a new study finds.
From 2009 to 2019, the Food and Drug Administration received 7,978 reports of new-onset alopecia in patients taking DMTs, particularly teriflunomide (3,255, 40.8%; 90% female), dimethyl fumarate (1,641, 20.6%; 89% female), natalizumab (955, 12.0%; 92% female), and fingolimod (776, 9.7% of the total reports; 93% female), several researchers reported at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC). Of these, only teriflunomide had previously been linked to alopecia, study coauthor Ahmed Obeidat, MD, PhD, a neurologist at the Medical College of Wisconsin, Milwaukee, said in an interview.
“Our finding of frequent reports of alopecia on DMTs studied calls for further investigation into the subject,” Dr. Obeidat said. “Alopecia can cause deep personal impacts and can be a source of significant psychological concern for some patients.”
According to Dr. Obeidat, alopecia has been linked to the only a few DMTs – cladribine and the interferons – in addition to teriflunomide. “To our surprise, we received anecdotal reports of hair thinning from several of our MS patients treated with various other [DMTs]. Upon further investigation, we could not find substantial literature to explain this phenomenon which led us to conduct our investigation.”
Dr. Obeidat and colleagues identified DMT-related alopecia cases (18.3%) among 43,655 reports in the skin and subcutaneous tissue disorder category in the FDA Adverse Event Reporting System. Other DMTs with more than 1 case report were interferon beta-1a (635, 8.0%; 92% female), glatiramer acetate (332, 4.2%; 87% female), ocrelizumab (142, 1.8%; 94% female), interferon beta-1b (126, 1.6%; 95% female), alemtuzumab (86, 1.1%; 88% female), cladribine (17, 0.2%; 65% female), and rituximab (10, 0.1%; 90% female).
The average age for the case reports varied from 42 to 51 years for most of the drugs except alemtuzumab (mean age, 40 years) and cladribine (average age, 38 years), which had low numbers of cases.
Siponimod (three cases) and ozanimod (no cases) were not included in the age and gender analyses.
Why do so many women seem to be affected, well beyond their percentage of MS cases overall? The answer is unclear, said medical student Mokshal H. Porwal, the study’s lead author. “There could be a biological explanation,” Mr. Porwal said, “or women may report cases more often: “Earlier studies suggested that alopecia may affect women more adversely in terms of body image as well as overall psychological well-being, compared to males.”
The researchers also noted that patients – not medical professionals – provided most of the case reports in the FDA database. “We believe this indicates that alopecia is a patient-centered concern that may have a larger impact on their lives than what the health care teams may perceive,” Mr. Porwal said. “Oftentimes, we as health care providers, look for the more acute and apparent adverse events, which can overshadow issues such as hair thinning/alopecia that could have even greater psychological impacts on our patients.”
Dr. Obeidat said there are still multiple mysteries about DMT and alopecia risk: the true incidence of cases per DMT or DMT class, the mechanism(s) behind a link, the permanent or transient nature of the alopecia cases, and the risk factors in individual patients.
Going forward, he said, “we advise clinicians to discuss hair thinning or alopecia as a possible side effect that has been reported in association with all DMTs in the real-world, postmarketing era.”
No study funding was reported. Dr. Obeidat reported various disclosures; the other authors reported no disclosures.
a new study finds.
From 2009 to 2019, the Food and Drug Administration received 7,978 reports of new-onset alopecia in patients taking DMTs, particularly teriflunomide (3,255, 40.8%; 90% female), dimethyl fumarate (1,641, 20.6%; 89% female), natalizumab (955, 12.0%; 92% female), and fingolimod (776, 9.7% of the total reports; 93% female), several researchers reported at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC). Of these, only teriflunomide had previously been linked to alopecia, study coauthor Ahmed Obeidat, MD, PhD, a neurologist at the Medical College of Wisconsin, Milwaukee, said in an interview.
“Our finding of frequent reports of alopecia on DMTs studied calls for further investigation into the subject,” Dr. Obeidat said. “Alopecia can cause deep personal impacts and can be a source of significant psychological concern for some patients.”
According to Dr. Obeidat, alopecia has been linked to the only a few DMTs – cladribine and the interferons – in addition to teriflunomide. “To our surprise, we received anecdotal reports of hair thinning from several of our MS patients treated with various other [DMTs]. Upon further investigation, we could not find substantial literature to explain this phenomenon which led us to conduct our investigation.”
Dr. Obeidat and colleagues identified DMT-related alopecia cases (18.3%) among 43,655 reports in the skin and subcutaneous tissue disorder category in the FDA Adverse Event Reporting System. Other DMTs with more than 1 case report were interferon beta-1a (635, 8.0%; 92% female), glatiramer acetate (332, 4.2%; 87% female), ocrelizumab (142, 1.8%; 94% female), interferon beta-1b (126, 1.6%; 95% female), alemtuzumab (86, 1.1%; 88% female), cladribine (17, 0.2%; 65% female), and rituximab (10, 0.1%; 90% female).
The average age for the case reports varied from 42 to 51 years for most of the drugs except alemtuzumab (mean age, 40 years) and cladribine (average age, 38 years), which had low numbers of cases.
Siponimod (three cases) and ozanimod (no cases) were not included in the age and gender analyses.
Why do so many women seem to be affected, well beyond their percentage of MS cases overall? The answer is unclear, said medical student Mokshal H. Porwal, the study’s lead author. “There could be a biological explanation,” Mr. Porwal said, “or women may report cases more often: “Earlier studies suggested that alopecia may affect women more adversely in terms of body image as well as overall psychological well-being, compared to males.”
The researchers also noted that patients – not medical professionals – provided most of the case reports in the FDA database. “We believe this indicates that alopecia is a patient-centered concern that may have a larger impact on their lives than what the health care teams may perceive,” Mr. Porwal said. “Oftentimes, we as health care providers, look for the more acute and apparent adverse events, which can overshadow issues such as hair thinning/alopecia that could have even greater psychological impacts on our patients.”
Dr. Obeidat said there are still multiple mysteries about DMT and alopecia risk: the true incidence of cases per DMT or DMT class, the mechanism(s) behind a link, the permanent or transient nature of the alopecia cases, and the risk factors in individual patients.
Going forward, he said, “we advise clinicians to discuss hair thinning or alopecia as a possible side effect that has been reported in association with all DMTs in the real-world, postmarketing era.”
No study funding was reported. Dr. Obeidat reported various disclosures; the other authors reported no disclosures.
a new study finds.
From 2009 to 2019, the Food and Drug Administration received 7,978 reports of new-onset alopecia in patients taking DMTs, particularly teriflunomide (3,255, 40.8%; 90% female), dimethyl fumarate (1,641, 20.6%; 89% female), natalizumab (955, 12.0%; 92% female), and fingolimod (776, 9.7% of the total reports; 93% female), several researchers reported at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC). Of these, only teriflunomide had previously been linked to alopecia, study coauthor Ahmed Obeidat, MD, PhD, a neurologist at the Medical College of Wisconsin, Milwaukee, said in an interview.
“Our finding of frequent reports of alopecia on DMTs studied calls for further investigation into the subject,” Dr. Obeidat said. “Alopecia can cause deep personal impacts and can be a source of significant psychological concern for some patients.”
According to Dr. Obeidat, alopecia has been linked to the only a few DMTs – cladribine and the interferons – in addition to teriflunomide. “To our surprise, we received anecdotal reports of hair thinning from several of our MS patients treated with various other [DMTs]. Upon further investigation, we could not find substantial literature to explain this phenomenon which led us to conduct our investigation.”
Dr. Obeidat and colleagues identified DMT-related alopecia cases (18.3%) among 43,655 reports in the skin and subcutaneous tissue disorder category in the FDA Adverse Event Reporting System. Other DMTs with more than 1 case report were interferon beta-1a (635, 8.0%; 92% female), glatiramer acetate (332, 4.2%; 87% female), ocrelizumab (142, 1.8%; 94% female), interferon beta-1b (126, 1.6%; 95% female), alemtuzumab (86, 1.1%; 88% female), cladribine (17, 0.2%; 65% female), and rituximab (10, 0.1%; 90% female).
The average age for the case reports varied from 42 to 51 years for most of the drugs except alemtuzumab (mean age, 40 years) and cladribine (average age, 38 years), which had low numbers of cases.
Siponimod (three cases) and ozanimod (no cases) were not included in the age and gender analyses.
Why do so many women seem to be affected, well beyond their percentage of MS cases overall? The answer is unclear, said medical student Mokshal H. Porwal, the study’s lead author. “There could be a biological explanation,” Mr. Porwal said, “or women may report cases more often: “Earlier studies suggested that alopecia may affect women more adversely in terms of body image as well as overall psychological well-being, compared to males.”
The researchers also noted that patients – not medical professionals – provided most of the case reports in the FDA database. “We believe this indicates that alopecia is a patient-centered concern that may have a larger impact on their lives than what the health care teams may perceive,” Mr. Porwal said. “Oftentimes, we as health care providers, look for the more acute and apparent adverse events, which can overshadow issues such as hair thinning/alopecia that could have even greater psychological impacts on our patients.”
Dr. Obeidat said there are still multiple mysteries about DMT and alopecia risk: the true incidence of cases per DMT or DMT class, the mechanism(s) behind a link, the permanent or transient nature of the alopecia cases, and the risk factors in individual patients.
Going forward, he said, “we advise clinicians to discuss hair thinning or alopecia as a possible side effect that has been reported in association with all DMTs in the real-world, postmarketing era.”
No study funding was reported. Dr. Obeidat reported various disclosures; the other authors reported no disclosures.
FROM CMSC 2021
Certain DMTs in MS linked to more psoriasis
, a new study finds. However, overall rates of reported disease are very low, and there’s no confirmation of a connection.
“People with MS and comorbid psoriasis – or those at a known high-risk for developing psoriasis – may benefit from a careful consideration of disease-modifying therapy (DMT), specifically when B cell-depleting therapies are considered,” study coauthor and Medical College of Wisconsin neurologist Ahmed Obeidat, MD, PhD, said in an interview. The findings were presented at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
Dr. Obeidat and colleagues launched the study after noticing cases of psoriasis that developed months to years after patients started taking ocrelizumab, a B cell-depleting therapy. “We referred to the published literature and only found very scant reports of MS, psoriasis, and B cell-depleting therapy use,” he said. “Thus we decided to pursue an investigation of a large [Food and Drug Administration] database to examine for possible out-of-proportion reports for psoriasis in patients with MS who were receiving B cell-depleting therapy.”
The researchers tracked case reports of psoriasis in patients with MS on DMTs from 2009 to 2020 via the FDA Adverse Event Reporting System. They found 517 psoriasis reports among 45,547 reports of skin/cutaneous conditions. The reports were linked to interferon beta 1a (136 reports, 26% of total), natalizumab (107, 21%), fingolimod (75, 15%), dimethyl fumarate (64, 12%), ocrelizumab (49, 10%), teriflunomide (28, 5%), interferon beta 1b (22, 4%), glatiramer acetate (12, 2%), rituximab (10, 2%), and alemtuzumab (9, 2%).
The total numbers of cases is low, but this may reflect underreporting due to the assumption that “autoimmunity begets autoimmunity” and therefore cases of psoriasis in MS are not alarming, medical student Mokshal H. Porwal, the study lead author, said in an interview.
The average age of patients – 48-51 – was similar for all of the drugs except alemtuzumab (mean age 41), which had a very small number of cases. The percentage of cases in females was 71%-77% for most of the drugs, with a few exceptions: rituximab (60%), ocrelizumab (63%), and alemtuzumab (33%).
Other drugs – cladribine, siponimod, and ozanimod – had 1, 1, and 0 reports, respectively, and were not included in the age and gender analyses.
The researchers also found that psoriasis made up about 65% of all skin/cutaneous adverse reports for rituximab, the highest number among DMTs. By comparison, that number was about 30% for ocrelizumab and under 1% for dimethyl fumarate and alemtuzumab.
Links between psoriasis and MS are murky, Dr. Obeidat said. “Some studies consider the presence of psoriasis as a possible indicator of increased future risk for MS, but there’s no clear association between the two conditions,” he said.
As for DMTs, “a few case reports of psoriasis in association with interferon-beta and rare case reports in association with ocrelizumab therapy have been published. However, the possible association between certain DMTs and psoriasis remains unclear,” he said.
Going forward, “we advise that patients with psoriasis on B cell-depleting agents are monitored more closely,” Dr. Obeidat said. “If the psoriasis worsens, it may be beneficial to think about potential alternative therapies.”
No study funding is reported. Dr. Obeidat reports various disclosures; the other authors report no disclosures.
, a new study finds. However, overall rates of reported disease are very low, and there’s no confirmation of a connection.
“People with MS and comorbid psoriasis – or those at a known high-risk for developing psoriasis – may benefit from a careful consideration of disease-modifying therapy (DMT), specifically when B cell-depleting therapies are considered,” study coauthor and Medical College of Wisconsin neurologist Ahmed Obeidat, MD, PhD, said in an interview. The findings were presented at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
Dr. Obeidat and colleagues launched the study after noticing cases of psoriasis that developed months to years after patients started taking ocrelizumab, a B cell-depleting therapy. “We referred to the published literature and only found very scant reports of MS, psoriasis, and B cell-depleting therapy use,” he said. “Thus we decided to pursue an investigation of a large [Food and Drug Administration] database to examine for possible out-of-proportion reports for psoriasis in patients with MS who were receiving B cell-depleting therapy.”
The researchers tracked case reports of psoriasis in patients with MS on DMTs from 2009 to 2020 via the FDA Adverse Event Reporting System. They found 517 psoriasis reports among 45,547 reports of skin/cutaneous conditions. The reports were linked to interferon beta 1a (136 reports, 26% of total), natalizumab (107, 21%), fingolimod (75, 15%), dimethyl fumarate (64, 12%), ocrelizumab (49, 10%), teriflunomide (28, 5%), interferon beta 1b (22, 4%), glatiramer acetate (12, 2%), rituximab (10, 2%), and alemtuzumab (9, 2%).
The total numbers of cases is low, but this may reflect underreporting due to the assumption that “autoimmunity begets autoimmunity” and therefore cases of psoriasis in MS are not alarming, medical student Mokshal H. Porwal, the study lead author, said in an interview.
The average age of patients – 48-51 – was similar for all of the drugs except alemtuzumab (mean age 41), which had a very small number of cases. The percentage of cases in females was 71%-77% for most of the drugs, with a few exceptions: rituximab (60%), ocrelizumab (63%), and alemtuzumab (33%).
Other drugs – cladribine, siponimod, and ozanimod – had 1, 1, and 0 reports, respectively, and were not included in the age and gender analyses.
The researchers also found that psoriasis made up about 65% of all skin/cutaneous adverse reports for rituximab, the highest number among DMTs. By comparison, that number was about 30% for ocrelizumab and under 1% for dimethyl fumarate and alemtuzumab.
Links between psoriasis and MS are murky, Dr. Obeidat said. “Some studies consider the presence of psoriasis as a possible indicator of increased future risk for MS, but there’s no clear association between the two conditions,” he said.
As for DMTs, “a few case reports of psoriasis in association with interferon-beta and rare case reports in association with ocrelizumab therapy have been published. However, the possible association between certain DMTs and psoriasis remains unclear,” he said.
Going forward, “we advise that patients with psoriasis on B cell-depleting agents are monitored more closely,” Dr. Obeidat said. “If the psoriasis worsens, it may be beneficial to think about potential alternative therapies.”
No study funding is reported. Dr. Obeidat reports various disclosures; the other authors report no disclosures.
, a new study finds. However, overall rates of reported disease are very low, and there’s no confirmation of a connection.
“People with MS and comorbid psoriasis – or those at a known high-risk for developing psoriasis – may benefit from a careful consideration of disease-modifying therapy (DMT), specifically when B cell-depleting therapies are considered,” study coauthor and Medical College of Wisconsin neurologist Ahmed Obeidat, MD, PhD, said in an interview. The findings were presented at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
Dr. Obeidat and colleagues launched the study after noticing cases of psoriasis that developed months to years after patients started taking ocrelizumab, a B cell-depleting therapy. “We referred to the published literature and only found very scant reports of MS, psoriasis, and B cell-depleting therapy use,” he said. “Thus we decided to pursue an investigation of a large [Food and Drug Administration] database to examine for possible out-of-proportion reports for psoriasis in patients with MS who were receiving B cell-depleting therapy.”
The researchers tracked case reports of psoriasis in patients with MS on DMTs from 2009 to 2020 via the FDA Adverse Event Reporting System. They found 517 psoriasis reports among 45,547 reports of skin/cutaneous conditions. The reports were linked to interferon beta 1a (136 reports, 26% of total), natalizumab (107, 21%), fingolimod (75, 15%), dimethyl fumarate (64, 12%), ocrelizumab (49, 10%), teriflunomide (28, 5%), interferon beta 1b (22, 4%), glatiramer acetate (12, 2%), rituximab (10, 2%), and alemtuzumab (9, 2%).
The total numbers of cases is low, but this may reflect underreporting due to the assumption that “autoimmunity begets autoimmunity” and therefore cases of psoriasis in MS are not alarming, medical student Mokshal H. Porwal, the study lead author, said in an interview.
The average age of patients – 48-51 – was similar for all of the drugs except alemtuzumab (mean age 41), which had a very small number of cases. The percentage of cases in females was 71%-77% for most of the drugs, with a few exceptions: rituximab (60%), ocrelizumab (63%), and alemtuzumab (33%).
Other drugs – cladribine, siponimod, and ozanimod – had 1, 1, and 0 reports, respectively, and were not included in the age and gender analyses.
The researchers also found that psoriasis made up about 65% of all skin/cutaneous adverse reports for rituximab, the highest number among DMTs. By comparison, that number was about 30% for ocrelizumab and under 1% for dimethyl fumarate and alemtuzumab.
Links between psoriasis and MS are murky, Dr. Obeidat said. “Some studies consider the presence of psoriasis as a possible indicator of increased future risk for MS, but there’s no clear association between the two conditions,” he said.
As for DMTs, “a few case reports of psoriasis in association with interferon-beta and rare case reports in association with ocrelizumab therapy have been published. However, the possible association between certain DMTs and psoriasis remains unclear,” he said.
Going forward, “we advise that patients with psoriasis on B cell-depleting agents are monitored more closely,” Dr. Obeidat said. “If the psoriasis worsens, it may be beneficial to think about potential alternative therapies.”
No study funding is reported. Dr. Obeidat reports various disclosures; the other authors report no disclosures.
FROM CMSC 2021
MS and COVID: Docs switched DMTs but maybe didn’t need to
These are the messages of a pair of new studies that examine the impact of the pandemic on the treatment of MS.
One report finds that 80% of specialists surveyed in the summer of 2020 said the pandemic may have changed how they prescribe disease-modifying therapies (DMTs). However, the other report finds no evidence that choice of DMT affects risk of COVID-19 infection. Both studies were presented at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
For the survey, researchers led by neurologist Elizabeth H. Morrison-Banks, MD, of the University of California, Riverside, sent questions to 188 clinicians who serve on regional National Multiple Sclerosis Society Healthcare Provider Councils. A total of 86 people responded: 45 physicians, 18 rehabilitation therapists, 7 psychologists, 8 advanced practice clinicians, 4 social workers, 2 nurses, a pharmacist, and a researcher.
The results, which were published earlier in 2021 in Multiple Sclerosis and Related Disorders, revealed that the survey participants were prescribing certain DMTs more often: beta-interferons (prescribed more by 28.6% of prescribers), natalizumab (23.8%), and glatiramer acetate (21.4%). Those prescribed less included alemtuzumab (64.2% prescribed it less), cladribine (52.4%), and B cell–depleting agents including ocrelizumab and rituximab (50%). Some specialists suspended drugs entirely (21.4% for alemtuzumab, 16.7% for B cell–depleting agents) or extending dosing intervals (38.1% for natalizumab, 11.9% for fingolimod and siponimod).
“We suspect that some of the lower-efficacy therapies were prescribed more often because these therapies were much less immunosuppressive, and because they did not require in-person visits that would increase risk of viral exposure from infusion center staff, or from other infusion patients,” Dr. Morrison-Banks said in an interview. “We also suspect that some of our survey respondents may have increased the dosing intervals for higher-efficacy therapies such as B cell–modulating agents – or even avoided these therapies altogether – because they were concerned that immunosuppressive agents might trigger severe complications from COVID-19.”
As she noted, “in retrospect, at least some of the concerns expressed in our survey may not have been entirely warranted, but then again, we all knew even less then about COVID-19.”
Indeed, researchers led by neurologist Tyler E. Smith, MD, of New York University Langone Multiple Sclerosis Care Center are reporting that they couldn’t find any link between the following DMTs and higher rates of COVID-19 at the New York City center: rituximab, ocrelizumab, fumerate (dimethyl fumarate, monomethyl fumarate, diroximel fumarate), sphingosine-1-phosphate modulators (fingolimod, siponimod), and natalizumab.
The researchers tracked 1,439 patients with MS who were taking the DMTs from March 2020 to March 2021. Of those, 16.0% were infected with COVID-19 (75% lab confirmed), 6.5% were hospitalized, and 0.9% died.
“We did not find an association between the choice of disease-modifying therapy and developing COVID-19 infection, nor having increased disease severity,” Dr. Smith said in an interview. “We are still analyzing data and hope to publish an updated analysis, but at this point, we don’t have conclusive evidence that DMTs, including anti-CD20 agents, need to be changed to lower the risk of COVID-19.”
Instead, he said, “at this point, we feel our energies should be spent on educating our patients on importance of vaccines and boosters. I don’t think it is necessary to switch DMTs because of COVID-19 concerns. However, this should be reviewed on a case-by-case basis.”
No funding is reported for the survey study, and the authors reported various disclosures. The DMT study was funded by an investigator-initiated grant from the Consortium of Multiple Sclerosis Centers, and the authors reported various disclosures.
These are the messages of a pair of new studies that examine the impact of the pandemic on the treatment of MS.
One report finds that 80% of specialists surveyed in the summer of 2020 said the pandemic may have changed how they prescribe disease-modifying therapies (DMTs). However, the other report finds no evidence that choice of DMT affects risk of COVID-19 infection. Both studies were presented at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
For the survey, researchers led by neurologist Elizabeth H. Morrison-Banks, MD, of the University of California, Riverside, sent questions to 188 clinicians who serve on regional National Multiple Sclerosis Society Healthcare Provider Councils. A total of 86 people responded: 45 physicians, 18 rehabilitation therapists, 7 psychologists, 8 advanced practice clinicians, 4 social workers, 2 nurses, a pharmacist, and a researcher.
The results, which were published earlier in 2021 in Multiple Sclerosis and Related Disorders, revealed that the survey participants were prescribing certain DMTs more often: beta-interferons (prescribed more by 28.6% of prescribers), natalizumab (23.8%), and glatiramer acetate (21.4%). Those prescribed less included alemtuzumab (64.2% prescribed it less), cladribine (52.4%), and B cell–depleting agents including ocrelizumab and rituximab (50%). Some specialists suspended drugs entirely (21.4% for alemtuzumab, 16.7% for B cell–depleting agents) or extending dosing intervals (38.1% for natalizumab, 11.9% for fingolimod and siponimod).
“We suspect that some of the lower-efficacy therapies were prescribed more often because these therapies were much less immunosuppressive, and because they did not require in-person visits that would increase risk of viral exposure from infusion center staff, or from other infusion patients,” Dr. Morrison-Banks said in an interview. “We also suspect that some of our survey respondents may have increased the dosing intervals for higher-efficacy therapies such as B cell–modulating agents – or even avoided these therapies altogether – because they were concerned that immunosuppressive agents might trigger severe complications from COVID-19.”
As she noted, “in retrospect, at least some of the concerns expressed in our survey may not have been entirely warranted, but then again, we all knew even less then about COVID-19.”
Indeed, researchers led by neurologist Tyler E. Smith, MD, of New York University Langone Multiple Sclerosis Care Center are reporting that they couldn’t find any link between the following DMTs and higher rates of COVID-19 at the New York City center: rituximab, ocrelizumab, fumerate (dimethyl fumarate, monomethyl fumarate, diroximel fumarate), sphingosine-1-phosphate modulators (fingolimod, siponimod), and natalizumab.
The researchers tracked 1,439 patients with MS who were taking the DMTs from March 2020 to March 2021. Of those, 16.0% were infected with COVID-19 (75% lab confirmed), 6.5% were hospitalized, and 0.9% died.
“We did not find an association between the choice of disease-modifying therapy and developing COVID-19 infection, nor having increased disease severity,” Dr. Smith said in an interview. “We are still analyzing data and hope to publish an updated analysis, but at this point, we don’t have conclusive evidence that DMTs, including anti-CD20 agents, need to be changed to lower the risk of COVID-19.”
Instead, he said, “at this point, we feel our energies should be spent on educating our patients on importance of vaccines and boosters. I don’t think it is necessary to switch DMTs because of COVID-19 concerns. However, this should be reviewed on a case-by-case basis.”
No funding is reported for the survey study, and the authors reported various disclosures. The DMT study was funded by an investigator-initiated grant from the Consortium of Multiple Sclerosis Centers, and the authors reported various disclosures.
These are the messages of a pair of new studies that examine the impact of the pandemic on the treatment of MS.
One report finds that 80% of specialists surveyed in the summer of 2020 said the pandemic may have changed how they prescribe disease-modifying therapies (DMTs). However, the other report finds no evidence that choice of DMT affects risk of COVID-19 infection. Both studies were presented at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
For the survey, researchers led by neurologist Elizabeth H. Morrison-Banks, MD, of the University of California, Riverside, sent questions to 188 clinicians who serve on regional National Multiple Sclerosis Society Healthcare Provider Councils. A total of 86 people responded: 45 physicians, 18 rehabilitation therapists, 7 psychologists, 8 advanced practice clinicians, 4 social workers, 2 nurses, a pharmacist, and a researcher.
The results, which were published earlier in 2021 in Multiple Sclerosis and Related Disorders, revealed that the survey participants were prescribing certain DMTs more often: beta-interferons (prescribed more by 28.6% of prescribers), natalizumab (23.8%), and glatiramer acetate (21.4%). Those prescribed less included alemtuzumab (64.2% prescribed it less), cladribine (52.4%), and B cell–depleting agents including ocrelizumab and rituximab (50%). Some specialists suspended drugs entirely (21.4% for alemtuzumab, 16.7% for B cell–depleting agents) or extending dosing intervals (38.1% for natalizumab, 11.9% for fingolimod and siponimod).
“We suspect that some of the lower-efficacy therapies were prescribed more often because these therapies were much less immunosuppressive, and because they did not require in-person visits that would increase risk of viral exposure from infusion center staff, or from other infusion patients,” Dr. Morrison-Banks said in an interview. “We also suspect that some of our survey respondents may have increased the dosing intervals for higher-efficacy therapies such as B cell–modulating agents – or even avoided these therapies altogether – because they were concerned that immunosuppressive agents might trigger severe complications from COVID-19.”
As she noted, “in retrospect, at least some of the concerns expressed in our survey may not have been entirely warranted, but then again, we all knew even less then about COVID-19.”
Indeed, researchers led by neurologist Tyler E. Smith, MD, of New York University Langone Multiple Sclerosis Care Center are reporting that they couldn’t find any link between the following DMTs and higher rates of COVID-19 at the New York City center: rituximab, ocrelizumab, fumerate (dimethyl fumarate, monomethyl fumarate, diroximel fumarate), sphingosine-1-phosphate modulators (fingolimod, siponimod), and natalizumab.
The researchers tracked 1,439 patients with MS who were taking the DMTs from March 2020 to March 2021. Of those, 16.0% were infected with COVID-19 (75% lab confirmed), 6.5% were hospitalized, and 0.9% died.
“We did not find an association between the choice of disease-modifying therapy and developing COVID-19 infection, nor having increased disease severity,” Dr. Smith said in an interview. “We are still analyzing data and hope to publish an updated analysis, but at this point, we don’t have conclusive evidence that DMTs, including anti-CD20 agents, need to be changed to lower the risk of COVID-19.”
Instead, he said, “at this point, we feel our energies should be spent on educating our patients on importance of vaccines and boosters. I don’t think it is necessary to switch DMTs because of COVID-19 concerns. However, this should be reviewed on a case-by-case basis.”
No funding is reported for the survey study, and the authors reported various disclosures. The DMT study was funded by an investigator-initiated grant from the Consortium of Multiple Sclerosis Centers, and the authors reported various disclosures.
FROM CMSC 2021
Good data is lacking on best first-line MS drug strategies
Personalized medicine is just about the biggest buzzword in health. But neurologist Ellen M. Mowry, MD, of Johns Hopkins University, Baltimore, steers patients with multiple sclerosis (MS) away from the concept when she first starts talking to them about initial therapy options and possible ways to forestall disability down the line.
“I try to be quite honest,” she told colleagues at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
Observational and clinical trials offer extremely limited insight, she said in a keynote address, so there aren’t any simple answers about the best strategies. However, she highlighted new research projects that aim to provide more reliable answers.
As Dr. Mowry noted, patients tend to do well early on regardless of the choice of drug, so the question isn’t how to immediately control MS. “I personally find that most people can have control of relapses and the development of new lesions. I don’t find that there are too many individuals these days who don’t achieve control of their inflammatory activity,” she said. “I’m really interested in understanding whether the treatment choices a person with MS and myself make – at the time of their diagnosis – matters with respect to how they’re doing several years down the road. One major question is: Should I be using higher-efficacy therapy right out of the gate to better impact long-term disability?”
Research suggests that disability in MS is declining dramatically, she said, although it’s not quite clear if this is caused by evolving definitions of the disease or better medications. If the latter is the case, it’s useful to know that “there have been several publications suggesting that using stronger therapies right out of the gate may have an even greater impact on the long-term disability trajectory [than lower-efficacy treatments],” she said.
But some studies in this area are observational and come with various weaknesses, she said. Clinical trials offer data of their own, but “the conditions of clinical trials are also not real world or generalizable.” They often have healthier subjects than physicians actually see, and their requirements – such as requiring patients to have failed certain therapies – can muddy the messages of their outcomes. And, she added, people are more complicated in real life than in these trials, with many having a mix of both higher- and lower-risk features.
So how can physicians make the best decisions? Dr. Mowry recommends considering several factors, such patient comorbidities and reproductive status, the way drugs are administered, monitoring requirements, and cost. Safety is crucial too. She noted that newly diagnosed patients with MS are very concerned about safety – “they’re very much afraid of risks of stronger medications” – and many choose escalation therapy instead of immediately embracing higher-efficacy therapy for that reason.
At her clinic, she doesn’t push quick decisions. “I find that the treatment-decision discussion with individuals with MS takes several appointments, which we offer typically in quick succession. If we go with the escalation route, we are very strongly conscientious about escalating if there’s breakthrough disease. For me, that means after the medication should have kicked in, we may indeed escalate that therapy right away if there’s a new relapse or more than one new lesion.”
As for the future, Dr. Mowry highlighted two ongoing clinical trials that are expected to provide guidance about first-line therapy options. One is TREAT-MS, which will track intermediate-term risk of disability based on choices regarding first-line and later therapy. The pragmatic trial aims to enroll 900 subjects for up to 5 years. The other is DELIVER-MS, which aims to track how treatment choices affect brain volume.
“We really do need more definitive data to support the early treatment choices that people need to make,” she said.
Dr. Mowry disclosed grant/research support from Biogen, Teva, and Genentech, as welll as honoraria (editorial royalties) from UpToDate.
Personalized medicine is just about the biggest buzzword in health. But neurologist Ellen M. Mowry, MD, of Johns Hopkins University, Baltimore, steers patients with multiple sclerosis (MS) away from the concept when she first starts talking to them about initial therapy options and possible ways to forestall disability down the line.
“I try to be quite honest,” she told colleagues at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
Observational and clinical trials offer extremely limited insight, she said in a keynote address, so there aren’t any simple answers about the best strategies. However, she highlighted new research projects that aim to provide more reliable answers.
As Dr. Mowry noted, patients tend to do well early on regardless of the choice of drug, so the question isn’t how to immediately control MS. “I personally find that most people can have control of relapses and the development of new lesions. I don’t find that there are too many individuals these days who don’t achieve control of their inflammatory activity,” she said. “I’m really interested in understanding whether the treatment choices a person with MS and myself make – at the time of their diagnosis – matters with respect to how they’re doing several years down the road. One major question is: Should I be using higher-efficacy therapy right out of the gate to better impact long-term disability?”
Research suggests that disability in MS is declining dramatically, she said, although it’s not quite clear if this is caused by evolving definitions of the disease or better medications. If the latter is the case, it’s useful to know that “there have been several publications suggesting that using stronger therapies right out of the gate may have an even greater impact on the long-term disability trajectory [than lower-efficacy treatments],” she said.
But some studies in this area are observational and come with various weaknesses, she said. Clinical trials offer data of their own, but “the conditions of clinical trials are also not real world or generalizable.” They often have healthier subjects than physicians actually see, and their requirements – such as requiring patients to have failed certain therapies – can muddy the messages of their outcomes. And, she added, people are more complicated in real life than in these trials, with many having a mix of both higher- and lower-risk features.
So how can physicians make the best decisions? Dr. Mowry recommends considering several factors, such patient comorbidities and reproductive status, the way drugs are administered, monitoring requirements, and cost. Safety is crucial too. She noted that newly diagnosed patients with MS are very concerned about safety – “they’re very much afraid of risks of stronger medications” – and many choose escalation therapy instead of immediately embracing higher-efficacy therapy for that reason.
At her clinic, she doesn’t push quick decisions. “I find that the treatment-decision discussion with individuals with MS takes several appointments, which we offer typically in quick succession. If we go with the escalation route, we are very strongly conscientious about escalating if there’s breakthrough disease. For me, that means after the medication should have kicked in, we may indeed escalate that therapy right away if there’s a new relapse or more than one new lesion.”
As for the future, Dr. Mowry highlighted two ongoing clinical trials that are expected to provide guidance about first-line therapy options. One is TREAT-MS, which will track intermediate-term risk of disability based on choices regarding first-line and later therapy. The pragmatic trial aims to enroll 900 subjects for up to 5 years. The other is DELIVER-MS, which aims to track how treatment choices affect brain volume.
“We really do need more definitive data to support the early treatment choices that people need to make,” she said.
Dr. Mowry disclosed grant/research support from Biogen, Teva, and Genentech, as welll as honoraria (editorial royalties) from UpToDate.
Personalized medicine is just about the biggest buzzword in health. But neurologist Ellen M. Mowry, MD, of Johns Hopkins University, Baltimore, steers patients with multiple sclerosis (MS) away from the concept when she first starts talking to them about initial therapy options and possible ways to forestall disability down the line.
“I try to be quite honest,” she told colleagues at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
Observational and clinical trials offer extremely limited insight, she said in a keynote address, so there aren’t any simple answers about the best strategies. However, she highlighted new research projects that aim to provide more reliable answers.
As Dr. Mowry noted, patients tend to do well early on regardless of the choice of drug, so the question isn’t how to immediately control MS. “I personally find that most people can have control of relapses and the development of new lesions. I don’t find that there are too many individuals these days who don’t achieve control of their inflammatory activity,” she said. “I’m really interested in understanding whether the treatment choices a person with MS and myself make – at the time of their diagnosis – matters with respect to how they’re doing several years down the road. One major question is: Should I be using higher-efficacy therapy right out of the gate to better impact long-term disability?”
Research suggests that disability in MS is declining dramatically, she said, although it’s not quite clear if this is caused by evolving definitions of the disease or better medications. If the latter is the case, it’s useful to know that “there have been several publications suggesting that using stronger therapies right out of the gate may have an even greater impact on the long-term disability trajectory [than lower-efficacy treatments],” she said.
But some studies in this area are observational and come with various weaknesses, she said. Clinical trials offer data of their own, but “the conditions of clinical trials are also not real world or generalizable.” They often have healthier subjects than physicians actually see, and their requirements – such as requiring patients to have failed certain therapies – can muddy the messages of their outcomes. And, she added, people are more complicated in real life than in these trials, with many having a mix of both higher- and lower-risk features.
So how can physicians make the best decisions? Dr. Mowry recommends considering several factors, such patient comorbidities and reproductive status, the way drugs are administered, monitoring requirements, and cost. Safety is crucial too. She noted that newly diagnosed patients with MS are very concerned about safety – “they’re very much afraid of risks of stronger medications” – and many choose escalation therapy instead of immediately embracing higher-efficacy therapy for that reason.
At her clinic, she doesn’t push quick decisions. “I find that the treatment-decision discussion with individuals with MS takes several appointments, which we offer typically in quick succession. If we go with the escalation route, we are very strongly conscientious about escalating if there’s breakthrough disease. For me, that means after the medication should have kicked in, we may indeed escalate that therapy right away if there’s a new relapse or more than one new lesion.”
As for the future, Dr. Mowry highlighted two ongoing clinical trials that are expected to provide guidance about first-line therapy options. One is TREAT-MS, which will track intermediate-term risk of disability based on choices regarding first-line and later therapy. The pragmatic trial aims to enroll 900 subjects for up to 5 years. The other is DELIVER-MS, which aims to track how treatment choices affect brain volume.
“We really do need more definitive data to support the early treatment choices that people need to make,” she said.
Dr. Mowry disclosed grant/research support from Biogen, Teva, and Genentech, as welll as honoraria (editorial royalties) from UpToDate.
FROM CMSC 2021