Neurology

People with clinically diagnosed depression and anxiety may be prone to developing Alzheimer’s disease at a younger age than other people, and those with a history of posttraumatic stress disorder may be prone to Alzheimer’s disease onset even earlier in life, according to findings from a review of 1,500 patients with Alzheimer’s disease from a single-center population.

“Could psychosis symptoms be the proverbial canary in a coal mine?” Emily Eijansantos, a medical student at the University of California, San Francisco, said in reporting results of the chart review at the 2021 annual meeting of the American Academy of Neurology. “Previously in this cohort it was found that neurodevelopmental factors as well as chronic insults such as autoimmunity and seizure were also associated with an early age of onset in Alzheimer’s disease.”

The link between depression and autoimmunity, and anxiety and seizure “beg more questions about underlying pathophysiology,” she said. The study included 750 patients with early-onset Alzheimer’s disease and a similar number of late-onset patients from the UCSF Memory and Aging Center.
 

An inverse correlation between psychiatric disorders and age of Alzheimer’s onset

In the total study population, 43.5% (n = 652) had a previous diagnosis of depression and 32.3% (n = 485) had been diagnosed with anxiety. That, Ms. Eijansantos said, falls into similar ranges that other studies have reported.

“When we look at individual psychiatric disorders, we find that those with depression, anxiety, or PTSD are younger on average,” she said. “Patients with depression and anxiety are more [likely] female and have less vascular risk factors, and we observed an association between depression and autoimmunity, anxiety, and seizures.”

Specifically, patients with a history of depression were 2.2 years younger, on average, at the age of onset than patients without such history (P = .01); those with anxiety were 3 years younger on average (P = .01); and those with PTSD were 6.8 years younger on average, although only 1% (n = 15) of study subjects had PTSD, making for a small sample to study. These age-of-onset disparities didn’t appear among patients with previously diagnosed bipolar disorder (BPD) or schizophrenia.

Ms. Eijansantos noted that there were no differences in education attained or apolipoprotein-E gene status between the patients with and without a history of psychosis, and, within the subgroups of individual psychiatric disorders, there were no differences between patients with past and current or formal and informal diagnoses.

“When we split the cohort into quintiles based on age of Alzheimer’s disease onset, we find an inverse correlation between the amount of depression, anxiety, and PTSD endorsed and their ages of onset,” Ms. Eijansantos said. For example, the youngest quintile had a greater than 50% rate of depression while the oldest quintile had a depression rate around 36%. A similar spread was found with anxiety: a rate around 46% in the youngest quantile versus around 25% in the oldest, whereas rates of PTSD, BPD, and schizophrenia were similar across the five age-of-onset groups.

Patients with a history of multiple psychiatric disorders had an even younger age of onset. “We see that those with two psychiatric disorder are younger than those with one, and those with three psychiatric disorders are younger still,” Ms. Eijansantos said. “And we find that the Alzheimer’s disease age-at-onset reduction doubles with each additional psychiatric disorder.” Multiple disorders also adversely impacted survival, she said.

Because they found no difference between patients with past versus active symptoms and informal versus formal diagnosis, Ms. Eijansantos explained that they further studied the National Alzheimer’s Coordinating Center cohort of 8,267 patients with Alzheimer’s disease and found a similar relationship between psychiatric history and age of onset among patients with depression or anxiety or both. This cohort also documented symptom severity, she noted. “So when we look at depression and anxiety we find similar reductions in the Alzheimer’s disease age of onset with each increasing degree of symptom severity,” she said.

“Does this mean that psychiatric disease is a risk factor for Alzheimr’s disease?” Ms. Eijansantos said. “We can’t answer that with this study because it was only designed to see if the psychiatric factors modulate the age of onset in those that have Alzheimer’s disease, but taken together we believe that these results fit the framework that there are pathophysiological and profound differences between earlier and later presentations of Alzheimer’s disease.”

She pointed to reports that early-onset Alzheimer’s disease is associated with more aggressive tau pathology and that depression is associated with tau. However, the evidence supporting a link between amyloid and psychiatric disease is less certain, she said.
 

Preliminary and speculative findings

Senior study author Zachary Miller, MD, an assistant professor in the UCSF Memory and Aging Center, explained the significance of the study findings of potential links between depression and autoimmunity, and anxiety and seizure. “There may be distinct underlying pathophysiological mechanisms in patients with Alzheimer’s disease who have symptoms of depression versus anxiety,” he said, acknowledging the findings “are quite preliminary and our interpretations quite speculative.”

The findings raise the question that the symptomatic presentation of greater amounts of depression in early-onset Alzheimer’s disease may be moderated by an underlying neuroinflammatory insult, he said. “If so, depression symptomatology could then be seen as a possible clinical marker of this inflammatory response and possibly be used in testing clinical endpoints for future intervention trials,” Dr. Miller said. “Similarly, if neuronal hyperexcitability in Alzheimer’s disease manifests itself as either seizure and/or anxiety, this would have significant impact for therapeutic monitoring and treatment.”

He said a multicenter study of Alzheimer’s disease cohorts would validate the findings. “At the same time, we are also interested in looking deeper into these findings, investigating the potential cognitive and neuroanatomical correlates associated with these conditions,” Dr. Miller said.

Clinical phenotyping may provide more insight into the relationship between psychosis and age of Alzheimer’s disease onset, said Vijay K. Ramanan, MD, PhD, an assistant professor of neurology at Mayo Clinic in Rochester, Minn.

People with clinically diagnosed depression and anxiety may be prone to developing Alzheimer’s disease at a younger age than other people, and those with a history of posttraumatic stress disorder may be prone to Alzheimer’s disease onset even earlier in life, according to findings from a review of 1,500 patients with Alzheimer’s disease from a single-center population.

“Could psychosis symptoms be the proverbial canary in a coal mine?” Emily Eijansantos, a medical student at the University of California, San Francisco, said in reporting results of the chart review at the 2021 annual meeting of the American Academy of Neurology. “Previously in this cohort it was found that neurodevelopmental factors as well as chronic insults such as autoimmunity and seizure were also associated with an early age of onset in Alzheimer’s disease.”

The link between depression and autoimmunity, and anxiety and seizure “beg more questions about underlying pathophysiology,” she said. The study included 750 patients with early-onset Alzheimer’s disease and a similar number of late-onset patients from the UCSF Memory and Aging Center.
 

An inverse correlation between psychiatric disorders and age of Alzheimer’s onset

In the total study population, 43.5% (n = 652) had a previous diagnosis of depression and 32.3% (n = 485) had been diagnosed with anxiety. That, Ms. Eijansantos said, falls into similar ranges that other studies have reported.

“When we look at individual psychiatric disorders, we find that those with depression, anxiety, or PTSD are younger on average,” she said. “Patients with depression and anxiety are more [likely] female and have less vascular risk factors, and we observed an association between depression and autoimmunity, anxiety, and seizures.”

Specifically, patients with a history of depression were 2.2 years younger, on average, at the age of onset than patients without such history (P = .01); those with anxiety were 3 years younger on average (P = .01); and those with PTSD were 6.8 years younger on average, although only 1% (n = 15) of study subjects had PTSD, making for a small sample to study. These age-of-onset disparities didn’t appear among patients with previously diagnosed bipolar disorder (BPD) or schizophrenia.

Ms. Eijansantos noted that there were no differences in education attained or apolipoprotein-E gene status between the patients with and without a history of psychosis, and, within the subgroups of individual psychiatric disorders, there were no differences between patients with past and current or formal and informal diagnoses.

“When we split the cohort into quintiles based on age of Alzheimer’s disease onset, we find an inverse correlation between the amount of depression, anxiety, and PTSD endorsed and their ages of onset,” Ms. Eijansantos said. For example, the youngest quintile had a greater than 50% rate of depression while the oldest quintile had a depression rate around 36%. A similar spread was found with anxiety: a rate around 46% in the youngest quantile versus around 25% in the oldest, whereas rates of PTSD, BPD, and schizophrenia were similar across the five age-of-onset groups.

Patients with a history of multiple psychiatric disorders had an even younger age of onset. “We see that those with two psychiatric disorder are younger than those with one, and those with three psychiatric disorders are younger still,” Ms. Eijansantos said. “And we find that the Alzheimer’s disease age-at-onset reduction doubles with each additional psychiatric disorder.” Multiple disorders also adversely impacted survival, she said.

Because they found no difference between patients with past versus active symptoms and informal versus formal diagnosis, Ms. Eijansantos explained that they further studied the National Alzheimer’s Coordinating Center cohort of 8,267 patients with Alzheimer’s disease and found a similar relationship between psychiatric history and age of onset among patients with depression or anxiety or both. This cohort also documented symptom severity, she noted. “So when we look at depression and anxiety we find similar reductions in the Alzheimer’s disease age of onset with each increasing degree of symptom severity,” she said.

“Does this mean that psychiatric disease is a risk factor for Alzheimr’s disease?” Ms. Eijansantos said. “We can’t answer that with this study because it was only designed to see if the psychiatric factors modulate the age of onset in those that have Alzheimer’s disease, but taken together we believe that these results fit the framework that there are pathophysiological and profound differences between earlier and later presentations of Alzheimer’s disease.”

She pointed to reports that early-onset Alzheimer’s disease is associated with more aggressive tau pathology and that depression is associated with tau. However, the evidence supporting a link between amyloid and psychiatric disease is less certain, she said.
 

Preliminary and speculative findings

Senior study author Zachary Miller, MD, an assistant professor in the UCSF Memory and Aging Center, explained the significance of the study findings of potential links between depression and autoimmunity, and anxiety and seizure. “There may be distinct underlying pathophysiological mechanisms in patients with Alzheimer’s disease who have symptoms of depression versus anxiety,” he said, acknowledging the findings “are quite preliminary and our interpretations quite speculative.”

The findings raise the question that the symptomatic presentation of greater amounts of depression in early-onset Alzheimer’s disease may be moderated by an underlying neuroinflammatory insult, he said. “If so, depression symptomatology could then be seen as a possible clinical marker of this inflammatory response and possibly be used in testing clinical endpoints for future intervention trials,” Dr. Miller said. “Similarly, if neuronal hyperexcitability in Alzheimer’s disease manifests itself as either seizure and/or anxiety, this would have significant impact for therapeutic monitoring and treatment.”

He said a multicenter study of Alzheimer’s disease cohorts would validate the findings. “At the same time, we are also interested in looking deeper into these findings, investigating the potential cognitive and neuroanatomical correlates associated with these conditions,” Dr. Miller said.

Clinical phenotyping may provide more insight into the relationship between psychosis and age of Alzheimer’s disease onset, said Vijay K. Ramanan, MD, PhD, an assistant professor of neurology at Mayo Clinic in Rochester, Minn.

People with clinically diagnosed depression and anxiety may be prone to developing Alzheimer’s disease at a younger age than other people, and those with a history of posttraumatic stress disorder may be prone to Alzheimer’s disease onset even earlier in life, according to findings from a review of 1,500 patients with Alzheimer’s disease from a single-center population.

“Could psychosis symptoms be the proverbial canary in a coal mine?” Emily Eijansantos, a medical student at the University of California, San Francisco, said in reporting results of the chart review at the 2021 annual meeting of the American Academy of Neurology. “Previously in this cohort it was found that neurodevelopmental factors as well as chronic insults such as autoimmunity and seizure were also associated with an early age of onset in Alzheimer’s disease.”

The link between depression and autoimmunity, and anxiety and seizure “beg more questions about underlying pathophysiology,” she said. The study included 750 patients with early-onset Alzheimer’s disease and a similar number of late-onset patients from the UCSF Memory and Aging Center.
 

An inverse correlation between psychiatric disorders and age of Alzheimer’s onset

In the total study population, 43.5% (n = 652) had a previous diagnosis of depression and 32.3% (n = 485) had been diagnosed with anxiety. That, Ms. Eijansantos said, falls into similar ranges that other studies have reported.

“When we look at individual psychiatric disorders, we find that those with depression, anxiety, or PTSD are younger on average,” she said. “Patients with depression and anxiety are more [likely] female and have less vascular risk factors, and we observed an association between depression and autoimmunity, anxiety, and seizures.”

Specifically, patients with a history of depression were 2.2 years younger, on average, at the age of onset than patients without such history (P = .01); those with anxiety were 3 years younger on average (P = .01); and those with PTSD were 6.8 years younger on average, although only 1% (n = 15) of study subjects had PTSD, making for a small sample to study. These age-of-onset disparities didn’t appear among patients with previously diagnosed bipolar disorder (BPD) or schizophrenia.

Ms. Eijansantos noted that there were no differences in education attained or apolipoprotein-E gene status between the patients with and without a history of psychosis, and, within the subgroups of individual psychiatric disorders, there were no differences between patients with past and current or formal and informal diagnoses.

“When we split the cohort into quintiles based on age of Alzheimer’s disease onset, we find an inverse correlation between the amount of depression, anxiety, and PTSD endorsed and their ages of onset,” Ms. Eijansantos said. For example, the youngest quintile had a greater than 50% rate of depression while the oldest quintile had a depression rate around 36%. A similar spread was found with anxiety: a rate around 46% in the youngest quantile versus around 25% in the oldest, whereas rates of PTSD, BPD, and schizophrenia were similar across the five age-of-onset groups.

Patients with a history of multiple psychiatric disorders had an even younger age of onset. “We see that those with two psychiatric disorder are younger than those with one, and those with three psychiatric disorders are younger still,” Ms. Eijansantos said. “And we find that the Alzheimer’s disease age-at-onset reduction doubles with each additional psychiatric disorder.” Multiple disorders also adversely impacted survival, she said.

Because they found no difference between patients with past versus active symptoms and informal versus formal diagnosis, Ms. Eijansantos explained that they further studied the National Alzheimer’s Coordinating Center cohort of 8,267 patients with Alzheimer’s disease and found a similar relationship between psychiatric history and age of onset among patients with depression or anxiety or both. This cohort also documented symptom severity, she noted. “So when we look at depression and anxiety we find similar reductions in the Alzheimer’s disease age of onset with each increasing degree of symptom severity,” she said.

“Does this mean that psychiatric disease is a risk factor for Alzheimr’s disease?” Ms. Eijansantos said. “We can’t answer that with this study because it was only designed to see if the psychiatric factors modulate the age of onset in those that have Alzheimer’s disease, but taken together we believe that these results fit the framework that there are pathophysiological and profound differences between earlier and later presentations of Alzheimer’s disease.”

She pointed to reports that early-onset Alzheimer’s disease is associated with more aggressive tau pathology and that depression is associated with tau. However, the evidence supporting a link between amyloid and psychiatric disease is less certain, she said.
 

Preliminary and speculative findings

Senior study author Zachary Miller, MD, an assistant professor in the UCSF Memory and Aging Center, explained the significance of the study findings of potential links between depression and autoimmunity, and anxiety and seizure. “There may be distinct underlying pathophysiological mechanisms in patients with Alzheimer’s disease who have symptoms of depression versus anxiety,” he said, acknowledging the findings “are quite preliminary and our interpretations quite speculative.”

The findings raise the question that the symptomatic presentation of greater amounts of depression in early-onset Alzheimer’s disease may be moderated by an underlying neuroinflammatory insult, he said. “If so, depression symptomatology could then be seen as a possible clinical marker of this inflammatory response and possibly be used in testing clinical endpoints for future intervention trials,” Dr. Miller said. “Similarly, if neuronal hyperexcitability in Alzheimer’s disease manifests itself as either seizure and/or anxiety, this would have significant impact for therapeutic monitoring and treatment.”

He said a multicenter study of Alzheimer’s disease cohorts would validate the findings. “At the same time, we are also interested in looking deeper into these findings, investigating the potential cognitive and neuroanatomical correlates associated with these conditions,” Dr. Miller said.

Clinical phenotyping may provide more insight into the relationship between psychosis and age of Alzheimer’s disease onset, said Vijay K. Ramanan, MD, PhD, an assistant professor of neurology at Mayo Clinic in Rochester, Minn.

COVID-19 is linked to novel seizures and subsequent adverse outcomes, including death, in patients without a previous history of epilepsy, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.

In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.

“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.

Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”

“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.

Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
 

Largest sample to date

“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.

Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.

However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.

For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.

For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).

The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
 

Significant adverse outcomes

Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).

In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).

In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).

Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).

Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.

Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”

He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”

Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.

The investigators have reported no relevant financial relationships.

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

COVID-19 is linked to novel seizures and subsequent adverse outcomes, including death, in patients without a previous history of epilepsy, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.

In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.

“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.

Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”

“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.

Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
 

Largest sample to date

“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.

Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.

However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.

For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.

For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).

The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
 

Significant adverse outcomes

Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).

In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).

In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).

Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).

Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.

Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”

He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”

Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.

The investigators have reported no relevant financial relationships.

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

COVID-19 is linked to novel seizures and subsequent adverse outcomes, including death, in patients without a previous history of epilepsy, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.

In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.

“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.

Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”

“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.

Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
 

Largest sample to date

“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.

Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.

However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.

For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.

For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).

The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
 

Significant adverse outcomes

Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).

In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).

In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).

Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).

Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.

Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”

He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”

Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.

The investigators have reported no relevant financial relationships.

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

Background: The beneficial role of high-intensity statins in secondary prevention of recurrent atherosclerotic stroke is well established. It is uncertain whether the observed benefit was from a reduction in the cholesterol level or to other pleotropic effects of atorvastatin. The ideal target cholesterol level for secondary prevention is unclear. This trial was conducted to help determine an ideal target LDL-C level in the prevention of CV events following ischemic stroke.

There were 2,860 patients enrolled, 1,430 were assigned to each target group. At the end of 3.5 years, the primary endpoint occurred in 8.5% of patients in the lower target group, compared with 10.9% in the higher target group (hazard ratio, 0.78; 95% confidence interval, 0.61-0.98; P = .04). Unfortunately, the trial was stopped early because of a lack of funding.

Bottom line: Using medications including statins to lower the LDL-C to less than 70 mg/dL leads to better cardiovascular outcomes following ischemic stroke.

Citation: Amarenco P et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med. 2020 Jan 2;382:9-19.

Dr. Garg is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Background: The beneficial role of high-intensity statins in secondary prevention of recurrent atherosclerotic stroke is well established. It is uncertain whether the observed benefit was from a reduction in the cholesterol level or to other pleotropic effects of atorvastatin. The ideal target cholesterol level for secondary prevention is unclear. This trial was conducted to help determine an ideal target LDL-C level in the prevention of CV events following ischemic stroke.

There were 2,860 patients enrolled, 1,430 were assigned to each target group. At the end of 3.5 years, the primary endpoint occurred in 8.5% of patients in the lower target group, compared with 10.9% in the higher target group (hazard ratio, 0.78; 95% confidence interval, 0.61-0.98; P = .04). Unfortunately, the trial was stopped early because of a lack of funding.

Bottom line: Using medications including statins to lower the LDL-C to less than 70 mg/dL leads to better cardiovascular outcomes following ischemic stroke.

Citation: Amarenco P et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med. 2020 Jan 2;382:9-19.

Dr. Garg is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Background: The beneficial role of high-intensity statins in secondary prevention of recurrent atherosclerotic stroke is well established. It is uncertain whether the observed benefit was from a reduction in the cholesterol level or to other pleotropic effects of atorvastatin. The ideal target cholesterol level for secondary prevention is unclear. This trial was conducted to help determine an ideal target LDL-C level in the prevention of CV events following ischemic stroke.

There were 2,860 patients enrolled, 1,430 were assigned to each target group. At the end of 3.5 years, the primary endpoint occurred in 8.5% of patients in the lower target group, compared with 10.9% in the higher target group (hazard ratio, 0.78; 95% confidence interval, 0.61-0.98; P = .04). Unfortunately, the trial was stopped early because of a lack of funding.

Bottom line: Using medications including statins to lower the LDL-C to less than 70 mg/dL leads to better cardiovascular outcomes following ischemic stroke.

Citation: Amarenco P et al. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J Med. 2020 Jan 2;382:9-19.

Dr. Garg is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Patients with chronic migraine who turn to cannabis to relieve headache pain may be setting themselves up for medication overuse headache, preliminary research suggests, although the direction of the relationship is unclear. Researchers at Stanford (Calif.) University found a significant increase in the likelihood of medication overuse headache (rebound headache) in chronic migraine patients who use cannabis.

“This study shows that there is some kind of association between cannabis use and medication overuse headache in people with chronic migraine,” said lead investigator Niushen Zhang, MD, a clinical assistant professor at Stanford.

“But it is unclear at this time whether patients are using cannabis to treat medication overuse headache or if cannabis is contributing to the development medication overuse headache, or both,” she said.

The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Sixfold increase

“Medication overuse occurs in about 1% to 3% of the general population. It affects nearly one-third of the patients (mostly patients with chronic migraine) seen at tertiary care centers such as the Stanford Headache Center,” Dr. Zhang said.

From clinical observations, patients with chronic migraine and medication overuse headache appear to be concomitantly using cannabis products, yet there is currently very little research on this topic, she added.

To investigate, the researchers reviewed the records of 368 adults who experienced chronic migraine (15 or more migraine days per month) for at least 1 year. Of the 368 patients, 150 were using cannabis, and 218 were not. In addition, 212 had medication overuse headache, and 156 did not.

Results showed that patients who used cannabis were nearly six times more likely to have medication overuse headache than those who did not use cannabis (odds ratio, 5.99; 95% confidence interval, 3.45-10.43; P < .0001).

There were significant bidirectional relationships between current cannabis use, opioid use, and medication overuse headache.
 

Jury out on cannabis for migraine

Commenting on the findings, Teshamae Monteith, MD, of the University of Miami, noted, “With increased legalization, greater access, and less stigmatization, there are more individuals using cannabis for migraine, but there is no solid evidence to suggest that cannabis is effective for acute or preventive treatment of migraine.”

The study is “interesting,” Dr. Monteith said, but, owing to methodologic limitations, it is not clear that cannabis contributes to medication overuse headache. “Patients with medication overuse headaches may have more comorbidities, such as anxiety, depression, and sleep disorders, that are driving the cannabis use. The patients on cannabis also had higher rates of opiate use, which itself is a stronger contributor to medication overuse headache and may indicate the presence of other pain disorders,” Dr. Monteith said.

“It is not clear if these patients were appropriately treated with migraine prevention; patients that use cannabis sometimes report that they prefer to avoid pharmaceutical treatments, such as antidepressants, etc., used for migraine,” Dr. Monteith noted.

She said that at this point, she would advise clinicians to ask about cannabis use “and let patients know that we do not know enough about the long-term effects of cannabis on the migraine brain.”

Most importantly, Dr. Monteith said, she would “encourage clinicians to be sensitive to the high prevalence of migraine, chronic migraine, and medication overuse. If we can treat more effectively and prevent migraine progression, which includes addressing comorbidities, there would be a lot less medication overuse headache.”

Also weighing in on the study, Jessica Ailani, MD, director, Medstar Georgetown Headache Center, Washington, D.C., noted that there is no conclusive evidence that cannabis is an effective acute or preventive treatment for migraine. “There is a suggestion that cannabis can help treat a migraine attack, but there is uncertainty about concentration of cannabidiol (CBD) to tetrahydrocannabinol (THC) needed to achieve pain freedom,” Dr. Ailani said.

“There has also been some concern about interactions between CBD and other medications used to treat migraine and that CBD can cause a condition known as reversible cerebral vasoconstrictive syndrome. These are reasons to be cautious with CBD,” Dr. Ailani added.

“At this time there is limited advice we can give our patients except that more studies need to be done. If cannabis is used, it should be reported, and medications that may interact with cannabis should be avoided. A headache calendar should be kept to ensure frequency of migraine and headache attacks do not go up,” said Dr. Ailani.

The study had no specific funding. Dr. Zhang, Dr. Monteith, and Dr. Ailani have disclosed no relevant financial relationships.

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

Patients with chronic migraine who turn to cannabis to relieve headache pain may be setting themselves up for medication overuse headache, preliminary research suggests, although the direction of the relationship is unclear. Researchers at Stanford (Calif.) University found a significant increase in the likelihood of medication overuse headache (rebound headache) in chronic migraine patients who use cannabis.

“This study shows that there is some kind of association between cannabis use and medication overuse headache in people with chronic migraine,” said lead investigator Niushen Zhang, MD, a clinical assistant professor at Stanford.

“But it is unclear at this time whether patients are using cannabis to treat medication overuse headache or if cannabis is contributing to the development medication overuse headache, or both,” she said.

The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Sixfold increase

“Medication overuse occurs in about 1% to 3% of the general population. It affects nearly one-third of the patients (mostly patients with chronic migraine) seen at tertiary care centers such as the Stanford Headache Center,” Dr. Zhang said.

From clinical observations, patients with chronic migraine and medication overuse headache appear to be concomitantly using cannabis products, yet there is currently very little research on this topic, she added.

To investigate, the researchers reviewed the records of 368 adults who experienced chronic migraine (15 or more migraine days per month) for at least 1 year. Of the 368 patients, 150 were using cannabis, and 218 were not. In addition, 212 had medication overuse headache, and 156 did not.

Results showed that patients who used cannabis were nearly six times more likely to have medication overuse headache than those who did not use cannabis (odds ratio, 5.99; 95% confidence interval, 3.45-10.43; P < .0001).

There were significant bidirectional relationships between current cannabis use, opioid use, and medication overuse headache.
 

Jury out on cannabis for migraine

Commenting on the findings, Teshamae Monteith, MD, of the University of Miami, noted, “With increased legalization, greater access, and less stigmatization, there are more individuals using cannabis for migraine, but there is no solid evidence to suggest that cannabis is effective for acute or preventive treatment of migraine.”

The study is “interesting,” Dr. Monteith said, but, owing to methodologic limitations, it is not clear that cannabis contributes to medication overuse headache. “Patients with medication overuse headaches may have more comorbidities, such as anxiety, depression, and sleep disorders, that are driving the cannabis use. The patients on cannabis also had higher rates of opiate use, which itself is a stronger contributor to medication overuse headache and may indicate the presence of other pain disorders,” Dr. Monteith said.

“It is not clear if these patients were appropriately treated with migraine prevention; patients that use cannabis sometimes report that they prefer to avoid pharmaceutical treatments, such as antidepressants, etc., used for migraine,” Dr. Monteith noted.

She said that at this point, she would advise clinicians to ask about cannabis use “and let patients know that we do not know enough about the long-term effects of cannabis on the migraine brain.”

Most importantly, Dr. Monteith said, she would “encourage clinicians to be sensitive to the high prevalence of migraine, chronic migraine, and medication overuse. If we can treat more effectively and prevent migraine progression, which includes addressing comorbidities, there would be a lot less medication overuse headache.”

Also weighing in on the study, Jessica Ailani, MD, director, Medstar Georgetown Headache Center, Washington, D.C., noted that there is no conclusive evidence that cannabis is an effective acute or preventive treatment for migraine. “There is a suggestion that cannabis can help treat a migraine attack, but there is uncertainty about concentration of cannabidiol (CBD) to tetrahydrocannabinol (THC) needed to achieve pain freedom,” Dr. Ailani said.

“There has also been some concern about interactions between CBD and other medications used to treat migraine and that CBD can cause a condition known as reversible cerebral vasoconstrictive syndrome. These are reasons to be cautious with CBD,” Dr. Ailani added.

“At this time there is limited advice we can give our patients except that more studies need to be done. If cannabis is used, it should be reported, and medications that may interact with cannabis should be avoided. A headache calendar should be kept to ensure frequency of migraine and headache attacks do not go up,” said Dr. Ailani.

The study had no specific funding. Dr. Zhang, Dr. Monteith, and Dr. Ailani have disclosed no relevant financial relationships.

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

Patients with chronic migraine who turn to cannabis to relieve headache pain may be setting themselves up for medication overuse headache, preliminary research suggests, although the direction of the relationship is unclear. Researchers at Stanford (Calif.) University found a significant increase in the likelihood of medication overuse headache (rebound headache) in chronic migraine patients who use cannabis.

“This study shows that there is some kind of association between cannabis use and medication overuse headache in people with chronic migraine,” said lead investigator Niushen Zhang, MD, a clinical assistant professor at Stanford.

“But it is unclear at this time whether patients are using cannabis to treat medication overuse headache or if cannabis is contributing to the development medication overuse headache, or both,” she said.

The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Sixfold increase

“Medication overuse occurs in about 1% to 3% of the general population. It affects nearly one-third of the patients (mostly patients with chronic migraine) seen at tertiary care centers such as the Stanford Headache Center,” Dr. Zhang said.

From clinical observations, patients with chronic migraine and medication overuse headache appear to be concomitantly using cannabis products, yet there is currently very little research on this topic, she added.

To investigate, the researchers reviewed the records of 368 adults who experienced chronic migraine (15 or more migraine days per month) for at least 1 year. Of the 368 patients, 150 were using cannabis, and 218 were not. In addition, 212 had medication overuse headache, and 156 did not.

Results showed that patients who used cannabis were nearly six times more likely to have medication overuse headache than those who did not use cannabis (odds ratio, 5.99; 95% confidence interval, 3.45-10.43; P < .0001).

There were significant bidirectional relationships between current cannabis use, opioid use, and medication overuse headache.
 

Jury out on cannabis for migraine

Commenting on the findings, Teshamae Monteith, MD, of the University of Miami, noted, “With increased legalization, greater access, and less stigmatization, there are more individuals using cannabis for migraine, but there is no solid evidence to suggest that cannabis is effective for acute or preventive treatment of migraine.”

The study is “interesting,” Dr. Monteith said, but, owing to methodologic limitations, it is not clear that cannabis contributes to medication overuse headache. “Patients with medication overuse headaches may have more comorbidities, such as anxiety, depression, and sleep disorders, that are driving the cannabis use. The patients on cannabis also had higher rates of opiate use, which itself is a stronger contributor to medication overuse headache and may indicate the presence of other pain disorders,” Dr. Monteith said.

“It is not clear if these patients were appropriately treated with migraine prevention; patients that use cannabis sometimes report that they prefer to avoid pharmaceutical treatments, such as antidepressants, etc., used for migraine,” Dr. Monteith noted.

She said that at this point, she would advise clinicians to ask about cannabis use “and let patients know that we do not know enough about the long-term effects of cannabis on the migraine brain.”

Most importantly, Dr. Monteith said, she would “encourage clinicians to be sensitive to the high prevalence of migraine, chronic migraine, and medication overuse. If we can treat more effectively and prevent migraine progression, which includes addressing comorbidities, there would be a lot less medication overuse headache.”

Also weighing in on the study, Jessica Ailani, MD, director, Medstar Georgetown Headache Center, Washington, D.C., noted that there is no conclusive evidence that cannabis is an effective acute or preventive treatment for migraine. “There is a suggestion that cannabis can help treat a migraine attack, but there is uncertainty about concentration of cannabidiol (CBD) to tetrahydrocannabinol (THC) needed to achieve pain freedom,” Dr. Ailani said.

“There has also been some concern about interactions between CBD and other medications used to treat migraine and that CBD can cause a condition known as reversible cerebral vasoconstrictive syndrome. These are reasons to be cautious with CBD,” Dr. Ailani added.

“At this time there is limited advice we can give our patients except that more studies need to be done. If cannabis is used, it should be reported, and medications that may interact with cannabis should be avoided. A headache calendar should be kept to ensure frequency of migraine and headache attacks do not go up,” said Dr. Ailani.

The study had no specific funding. Dr. Zhang, Dr. Monteith, and Dr. Ailani have disclosed no relevant financial relationships.

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

SEP-363856, an investigational nondopamine antipsychotic that’s been the focus of a trial in schizophrenia, has shown signals that it may improve psychosis symptoms in patients with Parkinson’s disease without worsening motor symptoms, according to results of a proof-of-principle study presented at the 2021 annual meeting of the American Academy of Neurology.

In presenting study results, Stuart H. Isaacson, MD, of the Parkinson’s Disease and Movement Disorders Center in Boca Raton, Fla., noted the one potential advantage of SEP-363856 is that it does not require blood monitoring, unlike clozapine, often used as an alternative to pimavanserin, the only Food and Drug Administration–approved treatment for Parkinson’s disease psychosis.* Quetiapine has also been used off label for Parkinson’s disease psychosis, but Dr. Isaacson said this lacks the evidence supporting the other two options and has side effects including sedation and orthostatic hypotension.

“Other non–FDA-approved treatment options are limited due to their lack of efficacy, safety concerns, and exacerbation of motor symptoms,” he said.

The study involved 38 patients, 24 of whom received SEP-363856 and the rest placebo, and evaluated total scores for the novel Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis (SAPS-PD) after 6 weeks of treatment. The treatment group was given one of three doses: 25 mg (n = 11), 50 mg (n = 9), and 75 mg (n = 10).

Dr. Isaacson described SEP-363856 as a novel molecule that has agonist activity at TARR1, which regulates dopamine, norepinephrine, and serotonin, as well as serotonin receptor 5-HT1A, but has no activity at the dopamine receptor D₂.

“There did appear to be improvement with this medication in patients’ psychosis symptoms, using the SAPS-PD subscale to identify the frequency and severity of hallucinations and delusions, but there was also improvement in the placebo group in this small study,” Dr. Isaacson said. “That did not demonstrate significance.” The improvement was maintained through the study period.

But the gap between the treatment and placebo groups widened as the degree of response increased. The rates were identical for the 30% or above response and the 50% or above response subgroups: 27.3% and 37.5% for placebo and treatment groups, respectively. However, 25% of patients taking SEP-363856 had a 100% response in terms of SAPS-PD score versus 0% in the placebo group, Dr. Isaacson said.

The study also found Mini-Mental State Examination (MMSE) scores improved more in the treatment group, with the gap wider in those with baseline MMSE scores below 24 versus scores above 24: –5.2 (standard deviation, 2.81) versus –2.1 (SD, 3.00; P = .460).

“The scope of daytime and nighttime sleep both showed improvement, with the score for daytime sleep being significant,” Dr. Isaacson said of the treatment group. “Importantly, UPDRS [Unified Parkinson’s Disease Rating Scale] Part III motor scores showed no difference from placebo. Indeed, there was a trend toward improvement, but this again was not significant.” That’s noteworthy, he said, because other antipsychotics, with the exception of clozapine – which requires blood monitoring – are contraindicated in PDP because of their effect on motor function.

During question-and-answer, Dr. Isaacson noted that the complete response rate of 25% with SEP-363856 compared favorably with the 14% complete response rate reported with pimavanserin in the pivotal trial.

“Hopefully greater-powered studies will be performed to further identify and determine the safety and efficacy and tolerably of SEP-363856 in Parkinson’s psychosis, aiming to minimize the placebo effect and to try to hopefully identify its efficacy in relationship to other treatments,” Dr. Isaacson said.

“Right now with only one approved treatment, one that has efficacy but requires blood monitoring, and another treatment that may be fraught sometimes with sleepiness and other side effects, we need other alternatives for our patients as many of them resort to lowering and lowering their dopaminergic therapies with the consequence [of] worsening motor activity,” Dr. Isaacson said.

“This study further supports the concept that Parkinson’s disease psychosis involves much more than simply dopamine,” said Daniel E. Kremens, MD, codirector of the Parkinson’s disease and movement disorders division at Thomas Jefferson University, Philadelphia. “Targeting nondopaminergic targets allows us to treat the psychosis without worsening motor symptoms. By targeting TAAR-1 along with 5HT1A, SEP-363856 is a novel compound that appears to be well tolerated and may treat PDP without worsening motor symptoms,”

Sunovion Pharmaceuticals provided funding for the study. Dr. Isaacson has no financial relationships to disclose. Three study coauthors are employees of Sunovion. Dr. Kremens reported serving as a consultant to Sunovion.

*Correction, 5/17/21: An earlier version of this article misstated the blood monitoring requirements for pimavanserin.

SEP-363856, an investigational nondopamine antipsychotic that’s been the focus of a trial in schizophrenia, has shown signals that it may improve psychosis symptoms in patients with Parkinson’s disease without worsening motor symptoms, according to results of a proof-of-principle study presented at the 2021 annual meeting of the American Academy of Neurology.

In presenting study results, Stuart H. Isaacson, MD, of the Parkinson’s Disease and Movement Disorders Center in Boca Raton, Fla., noted the one potential advantage of SEP-363856 is that it does not require blood monitoring, unlike clozapine, often used as an alternative to pimavanserin, the only Food and Drug Administration–approved treatment for Parkinson’s disease psychosis.* Quetiapine has also been used off label for Parkinson’s disease psychosis, but Dr. Isaacson said this lacks the evidence supporting the other two options and has side effects including sedation and orthostatic hypotension.

“Other non–FDA-approved treatment options are limited due to their lack of efficacy, safety concerns, and exacerbation of motor symptoms,” he said.

The study involved 38 patients, 24 of whom received SEP-363856 and the rest placebo, and evaluated total scores for the novel Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis (SAPS-PD) after 6 weeks of treatment. The treatment group was given one of three doses: 25 mg (n = 11), 50 mg (n = 9), and 75 mg (n = 10).

Dr. Isaacson described SEP-363856 as a novel molecule that has agonist activity at TARR1, which regulates dopamine, norepinephrine, and serotonin, as well as serotonin receptor 5-HT1A, but has no activity at the dopamine receptor D₂.

“There did appear to be improvement with this medication in patients’ psychosis symptoms, using the SAPS-PD subscale to identify the frequency and severity of hallucinations and delusions, but there was also improvement in the placebo group in this small study,” Dr. Isaacson said. “That did not demonstrate significance.” The improvement was maintained through the study period.

But the gap between the treatment and placebo groups widened as the degree of response increased. The rates were identical for the 30% or above response and the 50% or above response subgroups: 27.3% and 37.5% for placebo and treatment groups, respectively. However, 25% of patients taking SEP-363856 had a 100% response in terms of SAPS-PD score versus 0% in the placebo group, Dr. Isaacson said.

The study also found Mini-Mental State Examination (MMSE) scores improved more in the treatment group, with the gap wider in those with baseline MMSE scores below 24 versus scores above 24: –5.2 (standard deviation, 2.81) versus –2.1 (SD, 3.00; P = .460).

“The scope of daytime and nighttime sleep both showed improvement, with the score for daytime sleep being significant,” Dr. Isaacson said of the treatment group. “Importantly, UPDRS [Unified Parkinson’s Disease Rating Scale] Part III motor scores showed no difference from placebo. Indeed, there was a trend toward improvement, but this again was not significant.” That’s noteworthy, he said, because other antipsychotics, with the exception of clozapine – which requires blood monitoring – are contraindicated in PDP because of their effect on motor function.

During question-and-answer, Dr. Isaacson noted that the complete response rate of 25% with SEP-363856 compared favorably with the 14% complete response rate reported with pimavanserin in the pivotal trial.

“Hopefully greater-powered studies will be performed to further identify and determine the safety and efficacy and tolerably of SEP-363856 in Parkinson’s psychosis, aiming to minimize the placebo effect and to try to hopefully identify its efficacy in relationship to other treatments,” Dr. Isaacson said.

“Right now with only one approved treatment, one that has efficacy but requires blood monitoring, and another treatment that may be fraught sometimes with sleepiness and other side effects, we need other alternatives for our patients as many of them resort to lowering and lowering their dopaminergic therapies with the consequence [of] worsening motor activity,” Dr. Isaacson said.

“This study further supports the concept that Parkinson’s disease psychosis involves much more than simply dopamine,” said Daniel E. Kremens, MD, codirector of the Parkinson’s disease and movement disorders division at Thomas Jefferson University, Philadelphia. “Targeting nondopaminergic targets allows us to treat the psychosis without worsening motor symptoms. By targeting TAAR-1 along with 5HT1A, SEP-363856 is a novel compound that appears to be well tolerated and may treat PDP without worsening motor symptoms,”

Sunovion Pharmaceuticals provided funding for the study. Dr. Isaacson has no financial relationships to disclose. Three study coauthors are employees of Sunovion. Dr. Kremens reported serving as a consultant to Sunovion.

*Correction, 5/17/21: An earlier version of this article misstated the blood monitoring requirements for pimavanserin.

SEP-363856, an investigational nondopamine antipsychotic that’s been the focus of a trial in schizophrenia, has shown signals that it may improve psychosis symptoms in patients with Parkinson’s disease without worsening motor symptoms, according to results of a proof-of-principle study presented at the 2021 annual meeting of the American Academy of Neurology.

In presenting study results, Stuart H. Isaacson, MD, of the Parkinson’s Disease and Movement Disorders Center in Boca Raton, Fla., noted the one potential advantage of SEP-363856 is that it does not require blood monitoring, unlike clozapine, often used as an alternative to pimavanserin, the only Food and Drug Administration–approved treatment for Parkinson’s disease psychosis.* Quetiapine has also been used off label for Parkinson’s disease psychosis, but Dr. Isaacson said this lacks the evidence supporting the other two options and has side effects including sedation and orthostatic hypotension.

“Other non–FDA-approved treatment options are limited due to their lack of efficacy, safety concerns, and exacerbation of motor symptoms,” he said.

The study involved 38 patients, 24 of whom received SEP-363856 and the rest placebo, and evaluated total scores for the novel Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis (SAPS-PD) after 6 weeks of treatment. The treatment group was given one of three doses: 25 mg (n = 11), 50 mg (n = 9), and 75 mg (n = 10).

Dr. Isaacson described SEP-363856 as a novel molecule that has agonist activity at TARR1, which regulates dopamine, norepinephrine, and serotonin, as well as serotonin receptor 5-HT1A, but has no activity at the dopamine receptor D₂.

“There did appear to be improvement with this medication in patients’ psychosis symptoms, using the SAPS-PD subscale to identify the frequency and severity of hallucinations and delusions, but there was also improvement in the placebo group in this small study,” Dr. Isaacson said. “That did not demonstrate significance.” The improvement was maintained through the study period.

But the gap between the treatment and placebo groups widened as the degree of response increased. The rates were identical for the 30% or above response and the 50% or above response subgroups: 27.3% and 37.5% for placebo and treatment groups, respectively. However, 25% of patients taking SEP-363856 had a 100% response in terms of SAPS-PD score versus 0% in the placebo group, Dr. Isaacson said.

The study also found Mini-Mental State Examination (MMSE) scores improved more in the treatment group, with the gap wider in those with baseline MMSE scores below 24 versus scores above 24: –5.2 (standard deviation, 2.81) versus –2.1 (SD, 3.00; P = .460).

“The scope of daytime and nighttime sleep both showed improvement, with the score for daytime sleep being significant,” Dr. Isaacson said of the treatment group. “Importantly, UPDRS [Unified Parkinson’s Disease Rating Scale] Part III motor scores showed no difference from placebo. Indeed, there was a trend toward improvement, but this again was not significant.” That’s noteworthy, he said, because other antipsychotics, with the exception of clozapine – which requires blood monitoring – are contraindicated in PDP because of their effect on motor function.

During question-and-answer, Dr. Isaacson noted that the complete response rate of 25% with SEP-363856 compared favorably with the 14% complete response rate reported with pimavanserin in the pivotal trial.

“Hopefully greater-powered studies will be performed to further identify and determine the safety and efficacy and tolerably of SEP-363856 in Parkinson’s psychosis, aiming to minimize the placebo effect and to try to hopefully identify its efficacy in relationship to other treatments,” Dr. Isaacson said.

“Right now with only one approved treatment, one that has efficacy but requires blood monitoring, and another treatment that may be fraught sometimes with sleepiness and other side effects, we need other alternatives for our patients as many of them resort to lowering and lowering their dopaminergic therapies with the consequence [of] worsening motor activity,” Dr. Isaacson said.

“This study further supports the concept that Parkinson’s disease psychosis involves much more than simply dopamine,” said Daniel E. Kremens, MD, codirector of the Parkinson’s disease and movement disorders division at Thomas Jefferson University, Philadelphia. “Targeting nondopaminergic targets allows us to treat the psychosis without worsening motor symptoms. By targeting TAAR-1 along with 5HT1A, SEP-363856 is a novel compound that appears to be well tolerated and may treat PDP without worsening motor symptoms,”

Sunovion Pharmaceuticals provided funding for the study. Dr. Isaacson has no financial relationships to disclose. Three study coauthors are employees of Sunovion. Dr. Kremens reported serving as a consultant to Sunovion.

*Correction, 5/17/21: An earlier version of this article misstated the blood monitoring requirements for pimavanserin.

A gene therapy strategy has produced impressive results in patients with Sanfilippo syndrome type A (mucopolysaccharidosis IIIA). Most of the benefit from the treatment came in patients who began treatment at younger age, but comparisons to natural history controls showed profound improvement among many recipients, some of whom attained normal developmental trajectories.

The study was presented at the American Academy of Neurology’s 2021 annual meeting by Kevin Flanigan, MD, an attending neurologist at Nationwide Children’s Hospital in Columbus, Ohio. He highlighted the improved developmental outcomes. “There’s been nothing shown to change the cognitive pathway of the disease. This is the first time it’s been seen as a treatment effect,” Dr. Flanigan said during a follow-up Q&A session.

The therapy was delivered using an adeno-associated virus-9 (AAV-9) vector, which led one questioner to ask about potential safety concerns, since AAV-associated risks date back to the death of Jesse Gelsinger in 1999. “There is concern about AAV therapies related to immune responses to potentially complement-mediated activation and thrombocytopenic syndrome, which has led to clinical holds on some other AAV-9 products related to muscular dystrophies. We’ve not seen signals of anything reminiscent of that, and we’re at AAV-9 dosages that are quite similar to what’s been used elsewhere in the field,” said Dr. Flanigan.

The results have him optimistic about the therapy. “I do think if it continues to be increasing divergent from the natural history, it will be questionable as to whether a subsequent trial will be necessary for this. That’s a decision for the [Food and Drug Administration] and the company to decide. Each observation point that goes by, each patient treated, and each time we get more data, I get more and more confident. It’s really gratifying to watch,” said Dr. Flanigan.

The study confirms the potential of gene replacement therapy autosomal recessive conditions, according to Nicholas Johnson, MD, associate professor of neurology at Virginia Commonwealth University, Richmond, as well as a fellow of the American Academy of Neurology. “Where the genetic problem is loss of gene function, the ability to replace that gene using a viral approach is going to be transformative across the board for many of these different conditions, including Sanfilippo syndrome,” said Dr. Johnson, who attended the session but was not involved in the research.

Toxicity could remain an issue, even in the absence of AAV-based safety concerns. “The rate limiting step in terms of gene replacement therapy development likely relates to the ability to provide those therapies to larger adults, because many approaches are weight based and it’s unclear what the upper limit of toxicity would be for adults,” said Dr. Johnson.
 

Transpher A study results

Dr. Flanigan presented results from Transpher A, a phase 1/2 clinical trial that has enrolled 20 patients to date in three cohorts: Cohort 1, with 3 patients, received 5 x 1,012 vg/kg, and had a mean follow-up of 58 months; cohort 2, with 3 patients, received 1 x 1,013 vg/kg, and had a mean follow-up of 49 months; and cohort 3, with 14 patients, received 3 x 1,013 vg/kg, with a mean follow-up of 24 months. Included patients ranged from birth to age 2, or older than age 2 with a development quotient of 60 or higher on the Bayley Scale.

Dr. Flanigan showed a plot of developmental progress compared with natural history controls, which showed that patients treated before age 2 or with a developmental quotient of 60 or higher had improved outcomes compared to other patients in the high dose cohort. They continued to show normal developmental progression at 30-36 months post treatment, at a time when the natural history data suggested they would suffer cognitive decline. Two years after administration, this group had cerebral spinal fluid levels of heparan sulfate that fell below the lower limit of detection. Patients in the high-dose cohort had normalized CSF levels of GM2 and GM3 gangliosides, and there were reductions in plasma heparan sulfate and urinary glycosaminoglycans. There was also a sustained decrease in liver volume.

The highest dose group was originally given to older patients, and most were similar to the natural history cohort, though some did stabilize. “More compellingly, patients (in the high-dose group) who were treated younger actually showed continued increase in development. One individual follows the normal development quotient line, and we would say that these are really quite distinct from what we typically see in patients,” said Dr. Flanigan.

The treatment was well tolerated. There were no deaths or treatment-related serious adverse events, and no clinically-significant adverse events within the first 5 years of follow-up.

The study was funded by Abeona Therapeutics. Dr. Flanigan has been on advisory boards for Apic Bio and 4D Molecular Therapeutics, consulted for Encoded Therapeutics, and has received royalties from Audentes Therapeutics. Dr. Flanigan has received funding from and been a consultant for Avidity.

A gene therapy strategy has produced impressive results in patients with Sanfilippo syndrome type A (mucopolysaccharidosis IIIA). Most of the benefit from the treatment came in patients who began treatment at younger age, but comparisons to natural history controls showed profound improvement among many recipients, some of whom attained normal developmental trajectories.

The study was presented at the American Academy of Neurology’s 2021 annual meeting by Kevin Flanigan, MD, an attending neurologist at Nationwide Children’s Hospital in Columbus, Ohio. He highlighted the improved developmental outcomes. “There’s been nothing shown to change the cognitive pathway of the disease. This is the first time it’s been seen as a treatment effect,” Dr. Flanigan said during a follow-up Q&A session.

The therapy was delivered using an adeno-associated virus-9 (AAV-9) vector, which led one questioner to ask about potential safety concerns, since AAV-associated risks date back to the death of Jesse Gelsinger in 1999. “There is concern about AAV therapies related to immune responses to potentially complement-mediated activation and thrombocytopenic syndrome, which has led to clinical holds on some other AAV-9 products related to muscular dystrophies. We’ve not seen signals of anything reminiscent of that, and we’re at AAV-9 dosages that are quite similar to what’s been used elsewhere in the field,” said Dr. Flanigan.

The results have him optimistic about the therapy. “I do think if it continues to be increasing divergent from the natural history, it will be questionable as to whether a subsequent trial will be necessary for this. That’s a decision for the [Food and Drug Administration] and the company to decide. Each observation point that goes by, each patient treated, and each time we get more data, I get more and more confident. It’s really gratifying to watch,” said Dr. Flanigan.

The study confirms the potential of gene replacement therapy autosomal recessive conditions, according to Nicholas Johnson, MD, associate professor of neurology at Virginia Commonwealth University, Richmond, as well as a fellow of the American Academy of Neurology. “Where the genetic problem is loss of gene function, the ability to replace that gene using a viral approach is going to be transformative across the board for many of these different conditions, including Sanfilippo syndrome,” said Dr. Johnson, who attended the session but was not involved in the research.

Toxicity could remain an issue, even in the absence of AAV-based safety concerns. “The rate limiting step in terms of gene replacement therapy development likely relates to the ability to provide those therapies to larger adults, because many approaches are weight based and it’s unclear what the upper limit of toxicity would be for adults,” said Dr. Johnson.
 

Transpher A study results

Dr. Flanigan presented results from Transpher A, a phase 1/2 clinical trial that has enrolled 20 patients to date in three cohorts: Cohort 1, with 3 patients, received 5 x 1,012 vg/kg, and had a mean follow-up of 58 months; cohort 2, with 3 patients, received 1 x 1,013 vg/kg, and had a mean follow-up of 49 months; and cohort 3, with 14 patients, received 3 x 1,013 vg/kg, with a mean follow-up of 24 months. Included patients ranged from birth to age 2, or older than age 2 with a development quotient of 60 or higher on the Bayley Scale.

Dr. Flanigan showed a plot of developmental progress compared with natural history controls, which showed that patients treated before age 2 or with a developmental quotient of 60 or higher had improved outcomes compared to other patients in the high dose cohort. They continued to show normal developmental progression at 30-36 months post treatment, at a time when the natural history data suggested they would suffer cognitive decline. Two years after administration, this group had cerebral spinal fluid levels of heparan sulfate that fell below the lower limit of detection. Patients in the high-dose cohort had normalized CSF levels of GM2 and GM3 gangliosides, and there were reductions in plasma heparan sulfate and urinary glycosaminoglycans. There was also a sustained decrease in liver volume.

The highest dose group was originally given to older patients, and most were similar to the natural history cohort, though some did stabilize. “More compellingly, patients (in the high-dose group) who were treated younger actually showed continued increase in development. One individual follows the normal development quotient line, and we would say that these are really quite distinct from what we typically see in patients,” said Dr. Flanigan.

The treatment was well tolerated. There were no deaths or treatment-related serious adverse events, and no clinically-significant adverse events within the first 5 years of follow-up.

The study was funded by Abeona Therapeutics. Dr. Flanigan has been on advisory boards for Apic Bio and 4D Molecular Therapeutics, consulted for Encoded Therapeutics, and has received royalties from Audentes Therapeutics. Dr. Flanigan has received funding from and been a consultant for Avidity.

A gene therapy strategy has produced impressive results in patients with Sanfilippo syndrome type A (mucopolysaccharidosis IIIA). Most of the benefit from the treatment came in patients who began treatment at younger age, but comparisons to natural history controls showed profound improvement among many recipients, some of whom attained normal developmental trajectories.

The study was presented at the American Academy of Neurology’s 2021 annual meeting by Kevin Flanigan, MD, an attending neurologist at Nationwide Children’s Hospital in Columbus, Ohio. He highlighted the improved developmental outcomes. “There’s been nothing shown to change the cognitive pathway of the disease. This is the first time it’s been seen as a treatment effect,” Dr. Flanigan said during a follow-up Q&A session.

The therapy was delivered using an adeno-associated virus-9 (AAV-9) vector, which led one questioner to ask about potential safety concerns, since AAV-associated risks date back to the death of Jesse Gelsinger in 1999. “There is concern about AAV therapies related to immune responses to potentially complement-mediated activation and thrombocytopenic syndrome, which has led to clinical holds on some other AAV-9 products related to muscular dystrophies. We’ve not seen signals of anything reminiscent of that, and we’re at AAV-9 dosages that are quite similar to what’s been used elsewhere in the field,” said Dr. Flanigan.

The results have him optimistic about the therapy. “I do think if it continues to be increasing divergent from the natural history, it will be questionable as to whether a subsequent trial will be necessary for this. That’s a decision for the [Food and Drug Administration] and the company to decide. Each observation point that goes by, each patient treated, and each time we get more data, I get more and more confident. It’s really gratifying to watch,” said Dr. Flanigan.

The study confirms the potential of gene replacement therapy autosomal recessive conditions, according to Nicholas Johnson, MD, associate professor of neurology at Virginia Commonwealth University, Richmond, as well as a fellow of the American Academy of Neurology. “Where the genetic problem is loss of gene function, the ability to replace that gene using a viral approach is going to be transformative across the board for many of these different conditions, including Sanfilippo syndrome,” said Dr. Johnson, who attended the session but was not involved in the research.

Toxicity could remain an issue, even in the absence of AAV-based safety concerns. “The rate limiting step in terms of gene replacement therapy development likely relates to the ability to provide those therapies to larger adults, because many approaches are weight based and it’s unclear what the upper limit of toxicity would be for adults,” said Dr. Johnson.
 

Transpher A study results

Dr. Flanigan presented results from Transpher A, a phase 1/2 clinical trial that has enrolled 20 patients to date in three cohorts: Cohort 1, with 3 patients, received 5 x 1,012 vg/kg, and had a mean follow-up of 58 months; cohort 2, with 3 patients, received 1 x 1,013 vg/kg, and had a mean follow-up of 49 months; and cohort 3, with 14 patients, received 3 x 1,013 vg/kg, with a mean follow-up of 24 months. Included patients ranged from birth to age 2, or older than age 2 with a development quotient of 60 or higher on the Bayley Scale.

Dr. Flanigan showed a plot of developmental progress compared with natural history controls, which showed that patients treated before age 2 or with a developmental quotient of 60 or higher had improved outcomes compared to other patients in the high dose cohort. They continued to show normal developmental progression at 30-36 months post treatment, at a time when the natural history data suggested they would suffer cognitive decline. Two years after administration, this group had cerebral spinal fluid levels of heparan sulfate that fell below the lower limit of detection. Patients in the high-dose cohort had normalized CSF levels of GM2 and GM3 gangliosides, and there were reductions in plasma heparan sulfate and urinary glycosaminoglycans. There was also a sustained decrease in liver volume.

The highest dose group was originally given to older patients, and most were similar to the natural history cohort, though some did stabilize. “More compellingly, patients (in the high-dose group) who were treated younger actually showed continued increase in development. One individual follows the normal development quotient line, and we would say that these are really quite distinct from what we typically see in patients,” said Dr. Flanigan.

The treatment was well tolerated. There were no deaths or treatment-related serious adverse events, and no clinically-significant adverse events within the first 5 years of follow-up.

The study was funded by Abeona Therapeutics. Dr. Flanigan has been on advisory boards for Apic Bio and 4D Molecular Therapeutics, consulted for Encoded Therapeutics, and has received royalties from Audentes Therapeutics. Dr. Flanigan has received funding from and been a consultant for Avidity.

Although most patients with chronic inflammatory diseases mounted immune responses after two doses of mRNA-based COVID-19 vaccines, glucocorticoids and B-cell–depleting therapies markedly reduced the response, according to a recently published preprint of a new study.

Mongkolchon Akesin/Getty Images

The study, published on MedRxiv and not yet peer reviewed, involved a prospective look at 133 patients with chronic inflammatory disease (CID) and 53 patients with healthy immune systems at Washington University, St. Louis, and the University of California, San Francisco. It is regarded as the largest and most detailed study yet in how vaccines perform in people with immune-mediated inflammatory disease. The patients were enrolled between December 2020 and March 2021, and the most common diseases were inflammatory bowel disease (32%), rheumatoid arthritis (29%), spondyloarthritis (15%), and systemic lupus erythematosus (11%).
 

A ‘modest’ reduction in antibody response

Senior author Alfred Kim, MD, PhD, of the department of medicine at Washington University, said the overall results so far are encouraging.

“Most patients with an autoimmune disease that are on immunosuppression can mount antibody responses,” he said. “We’re seeing the majority of our subjects respond.”

The immune-healthy controls and most of the patients with CID had a robust immune response against the spike protein, although the CID group had a mean reduction in antibody titers that was three times lower than the controls (P = .0092). The CID group similarly had a 2.7-fold reduction in preventing neutralization, or halting the virus’ ability to infect (P < .0001), researchers reported.

This reduction in response is “modest,” he said.

“Is the level of reduction going to be detrimental for protection? Time will tell,” he said, adding that researchers anticipate that it won’t have a critical effect on protection because responses tended to be within the range of the immunocompetent controls, who themselves had wildly varied antibody titers across a 20-fold range. “ ‘Optimal’ isn’t necessarily the same as ‘sufficient.’ ”
 

Type of medication has big impact on antibody titers

But there was a wide variety of effects on the immune response depending on the medication. Glucorticoids resulted in a response that was 10 times lower than the immune-healthy controls, as well as fewer circulating plasmablasts after vaccination. Researchers found that 98% of controls were seropositive for antibody, compared with 92% of those with CID who were not taking prednisone, and 65% of CID patients on prednisone (P = .0006 and .0115, respectively). Prevention of neutralization of the virus was similarly reduced in those groups, compared with the controls. Dr. Kim noted this was a small sample size, with about 15 patients. These effects were seen regardless of the dose.

“We would’ve anticipated this would have been dose dependent, so this was a little bit surprising,” Dr. Kim said.

B-cell–depleting therapies, such as rituximab (Rituxan) and ocrelizumab (Ocrevus), reduced antibody titers by 36 times, compared with controls (P < .0001), with a similar reduction in preventing infection (P = .0066), the researchers found. The reduction in antibody titers was the most pronounced among those who had received B-cell–depleting therapies within the previous 6 months. Dr. Kim noted this was a small sample size, with about 10 patients.

CID study subjects taking an antimetabolite, including methotrexate, had an average of a two- to threefold reduction in antibody titers and in neutralization (P = .0006). This reduction was greatest with methotrexate, researchers found (P = .0027).

JAK inhibitors also significantly reduced antibody titers (P = .0066), but the reduction in neutralization of the virus was not significant. In addition, researchers found a reduction in antibody titers, the prevention of viral infection, and circulating plasmablasts among those on tumor necrosis factor (TNF) inhibitors, compared with controls, but these were insignificant statistically except for virus neutralization.

Dr. Kim said he hopes the glucocorticoid data spur physicians to try harder to wean patients off the drugs, when possible, in keeping with recommendations already in place.

“The general culture in rheumatology has been very lax about the need to reduce glucocorticoids,” he said. “This reinvigorates that call.” Questions about possible drug holidays from glucocorticoids remain, regarding how long a holiday would be needed, he said. He noted that many patients on glucocorticoids nonetheless mounted responses.

Those on B-cell–depleting therapies present a “much more difficult” question, he said. Some patients possibly could wait a bit longer than their normal, every-6-month schedule, but it’s an individual decision, he said. Since a booster of influenza vaccine has been found to enhance the response even within the 6-month window among ocrelizumab patients, a booster of COVID-19 vaccine might also help, although this remains to be studied.

The study group has already increased its sample size and is looking at adverse reactions and long-term immune responses, Dr. Kim said.

Encouraging, rather than discouraging, results

Leonard Calabrese, DO, professor of medicine at the Cleveland Clinic in Ohio, said the findings shouldn’t discourage clinicians from encouraging vaccination.

“There’s still a preponderance of people who will develop a robust antibody vaccine response,” he said.

He cautioned that the findings look only at antibodies to the spike protein and at plasmablasts. The reduction in these titers is “of concern,” he said, but “we don’t really know with certainty what are the effects of these drugs, and these data are on the overall biologic protective effect of the vaccine. There’s much more to a vaccine response than anti–spike protein and plasmablasts,” including cell-mediated immune response.

For an individual patient, the findings “mean a lot,” he said.

“I think that people who are on significant prednisone and B-cell–depleting agents, I think you have to share with them that there’s a reasonable chance that you’re not going to be making a response similar to healthy people,” he said. “Thus, even with your vaccine, we’re not going to cut you loose to do things that are violating social distancing and group settings. … Should you be hugging your grandchildren if you’re a rituximab vaccine recipient? I think I would wait until we have a little bit more data.”

Kevin Winthrop, MD, MPH, professor of ophthalmology at Oregon Health & Science University, Portland, where he studies vaccinations in the immunocompromised, said that glucocorticoids tend to have little effect on vaccinations generally at low doses.

When effects are seen they can be difficult to interpret, he said.

“It’s hard to extricate that from the effect of the underlying disease,” he said. The drug can be a proxy for worse disease control.

Although it’s a small study, it’s reassuring that overall the responses were similar to healthy controls.

For B-cell–depleting therapies, his usual guidance is to not give vaccine until a patient is at least 3 months out from their last dose, and not to restart until at least 2 weeks after vaccination.

“It’s not surprising that some of these DMARDs [disease-modifying antirheumatic drugs] do negatively affect vaccine response, particularly B-cell–depletion therapy. We need to do some studies to find a way to overcome that, or optimize delivery of the vaccine.”

Dr. Kim reported participating in consulting, advisory board, or speaker’s bureau for Alexion, Aurinia, Annexon Biosciences, Exagen Diagnostics, and GlaxoSmithKline, and receiving funding under a sponsored research agreement unrelated to the data in the paper from GlaxoSmithKline. Dr. Winthrop reported receiving consulting fees from Pfizer, AbbVie, UCB, Eli Lilly, Galapagos, GlaxoSmithKline, Roche, Gilead, Bristol-Myers Squibb, Regeneron, Sanofi, AstraZeneca, Novartis, and research grants from Bristol-Myers Squibb and Pfizer. Dr. Calabrese reported no relevant disclosures.

Although most patients with chronic inflammatory diseases mounted immune responses after two doses of mRNA-based COVID-19 vaccines, glucocorticoids and B-cell–depleting therapies markedly reduced the response, according to a recently published preprint of a new study.

Mongkolchon Akesin/Getty Images

The study, published on MedRxiv and not yet peer reviewed, involved a prospective look at 133 patients with chronic inflammatory disease (CID) and 53 patients with healthy immune systems at Washington University, St. Louis, and the University of California, San Francisco. It is regarded as the largest and most detailed study yet in how vaccines perform in people with immune-mediated inflammatory disease. The patients were enrolled between December 2020 and March 2021, and the most common diseases were inflammatory bowel disease (32%), rheumatoid arthritis (29%), spondyloarthritis (15%), and systemic lupus erythematosus (11%).
 

A ‘modest’ reduction in antibody response

Senior author Alfred Kim, MD, PhD, of the department of medicine at Washington University, said the overall results so far are encouraging.

“Most patients with an autoimmune disease that are on immunosuppression can mount antibody responses,” he said. “We’re seeing the majority of our subjects respond.”

The immune-healthy controls and most of the patients with CID had a robust immune response against the spike protein, although the CID group had a mean reduction in antibody titers that was three times lower than the controls (P = .0092). The CID group similarly had a 2.7-fold reduction in preventing neutralization, or halting the virus’ ability to infect (P < .0001), researchers reported.

This reduction in response is “modest,” he said.

“Is the level of reduction going to be detrimental for protection? Time will tell,” he said, adding that researchers anticipate that it won’t have a critical effect on protection because responses tended to be within the range of the immunocompetent controls, who themselves had wildly varied antibody titers across a 20-fold range. “ ‘Optimal’ isn’t necessarily the same as ‘sufficient.’ ”
 

Type of medication has big impact on antibody titers

But there was a wide variety of effects on the immune response depending on the medication. Glucorticoids resulted in a response that was 10 times lower than the immune-healthy controls, as well as fewer circulating plasmablasts after vaccination. Researchers found that 98% of controls were seropositive for antibody, compared with 92% of those with CID who were not taking prednisone, and 65% of CID patients on prednisone (P = .0006 and .0115, respectively). Prevention of neutralization of the virus was similarly reduced in those groups, compared with the controls. Dr. Kim noted this was a small sample size, with about 15 patients. These effects were seen regardless of the dose.

“We would’ve anticipated this would have been dose dependent, so this was a little bit surprising,” Dr. Kim said.

B-cell–depleting therapies, such as rituximab (Rituxan) and ocrelizumab (Ocrevus), reduced antibody titers by 36 times, compared with controls (P < .0001), with a similar reduction in preventing infection (P = .0066), the researchers found. The reduction in antibody titers was the most pronounced among those who had received B-cell–depleting therapies within the previous 6 months. Dr. Kim noted this was a small sample size, with about 10 patients.

CID study subjects taking an antimetabolite, including methotrexate, had an average of a two- to threefold reduction in antibody titers and in neutralization (P = .0006). This reduction was greatest with methotrexate, researchers found (P = .0027).

JAK inhibitors also significantly reduced antibody titers (P = .0066), but the reduction in neutralization of the virus was not significant. In addition, researchers found a reduction in antibody titers, the prevention of viral infection, and circulating plasmablasts among those on tumor necrosis factor (TNF) inhibitors, compared with controls, but these were insignificant statistically except for virus neutralization.

Dr. Kim said he hopes the glucocorticoid data spur physicians to try harder to wean patients off the drugs, when possible, in keeping with recommendations already in place.

“The general culture in rheumatology has been very lax about the need to reduce glucocorticoids,” he said. “This reinvigorates that call.” Questions about possible drug holidays from glucocorticoids remain, regarding how long a holiday would be needed, he said. He noted that many patients on glucocorticoids nonetheless mounted responses.

Those on B-cell–depleting therapies present a “much more difficult” question, he said. Some patients possibly could wait a bit longer than their normal, every-6-month schedule, but it’s an individual decision, he said. Since a booster of influenza vaccine has been found to enhance the response even within the 6-month window among ocrelizumab patients, a booster of COVID-19 vaccine might also help, although this remains to be studied.

The study group has already increased its sample size and is looking at adverse reactions and long-term immune responses, Dr. Kim said.

Encouraging, rather than discouraging, results

Leonard Calabrese, DO, professor of medicine at the Cleveland Clinic in Ohio, said the findings shouldn’t discourage clinicians from encouraging vaccination.

“There’s still a preponderance of people who will develop a robust antibody vaccine response,” he said.

He cautioned that the findings look only at antibodies to the spike protein and at plasmablasts. The reduction in these titers is “of concern,” he said, but “we don’t really know with certainty what are the effects of these drugs, and these data are on the overall biologic protective effect of the vaccine. There’s much more to a vaccine response than anti–spike protein and plasmablasts,” including cell-mediated immune response.

For an individual patient, the findings “mean a lot,” he said.

“I think that people who are on significant prednisone and B-cell–depleting agents, I think you have to share with them that there’s a reasonable chance that you’re not going to be making a response similar to healthy people,” he said. “Thus, even with your vaccine, we’re not going to cut you loose to do things that are violating social distancing and group settings. … Should you be hugging your grandchildren if you’re a rituximab vaccine recipient? I think I would wait until we have a little bit more data.”

Kevin Winthrop, MD, MPH, professor of ophthalmology at Oregon Health & Science University, Portland, where he studies vaccinations in the immunocompromised, said that glucocorticoids tend to have little effect on vaccinations generally at low doses.

When effects are seen they can be difficult to interpret, he said.

“It’s hard to extricate that from the effect of the underlying disease,” he said. The drug can be a proxy for worse disease control.

Although it’s a small study, it’s reassuring that overall the responses were similar to healthy controls.

For B-cell–depleting therapies, his usual guidance is to not give vaccine until a patient is at least 3 months out from their last dose, and not to restart until at least 2 weeks after vaccination.

“It’s not surprising that some of these DMARDs [disease-modifying antirheumatic drugs] do negatively affect vaccine response, particularly B-cell–depletion therapy. We need to do some studies to find a way to overcome that, or optimize delivery of the vaccine.”

Dr. Kim reported participating in consulting, advisory board, or speaker’s bureau for Alexion, Aurinia, Annexon Biosciences, Exagen Diagnostics, and GlaxoSmithKline, and receiving funding under a sponsored research agreement unrelated to the data in the paper from GlaxoSmithKline. Dr. Winthrop reported receiving consulting fees from Pfizer, AbbVie, UCB, Eli Lilly, Galapagos, GlaxoSmithKline, Roche, Gilead, Bristol-Myers Squibb, Regeneron, Sanofi, AstraZeneca, Novartis, and research grants from Bristol-Myers Squibb and Pfizer. Dr. Calabrese reported no relevant disclosures.

Although most patients with chronic inflammatory diseases mounted immune responses after two doses of mRNA-based COVID-19 vaccines, glucocorticoids and B-cell–depleting therapies markedly reduced the response, according to a recently published preprint of a new study.

Mongkolchon Akesin/Getty Images

The study, published on MedRxiv and not yet peer reviewed, involved a prospective look at 133 patients with chronic inflammatory disease (CID) and 53 patients with healthy immune systems at Washington University, St. Louis, and the University of California, San Francisco. It is regarded as the largest and most detailed study yet in how vaccines perform in people with immune-mediated inflammatory disease. The patients were enrolled between December 2020 and March 2021, and the most common diseases were inflammatory bowel disease (32%), rheumatoid arthritis (29%), spondyloarthritis (15%), and systemic lupus erythematosus (11%).
 

A ‘modest’ reduction in antibody response

Senior author Alfred Kim, MD, PhD, of the department of medicine at Washington University, said the overall results so far are encouraging.

“Most patients with an autoimmune disease that are on immunosuppression can mount antibody responses,” he said. “We’re seeing the majority of our subjects respond.”

The immune-healthy controls and most of the patients with CID had a robust immune response against the spike protein, although the CID group had a mean reduction in antibody titers that was three times lower than the controls (P = .0092). The CID group similarly had a 2.7-fold reduction in preventing neutralization, or halting the virus’ ability to infect (P < .0001), researchers reported.

This reduction in response is “modest,” he said.

“Is the level of reduction going to be detrimental for protection? Time will tell,” he said, adding that researchers anticipate that it won’t have a critical effect on protection because responses tended to be within the range of the immunocompetent controls, who themselves had wildly varied antibody titers across a 20-fold range. “ ‘Optimal’ isn’t necessarily the same as ‘sufficient.’ ”
 

Type of medication has big impact on antibody titers

But there was a wide variety of effects on the immune response depending on the medication. Glucorticoids resulted in a response that was 10 times lower than the immune-healthy controls, as well as fewer circulating plasmablasts after vaccination. Researchers found that 98% of controls were seropositive for antibody, compared with 92% of those with CID who were not taking prednisone, and 65% of CID patients on prednisone (P = .0006 and .0115, respectively). Prevention of neutralization of the virus was similarly reduced in those groups, compared with the controls. Dr. Kim noted this was a small sample size, with about 15 patients. These effects were seen regardless of the dose.

“We would’ve anticipated this would have been dose dependent, so this was a little bit surprising,” Dr. Kim said.

B-cell–depleting therapies, such as rituximab (Rituxan) and ocrelizumab (Ocrevus), reduced antibody titers by 36 times, compared with controls (P < .0001), with a similar reduction in preventing infection (P = .0066), the researchers found. The reduction in antibody titers was the most pronounced among those who had received B-cell–depleting therapies within the previous 6 months. Dr. Kim noted this was a small sample size, with about 10 patients.

CID study subjects taking an antimetabolite, including methotrexate, had an average of a two- to threefold reduction in antibody titers and in neutralization (P = .0006). This reduction was greatest with methotrexate, researchers found (P = .0027).

JAK inhibitors also significantly reduced antibody titers (P = .0066), but the reduction in neutralization of the virus was not significant. In addition, researchers found a reduction in antibody titers, the prevention of viral infection, and circulating plasmablasts among those on tumor necrosis factor (TNF) inhibitors, compared with controls, but these were insignificant statistically except for virus neutralization.

Dr. Kim said he hopes the glucocorticoid data spur physicians to try harder to wean patients off the drugs, when possible, in keeping with recommendations already in place.

“The general culture in rheumatology has been very lax about the need to reduce glucocorticoids,” he said. “This reinvigorates that call.” Questions about possible drug holidays from glucocorticoids remain, regarding how long a holiday would be needed, he said. He noted that many patients on glucocorticoids nonetheless mounted responses.

Those on B-cell–depleting therapies present a “much more difficult” question, he said. Some patients possibly could wait a bit longer than their normal, every-6-month schedule, but it’s an individual decision, he said. Since a booster of influenza vaccine has been found to enhance the response even within the 6-month window among ocrelizumab patients, a booster of COVID-19 vaccine might also help, although this remains to be studied.

The study group has already increased its sample size and is looking at adverse reactions and long-term immune responses, Dr. Kim said.

Encouraging, rather than discouraging, results

Leonard Calabrese, DO, professor of medicine at the Cleveland Clinic in Ohio, said the findings shouldn’t discourage clinicians from encouraging vaccination.

“There’s still a preponderance of people who will develop a robust antibody vaccine response,” he said.

He cautioned that the findings look only at antibodies to the spike protein and at plasmablasts. The reduction in these titers is “of concern,” he said, but “we don’t really know with certainty what are the effects of these drugs, and these data are on the overall biologic protective effect of the vaccine. There’s much more to a vaccine response than anti–spike protein and plasmablasts,” including cell-mediated immune response.

For an individual patient, the findings “mean a lot,” he said.

“I think that people who are on significant prednisone and B-cell–depleting agents, I think you have to share with them that there’s a reasonable chance that you’re not going to be making a response similar to healthy people,” he said. “Thus, even with your vaccine, we’re not going to cut you loose to do things that are violating social distancing and group settings. … Should you be hugging your grandchildren if you’re a rituximab vaccine recipient? I think I would wait until we have a little bit more data.”

Kevin Winthrop, MD, MPH, professor of ophthalmology at Oregon Health & Science University, Portland, where he studies vaccinations in the immunocompromised, said that glucocorticoids tend to have little effect on vaccinations generally at low doses.

When effects are seen they can be difficult to interpret, he said.

“It’s hard to extricate that from the effect of the underlying disease,” he said. The drug can be a proxy for worse disease control.

Although it’s a small study, it’s reassuring that overall the responses were similar to healthy controls.

For B-cell–depleting therapies, his usual guidance is to not give vaccine until a patient is at least 3 months out from their last dose, and not to restart until at least 2 weeks after vaccination.

“It’s not surprising that some of these DMARDs [disease-modifying antirheumatic drugs] do negatively affect vaccine response, particularly B-cell–depletion therapy. We need to do some studies to find a way to overcome that, or optimize delivery of the vaccine.”

Dr. Kim reported participating in consulting, advisory board, or speaker’s bureau for Alexion, Aurinia, Annexon Biosciences, Exagen Diagnostics, and GlaxoSmithKline, and receiving funding under a sponsored research agreement unrelated to the data in the paper from GlaxoSmithKline. Dr. Winthrop reported receiving consulting fees from Pfizer, AbbVie, UCB, Eli Lilly, Galapagos, GlaxoSmithKline, Roche, Gilead, Bristol-Myers Squibb, Regeneron, Sanofi, AstraZeneca, Novartis, and research grants from Bristol-Myers Squibb and Pfizer. Dr. Calabrese reported no relevant disclosures.

Rare is the parent who has never so much as thought about spanking an unruly child. But a new study provides another reason to avoid corporal punishment: Spanking may cause changes in the same areas of a child’s brain that are affected by more severe physical and sexual abuse.

Previous research has consistently found links between spanking and behavioral problems, aggression, depression, and anxiety, says Jorge Cuartas, a doctoral candidate at the Harvard Graduate School of Education and first author of the study. “We wanted to look at one potential mechanism, brain development, that might explain how corporal punishment can impact children’s behavior and cognitive development.”

The study, published in Child Development, used functional MRIs to map brain changes in 147 tweens who’d never experienced physical or sexual abuse. Researchers tracked which parts of the children’s brains activated in response to neutral or fearful facial expressions. When shown pictures of someone looking fearful, kids who reported having been spanked had a larger response in certain parts of the brain than kids who hadn’t been. Those areas drive the response to environmental cues, recognizing threats and reacting to them. If a child’s brain overreacts, behavioral challenges can result.

“We saw those changes in the same areas as more severe forms of abuse or domestic violence. It suggests the difference is of degree rather than type,” Mr. Cuartas says. As far as a child’s brain is concerned, “It’s all violence.”

It’s a significant finding because many parents don’t think of spanking as being violent, says Vincent J. Palusci, MD, a pediatrician and editor-in-chief of the journal Child Maltreatment. “We want to raise kids who are happy and healthy, and many parents who use spanking are doing it with that goal.”
 

Spanking in the U.S.

Around the world, 62 states and countries have outlawed corporal punishment. While the U.S. has no such protections, both the American Academy of Pediatrics and the American Psychological Association have condemned the practice. Acceptance of spanking seems to be shrinking: The percentage of parents in this country who say they spank their children is trending downward. In 1993, 50% of parents surveyed said they did, but by 2017 that number had fallen to 35%. Still far too many, Mr. Cuartas and Dr. Palusci say, but a promising trend.

“While we wouldn’t as parents want to hurt our kids,” Dr. Palusci says, “we need to understand that spanking can be just as bad as things we’d never do.”
 

Discipline vs. punishment

For some parents, it may require a shift in thinking, differentiating between discipline and punishment. “Discipline changes behavior – it teaches positive behavior, empathy, essential social skills. But that’s different from punishment,” Mr. Cuartas says. “That makes somebody feel pain or shame. We have to start thinking about spanking as punishment.”

That can be difficult, especially for adults who’ve been spanked themselves. They may believe that since they turned out fine, spanking must be fine, too. But the study doesn’t suggest that every child who’s spanked will have these difficulties – it just shows they happen, Mr. Cuartas says. “Compare this to smoking. We all know someone who smokes who’s healthy, but that doesn’t mean smoking is good,” he says. “Individual cases aren’t enough to understand whether certain experiences are good or bad.”

Dr. Palusci draws parallels to the advice pregnant women receive about taking medications: If it hasn’t been tested in pregnancy specifically, no amount can be considered safe. “We don’t have the studies to say how much spanking is dangerous, so we have to think that any amount has this potential.”

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

Rare is the parent who has never so much as thought about spanking an unruly child. But a new study provides another reason to avoid corporal punishment: Spanking may cause changes in the same areas of a child’s brain that are affected by more severe physical and sexual abuse.

Previous research has consistently found links between spanking and behavioral problems, aggression, depression, and anxiety, says Jorge Cuartas, a doctoral candidate at the Harvard Graduate School of Education and first author of the study. “We wanted to look at one potential mechanism, brain development, that might explain how corporal punishment can impact children’s behavior and cognitive development.”

The study, published in Child Development, used functional MRIs to map brain changes in 147 tweens who’d never experienced physical or sexual abuse. Researchers tracked which parts of the children’s brains activated in response to neutral or fearful facial expressions. When shown pictures of someone looking fearful, kids who reported having been spanked had a larger response in certain parts of the brain than kids who hadn’t been. Those areas drive the response to environmental cues, recognizing threats and reacting to them. If a child’s brain overreacts, behavioral challenges can result.

“We saw those changes in the same areas as more severe forms of abuse or domestic violence. It suggests the difference is of degree rather than type,” Mr. Cuartas says. As far as a child’s brain is concerned, “It’s all violence.”

It’s a significant finding because many parents don’t think of spanking as being violent, says Vincent J. Palusci, MD, a pediatrician and editor-in-chief of the journal Child Maltreatment. “We want to raise kids who are happy and healthy, and many parents who use spanking are doing it with that goal.”
 

Spanking in the U.S.

Around the world, 62 states and countries have outlawed corporal punishment. While the U.S. has no such protections, both the American Academy of Pediatrics and the American Psychological Association have condemned the practice. Acceptance of spanking seems to be shrinking: The percentage of parents in this country who say they spank their children is trending downward. In 1993, 50% of parents surveyed said they did, but by 2017 that number had fallen to 35%. Still far too many, Mr. Cuartas and Dr. Palusci say, but a promising trend.

“While we wouldn’t as parents want to hurt our kids,” Dr. Palusci says, “we need to understand that spanking can be just as bad as things we’d never do.”
 

Discipline vs. punishment

For some parents, it may require a shift in thinking, differentiating between discipline and punishment. “Discipline changes behavior – it teaches positive behavior, empathy, essential social skills. But that’s different from punishment,” Mr. Cuartas says. “That makes somebody feel pain or shame. We have to start thinking about spanking as punishment.”

That can be difficult, especially for adults who’ve been spanked themselves. They may believe that since they turned out fine, spanking must be fine, too. But the study doesn’t suggest that every child who’s spanked will have these difficulties – it just shows they happen, Mr. Cuartas says. “Compare this to smoking. We all know someone who smokes who’s healthy, but that doesn’t mean smoking is good,” he says. “Individual cases aren’t enough to understand whether certain experiences are good or bad.”

Dr. Palusci draws parallels to the advice pregnant women receive about taking medications: If it hasn’t been tested in pregnancy specifically, no amount can be considered safe. “We don’t have the studies to say how much spanking is dangerous, so we have to think that any amount has this potential.”

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

Rare is the parent who has never so much as thought about spanking an unruly child. But a new study provides another reason to avoid corporal punishment: Spanking may cause changes in the same areas of a child’s brain that are affected by more severe physical and sexual abuse.

Previous research has consistently found links between spanking and behavioral problems, aggression, depression, and anxiety, says Jorge Cuartas, a doctoral candidate at the Harvard Graduate School of Education and first author of the study. “We wanted to look at one potential mechanism, brain development, that might explain how corporal punishment can impact children’s behavior and cognitive development.”

The study, published in Child Development, used functional MRIs to map brain changes in 147 tweens who’d never experienced physical or sexual abuse. Researchers tracked which parts of the children’s brains activated in response to neutral or fearful facial expressions. When shown pictures of someone looking fearful, kids who reported having been spanked had a larger response in certain parts of the brain than kids who hadn’t been. Those areas drive the response to environmental cues, recognizing threats and reacting to them. If a child’s brain overreacts, behavioral challenges can result.

“We saw those changes in the same areas as more severe forms of abuse or domestic violence. It suggests the difference is of degree rather than type,” Mr. Cuartas says. As far as a child’s brain is concerned, “It’s all violence.”

It’s a significant finding because many parents don’t think of spanking as being violent, says Vincent J. Palusci, MD, a pediatrician and editor-in-chief of the journal Child Maltreatment. “We want to raise kids who are happy and healthy, and many parents who use spanking are doing it with that goal.”
 

Spanking in the U.S.

Around the world, 62 states and countries have outlawed corporal punishment. While the U.S. has no such protections, both the American Academy of Pediatrics and the American Psychological Association have condemned the practice. Acceptance of spanking seems to be shrinking: The percentage of parents in this country who say they spank their children is trending downward. In 1993, 50% of parents surveyed said they did, but by 2017 that number had fallen to 35%. Still far too many, Mr. Cuartas and Dr. Palusci say, but a promising trend.

“While we wouldn’t as parents want to hurt our kids,” Dr. Palusci says, “we need to understand that spanking can be just as bad as things we’d never do.”
 

Discipline vs. punishment

For some parents, it may require a shift in thinking, differentiating between discipline and punishment. “Discipline changes behavior – it teaches positive behavior, empathy, essential social skills. But that’s different from punishment,” Mr. Cuartas says. “That makes somebody feel pain or shame. We have to start thinking about spanking as punishment.”

That can be difficult, especially for adults who’ve been spanked themselves. They may believe that since they turned out fine, spanking must be fine, too. But the study doesn’t suggest that every child who’s spanked will have these difficulties – it just shows they happen, Mr. Cuartas says. “Compare this to smoking. We all know someone who smokes who’s healthy, but that doesn’t mean smoking is good,” he says. “Individual cases aren’t enough to understand whether certain experiences are good or bad.”

Dr. Palusci draws parallels to the advice pregnant women receive about taking medications: If it hasn’t been tested in pregnancy specifically, no amount can be considered safe. “We don’t have the studies to say how much spanking is dangerous, so we have to think that any amount has this potential.”

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

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

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

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

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

Two new large international studies have found relatively low rates of stroke in patients hospitalized with COVID-19. One study showed a stroke rate of 2.2% among patients with COVID-19 admitted to intensive care in 52 different countries. Another found a stroke rate of 1.48% in patients hospitalized with COVID-19 from 70 different countries. These researchers also found a reduction in stroke presentations and stroke care during the pandemic.

Both studies will be presented at the American Academy of Neurology’s 2021 annual meeting.

“Stroke has been a known serious complication of COVID-19, with some studies reporting a higher-than-expected occurrence, especially in young people,” said coauthor of the intensive care study, Jonathon Fanning, MBBS, PhD, University of Queensland, Brisbane, Australia.

“However, among the sickest of COVID patients – those admitted to an ICU – our research found that stroke was not a common complication and that ischemic stroke did not increase the risk of death,” he added.
 

Hemorrhagic stroke more common?

In this study, researchers analyzed a database of 2,699 patients who were admitted to the intensive care unit with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke. 

Most of the strokes identified in this cohort were hemorrhagic (46%), with 32% being ischemic and 22% unspecified. Hemorrhagic stroke was associated with a fivefold increased risk for death compared with patients who did not have a stroke. Of those with a hemorrhagic stroke, 72% died, but only 15% died of the stroke. Rather, multiorgan failure was the leading cause of death.

There was no association between ischemic stroke and mortality.

“There is scarce research on new-onset stroke complicating ICU admissions, and many of the limitations of assessing stroke in ICU populations confound the true values and result in variability in reported incidence anywhere from a 1%-4% incidence,” Dr. Fanning said. 

He noted that a  large Korean study had shown a 1.2% rate of stroke in patients without COVID admitted to non-neurologic ICUs. “In light of this, I think this 2% is higher than we would expect in a general ICU population, but in the context of earlier reports of COVID-19–associated risk for stroke, this figure is actually somewhat reassuring,” Dr. Fanning said.  

Asked how this study compared with the large American Heart Association study recently reported that showed an overall rate of ischemic stroke of 0.75%, Dr. Fanning said the two studies reported on different populations, which makes them difficult to compare.

“Our study specifically reports on new-onset stroke complicating ICU admission,” he noted. “The AHA study is a large study of all patients admitted to hospital, but both studies identified less than previous estimates of COVID-related stroke.”
 

Largest sample to date  

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date, was presented at the AAN meeting by Thanh N. Nguyen, MD, a professor at Boston University.

This study has also been published online in Neurology, with first author Raul G. Nogueira, MD, Emory University, Atlanta.  

In this international observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers, there was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1,722) of all stroke admissions, which numbered 52,026.

The researchers identified stroke diagnoses by the International Classification of Diseases, 10th revision, codes and/or classifications in stroke center databases, and rates of stroke hospitalizations and numbers of patients receiving thrombolysis were compared between the first 4 months of the pandemic (March to June 2020) compared with two control 4-month periods.
 

Global decline in stroke care during pandemic

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. The researchers found that there were 91,373 stroke admissions in the 4 months immediately before the pandemic, compared with 80,894 admissions during the first 4 pandemic months, representing an 11.5% decline.

They also report that 13,334 stroke patients received intravenous thrombolysis in the 4 months preceding the pandemic, compared with 11,570 during the first 4 pandemic months, representing a 13.2% drop.

Interhospital transfers after thrombolysis for a higher level of stroke care decreased from 1,337 before the pandemic to 1,178 during the pandemic, a reduction of 11.9%.  

There were greater declines in primary compared with comprehensive stroke centers for stroke hospitalizations (change, –17.3% vs. –10.3%) and for the number of patients receiving thrombolysis (change, –15.5% vs. –12.6%).

The volume of stroke hospitalizations increased by 9.5% in the two later pandemic months (May, June) versus the two earlier months (March, April), with greater recovery in hospitals with lower COVID-19 hospitalization volume, high-volume stroke centers, and comprehensive stroke centers.

Dr. Nguyen suggested that reasons for the reductions in these stroke numbers at the beginning of the pandemic could include a reduction in stroke risk due to a reduction of exposure to other viral infections or patients not presenting to the hospital for fear of contracting the coronavirus.

The higher recovery of stroke volume in high-volume stroke centers and comprehensive stroke centers may represent patients with higher needs – those having more severe strokes – seeking care more frequently than those with milder symptoms, she noted.

“Preserving access to stroke care and emergency stroke care amidst a pandemic is as important as educating patients on the importance of presenting to the hospital in the event of stroke-like symptoms,” Dr. Nguyen concluded.

“We continue to advocate that if a patient has stroke-like symptoms, such as loss of speech, strength, vision, or balance, it is important for the patient to seek medical care as an emergency, as there are treatments that can improve a patient’s ability to recover from disabling stroke in earlier rather than later time windows,” she added.

In the publication, the authors wrote, “Our results concur with other recent reports on the collateral effects of the COVID-19 pandemic on stroke systems of care,” but added that “this is among the first descriptions of the change at a global level, including primary and comprehensive stroke centers.”

They said that hospital access related to high COVID-19 burden was unlikely a factor because the decline was seen in centers with a few or no patients with COVID-19. They suggested that patient fear of contracting coronavirus may have played a role, along with a decrease in presentation of transient ischemic attacks, mild strokes, or moderate strokes, and physical distancing measures may have prevented the timely witnessing of a stroke.

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

Exposure to epidural analgesia during labor did not show a link to a later diagnosis of autism spectrum disorder (ASD) in a population-based cohort study published April 19 in JAMA Pediatrics.

Though the initial analysis showed an association, adjustment for a wide range of demographic, medical, and birth factors eliminated the link. The authors note that their findings contrast with those of a cohort study in California published in the same journal last year.

“It is possible that residual confounding explains this positive association because key perinatal variables, including induction of labor, labor dystocia, and fetal distress, were not included as confounders in that study,” write Elizabeth Wall-Wieler, PhD, of the University of Manitoba in Winnipeg and her colleagues. “To limit potential bias from unmeasured confounders, we included the aforementioned variables within a wide set of potential confounders.”

The researchers analyzed linked datasets from all singleton infants born in a hospital from 2005 to 2016 in Manitoba, Canada, to compare use of epidurals during birth with diagnoses of ASD before 18 months of age. The four data sources included the Statistics Canada, Manitoba Education, Manitoba Families, and Manitoba Health, Seniors and Active Living, which includes the Manitoba Health Insurance Registry, Medical Services, Hospital Abstracts, and Drug Program Information Network. The researchers excluded women with cesarean deliveries because it was not possible to differentiate between scheduled and unscheduled cesarean deliveries.

Among 123,175 children born to mothers with an average age of 28 years, 38.2% had been exposed to epidural analgesia during their labor. Autism diagnoses occurred among 2.1% of those exposed to epidurals and 1.7% of those not exposed to epidurals. After the researchers controlled for a range of potential confounders, the difference became nonsignificant (hazard ratio, 1.08).

The adjusted analysis accounted for mother’s age; high school degree; marital status; neighborhood socioeconomic status; receipt of public assistance during pregnancy; and presence of diabetes, hypertension, anxiety, or depression in the year before the birth. Other covariates included in the adjustment included the following pregnancy factors: “parity, gestational diabetes, gestational hypertension or preeclampsia, self-reported and diagnosed drug use, smoking, alcohol use, premature rupture of membranes, antepartum hemorrhage, infection of the amniotic sac and membrane, urogenital infection, antenatal mental health hospitalization, hypothyroidism, benzodiazepine use, antidepressant use, and antiepileptic use.” The researchers also included birth year, labor induction or augmentation, labor dystocia, fetal distress or macrosomia, gestational age at birth, the infant’s sex, and hospital type.

“There were substantial differences in maternal sociodemographic, preexisting, pregnancy-related, and birth-specific covariates between births who were exposed vs. nonexposed to epidural labor analgesia,” the authors report. “For example, births exposed to epidural labor analgesia were more likely to be nulliparous, have premature rupture of membranes, antepartum hemorrhage, induction of labor, augmentation of labor, and fetal distress.”

To take family history of ASD into account, the researchers also compared siblings who were and were not exposed to an epidural during labor: 80,459 children in the cohort had at least one sibling in it as well. The researchers still found no association between use of an epidural and a subsequent autism diagnosis (HR, 0.97). The authors conducted several sensitivity analyses for first-born children, those with two or more diagnostic codes for ASD on different days, and women with missing data on high school completion or marital status who delivered at 37 weeks of gestation or later; these results consistently showed no association between epidurals and ASD.

The findings are important but unsurprising, said Scott M. Myers, MD, a neurodevelopmental pediatrician and associate professor at the Geisinger Commonwealth School of Medicine’s Autism & Developmental Medicine Institute in Scranton, Pa. Dr. Myers, who was not involved in the study, said it was strengthened by the inclusion of a wide range of covariates and multiple sensitivity analyses.

“It confirms the suspicion of many experts who were skeptical of the association reported previously, that the small increase in ASD in offspring of mothers who had epidural labor analgesia was likely attributable to other factors that differed substantially between the exposed and unexposed groups,” Dr. Myers said in an interview. “The plausibility of exposure to epidural analgesia in labor having a large effect on ASD risk and accounting for changes in ASD prevalence over time is low.”

It’s possible to hypothesize about subgroups that are genetically susceptible to certain environmental risk factors, including epidurals, but such an association should show up in epidemiological research if the subgroup is large enough.

“For example, epidural labor analgesia can prolong labor, and if it were a significant risk factor for ASD, one might expect that longer labor would have been demonstrated to be associated with increased ASD risk, but this has been examined and is not the case,” he said. He also noted that other perinatal factors previously linked to ASD, such as cesarean delivery, may result from a shared factor that affects risk of both ASD and cesarean delivery.

“Although there haven’t been enough systematic postmortem brain studies to be certain that the findings are generalizable, the most consistent neuropathological findings associated with ASD clearly arise long before birth,”Dr. Myers said. “The information I would provide to a concerned pregnant mother is that the current weight of the evidence does not suggest an association between epidural analgesia in labor and increased likelihood of ASD in offspring, much less a causal association.”

Clay Jones, MD, a hospitalist specializing in neonatal-perinatal medicine at Newton (Mass.)–Wellesley Hospital, was not involved in the research and offered a similar assessment of the findings.

“Our understanding of autism is that it is more of a genetic condition which interferes with the organization of brain architecture, so the evidence for any environmental cause would need to be robust for it to change medical practice or our recommendations to the general public,” Dr. Jones said in an interview. Compared to the previous California study, “this new research is larger and better accounts for confounding variables that might increase the risk of a child eventually being diagnosed with autism,” he said.

While recognizing the value in conducting studies to uncover any potential environmental factors contributing to autism diagnoses, Dr. Jones also addressed science communication challenges related to this research.

“While many of these studies are valid early efforts at honing in on potential risk factors, they can be overhyped and lead to increased patient anxiety and potentially harmful changes in behavior,” Dr. Jones said. “There is already a significant amount of pressure for many women to avoid certain safe and effective pain reduction strategies during labor, such as epidural labor analgesia. This pressure is often based on misunderstandings of the risks, pseudoscientific beliefs regarding the benefits of so-called ‘natural childbirth,’ and blatant misogyny. I hope that this new study helps to reassure women that it is okay to request to be more comfortable during their labor experience with the help of epidural labor analgesia.”

The authors of the study also noted the benefits of epidural use during labor.

“It is recognized as the most effective method of providing labor analgesia,” they write. In addition, “the presence of an indwelling epidural catheter allows epidural anesthesia to be administered for an unplanned (intrapartum) cesarean delivery, thus secondarily avoiding any maternal complications or fetal exposure from general anesthesia.”

JAMA Pediatrics editor Dimitri A. Christakis, MD, MPH, wrote his second-ever Editor’s Note about this topic after the journal published two similar studies with different conclusions.

“Because there will never be experimental studies of environmental exposures, we are left with imperfect observational studies that are always at risk for residual confounding, especially when observed effect sizes are small,” Dr. Christakis writes. “Science is an imperfect and iterative process, and our responsibility as journal editors is to manage the process as best we can. Publishing two conflicting studies in such a short time frame serves as testament that we recognize the process for what it is.” His personal opinion is that any association has yet to be definitively established but that the journal will publish the study if a more definitive one is done.

In considering potentially contributing environmental risk factors to ASD, Gillian E. Hanley, PhD, of the University of British Columbia in Vancouver and two colleagues write that “meta-analyses have been unable to identify a single perinatal and neonatal factor associated with ASD risk, although some evidence suggested that exposure to a broad class of conditions such as fetal presentation, umbilical-cord complications, fetal distress, or multiple births, reflecting compromised neonatal health, may increase risk.”

Yet, they add, these studies are inconsistent in their effect size, likely because of differences in study methodology, comparison groups, sample size, diagnostic criteria, and exposure assessment.

“Thus, we continue to ask questions about whether biologically plausible associations exist or whether associations reflect residual confounding related to yet-to-be-determined maternal genetic or environmental factors,” Dr. Hanley and her colleagues write. They discuss precise differences between the California and Manitoba studies and the inevitability of selection bias since people who choose an epidural will differ in other ways from those who don’t.

“Epidural labor analgesia is an extremely effective approach to obstetric analgesia, and we have a collective responsibility to understand whether it is a safe option that sets a healthy developmental pathway well into childhood,” Dr. Hanley and her colleagues conclude. “Women have the right to make a truly informed choice about their pain relief during labor.”

The research was funded by the Canadian Institutes of Health. One author reported receiving personal fees or grants from Aetion, Alosa Foundation, Lilly, GSK, Pacira, and Takeda. No other authors had disclosures. Dr. Jones, Dr. Myers, and the editorial authors had no disclosures.

Exposure to epidural analgesia during labor did not show a link to a later diagnosis of autism spectrum disorder (ASD) in a population-based cohort study published April 19 in JAMA Pediatrics.

Though the initial analysis showed an association, adjustment for a wide range of demographic, medical, and birth factors eliminated the link. The authors note that their findings contrast with those of a cohort study in California published in the same journal last year.

“It is possible that residual confounding explains this positive association because key perinatal variables, including induction of labor, labor dystocia, and fetal distress, were not included as confounders in that study,” write Elizabeth Wall-Wieler, PhD, of the University of Manitoba in Winnipeg and her colleagues. “To limit potential bias from unmeasured confounders, we included the aforementioned variables within a wide set of potential confounders.”

The researchers analyzed linked datasets from all singleton infants born in a hospital from 2005 to 2016 in Manitoba, Canada, to compare use of epidurals during birth with diagnoses of ASD before 18 months of age. The four data sources included the Statistics Canada, Manitoba Education, Manitoba Families, and Manitoba Health, Seniors and Active Living, which includes the Manitoba Health Insurance Registry, Medical Services, Hospital Abstracts, and Drug Program Information Network. The researchers excluded women with cesarean deliveries because it was not possible to differentiate between scheduled and unscheduled cesarean deliveries.

Among 123,175 children born to mothers with an average age of 28 years, 38.2% had been exposed to epidural analgesia during their labor. Autism diagnoses occurred among 2.1% of those exposed to epidurals and 1.7% of those not exposed to epidurals. After the researchers controlled for a range of potential confounders, the difference became nonsignificant (hazard ratio, 1.08).

The adjusted analysis accounted for mother’s age; high school degree; marital status; neighborhood socioeconomic status; receipt of public assistance during pregnancy; and presence of diabetes, hypertension, anxiety, or depression in the year before the birth. Other covariates included in the adjustment included the following pregnancy factors: “parity, gestational diabetes, gestational hypertension or preeclampsia, self-reported and diagnosed drug use, smoking, alcohol use, premature rupture of membranes, antepartum hemorrhage, infection of the amniotic sac and membrane, urogenital infection, antenatal mental health hospitalization, hypothyroidism, benzodiazepine use, antidepressant use, and antiepileptic use.” The researchers also included birth year, labor induction or augmentation, labor dystocia, fetal distress or macrosomia, gestational age at birth, the infant’s sex, and hospital type.

“There were substantial differences in maternal sociodemographic, preexisting, pregnancy-related, and birth-specific covariates between births who were exposed vs. nonexposed to epidural labor analgesia,” the authors report. “For example, births exposed to epidural labor analgesia were more likely to be nulliparous, have premature rupture of membranes, antepartum hemorrhage, induction of labor, augmentation of labor, and fetal distress.”

To take family history of ASD into account, the researchers also compared siblings who were and were not exposed to an epidural during labor: 80,459 children in the cohort had at least one sibling in it as well. The researchers still found no association between use of an epidural and a subsequent autism diagnosis (HR, 0.97). The authors conducted several sensitivity analyses for first-born children, those with two or more diagnostic codes for ASD on different days, and women with missing data on high school completion or marital status who delivered at 37 weeks of gestation or later; these results consistently showed no association between epidurals and ASD.

The findings are important but unsurprising, said Scott M. Myers, MD, a neurodevelopmental pediatrician and associate professor at the Geisinger Commonwealth School of Medicine’s Autism & Developmental Medicine Institute in Scranton, Pa. Dr. Myers, who was not involved in the study, said it was strengthened by the inclusion of a wide range of covariates and multiple sensitivity analyses.

“It confirms the suspicion of many experts who were skeptical of the association reported previously, that the small increase in ASD in offspring of mothers who had epidural labor analgesia was likely attributable to other factors that differed substantially between the exposed and unexposed groups,” Dr. Myers said in an interview. “The plausibility of exposure to epidural analgesia in labor having a large effect on ASD risk and accounting for changes in ASD prevalence over time is low.”

It’s possible to hypothesize about subgroups that are genetically susceptible to certain environmental risk factors, including epidurals, but such an association should show up in epidemiological research if the subgroup is large enough.

“For example, epidural labor analgesia can prolong labor, and if it were a significant risk factor for ASD, one might expect that longer labor would have been demonstrated to be associated with increased ASD risk, but this has been examined and is not the case,” he said. He also noted that other perinatal factors previously linked to ASD, such as cesarean delivery, may result from a shared factor that affects risk of both ASD and cesarean delivery.

“Although there haven’t been enough systematic postmortem brain studies to be certain that the findings are generalizable, the most consistent neuropathological findings associated with ASD clearly arise long before birth,”Dr. Myers said. “The information I would provide to a concerned pregnant mother is that the current weight of the evidence does not suggest an association between epidural analgesia in labor and increased likelihood of ASD in offspring, much less a causal association.”

Clay Jones, MD, a hospitalist specializing in neonatal-perinatal medicine at Newton (Mass.)–Wellesley Hospital, was not involved in the research and offered a similar assessment of the findings.

“Our understanding of autism is that it is more of a genetic condition which interferes with the organization of brain architecture, so the evidence for any environmental cause would need to be robust for it to change medical practice or our recommendations to the general public,” Dr. Jones said in an interview. Compared to the previous California study, “this new research is larger and better accounts for confounding variables that might increase the risk of a child eventually being diagnosed with autism,” he said.

While recognizing the value in conducting studies to uncover any potential environmental factors contributing to autism diagnoses, Dr. Jones also addressed science communication challenges related to this research.

“While many of these studies are valid early efforts at honing in on potential risk factors, they can be overhyped and lead to increased patient anxiety and potentially harmful changes in behavior,” Dr. Jones said. “There is already a significant amount of pressure for many women to avoid certain safe and effective pain reduction strategies during labor, such as epidural labor analgesia. This pressure is often based on misunderstandings of the risks, pseudoscientific beliefs regarding the benefits of so-called ‘natural childbirth,’ and blatant misogyny. I hope that this new study helps to reassure women that it is okay to request to be more comfortable during their labor experience with the help of epidural labor analgesia.”

The authors of the study also noted the benefits of epidural use during labor.

“It is recognized as the most effective method of providing labor analgesia,” they write. In addition, “the presence of an indwelling epidural catheter allows epidural anesthesia to be administered for an unplanned (intrapartum) cesarean delivery, thus secondarily avoiding any maternal complications or fetal exposure from general anesthesia.”

JAMA Pediatrics editor Dimitri A. Christakis, MD, MPH, wrote his second-ever Editor’s Note about this topic after the journal published two similar studies with different conclusions.

“Because there will never be experimental studies of environmental exposures, we are left with imperfect observational studies that are always at risk for residual confounding, especially when observed effect sizes are small,” Dr. Christakis writes. “Science is an imperfect and iterative process, and our responsibility as journal editors is to manage the process as best we can. Publishing two conflicting studies in such a short time frame serves as testament that we recognize the process for what it is.” His personal opinion is that any association has yet to be definitively established but that the journal will publish the study if a more definitive one is done.

In considering potentially contributing environmental risk factors to ASD, Gillian E. Hanley, PhD, of the University of British Columbia in Vancouver and two colleagues write that “meta-analyses have been unable to identify a single perinatal and neonatal factor associated with ASD risk, although some evidence suggested that exposure to a broad class of conditions such as fetal presentation, umbilical-cord complications, fetal distress, or multiple births, reflecting compromised neonatal health, may increase risk.”

Yet, they add, these studies are inconsistent in their effect size, likely because of differences in study methodology, comparison groups, sample size, diagnostic criteria, and exposure assessment.

“Thus, we continue to ask questions about whether biologically plausible associations exist or whether associations reflect residual confounding related to yet-to-be-determined maternal genetic or environmental factors,” Dr. Hanley and her colleagues write. They discuss precise differences between the California and Manitoba studies and the inevitability of selection bias since people who choose an epidural will differ in other ways from those who don’t.

“Epidural labor analgesia is an extremely effective approach to obstetric analgesia, and we have a collective responsibility to understand whether it is a safe option that sets a healthy developmental pathway well into childhood,” Dr. Hanley and her colleagues conclude. “Women have the right to make a truly informed choice about their pain relief during labor.”

The research was funded by the Canadian Institutes of Health. One author reported receiving personal fees or grants from Aetion, Alosa Foundation, Lilly, GSK, Pacira, and Takeda. No other authors had disclosures. Dr. Jones, Dr. Myers, and the editorial authors had no disclosures.

Exposure to epidural analgesia during labor did not show a link to a later diagnosis of autism spectrum disorder (ASD) in a population-based cohort study published April 19 in JAMA Pediatrics.

Though the initial analysis showed an association, adjustment for a wide range of demographic, medical, and birth factors eliminated the link. The authors note that their findings contrast with those of a cohort study in California published in the same journal last year.

“It is possible that residual confounding explains this positive association because key perinatal variables, including induction of labor, labor dystocia, and fetal distress, were not included as confounders in that study,” write Elizabeth Wall-Wieler, PhD, of the University of Manitoba in Winnipeg and her colleagues. “To limit potential bias from unmeasured confounders, we included the aforementioned variables within a wide set of potential confounders.”

The researchers analyzed linked datasets from all singleton infants born in a hospital from 2005 to 2016 in Manitoba, Canada, to compare use of epidurals during birth with diagnoses of ASD before 18 months of age. The four data sources included the Statistics Canada, Manitoba Education, Manitoba Families, and Manitoba Health, Seniors and Active Living, which includes the Manitoba Health Insurance Registry, Medical Services, Hospital Abstracts, and Drug Program Information Network. The researchers excluded women with cesarean deliveries because it was not possible to differentiate between scheduled and unscheduled cesarean deliveries.

Among 123,175 children born to mothers with an average age of 28 years, 38.2% had been exposed to epidural analgesia during their labor. Autism diagnoses occurred among 2.1% of those exposed to epidurals and 1.7% of those not exposed to epidurals. After the researchers controlled for a range of potential confounders, the difference became nonsignificant (hazard ratio, 1.08).

The adjusted analysis accounted for mother’s age; high school degree; marital status; neighborhood socioeconomic status; receipt of public assistance during pregnancy; and presence of diabetes, hypertension, anxiety, or depression in the year before the birth. Other covariates included in the adjustment included the following pregnancy factors: “parity, gestational diabetes, gestational hypertension or preeclampsia, self-reported and diagnosed drug use, smoking, alcohol use, premature rupture of membranes, antepartum hemorrhage, infection of the amniotic sac and membrane, urogenital infection, antenatal mental health hospitalization, hypothyroidism, benzodiazepine use, antidepressant use, and antiepileptic use.” The researchers also included birth year, labor induction or augmentation, labor dystocia, fetal distress or macrosomia, gestational age at birth, the infant’s sex, and hospital type.

“There were substantial differences in maternal sociodemographic, preexisting, pregnancy-related, and birth-specific covariates between births who were exposed vs. nonexposed to epidural labor analgesia,” the authors report. “For example, births exposed to epidural labor analgesia were more likely to be nulliparous, have premature rupture of membranes, antepartum hemorrhage, induction of labor, augmentation of labor, and fetal distress.”

To take family history of ASD into account, the researchers also compared siblings who were and were not exposed to an epidural during labor: 80,459 children in the cohort had at least one sibling in it as well. The researchers still found no association between use of an epidural and a subsequent autism diagnosis (HR, 0.97). The authors conducted several sensitivity analyses for first-born children, those with two or more diagnostic codes for ASD on different days, and women with missing data on high school completion or marital status who delivered at 37 weeks of gestation or later; these results consistently showed no association between epidurals and ASD.

The findings are important but unsurprising, said Scott M. Myers, MD, a neurodevelopmental pediatrician and associate professor at the Geisinger Commonwealth School of Medicine’s Autism & Developmental Medicine Institute in Scranton, Pa. Dr. Myers, who was not involved in the study, said it was strengthened by the inclusion of a wide range of covariates and multiple sensitivity analyses.

“It confirms the suspicion of many experts who were skeptical of the association reported previously, that the small increase in ASD in offspring of mothers who had epidural labor analgesia was likely attributable to other factors that differed substantially between the exposed and unexposed groups,” Dr. Myers said in an interview. “The plausibility of exposure to epidural analgesia in labor having a large effect on ASD risk and accounting for changes in ASD prevalence over time is low.”

It’s possible to hypothesize about subgroups that are genetically susceptible to certain environmental risk factors, including epidurals, but such an association should show up in epidemiological research if the subgroup is large enough.

“For example, epidural labor analgesia can prolong labor, and if it were a significant risk factor for ASD, one might expect that longer labor would have been demonstrated to be associated with increased ASD risk, but this has been examined and is not the case,” he said. He also noted that other perinatal factors previously linked to ASD, such as cesarean delivery, may result from a shared factor that affects risk of both ASD and cesarean delivery.

“Although there haven’t been enough systematic postmortem brain studies to be certain that the findings are generalizable, the most consistent neuropathological findings associated with ASD clearly arise long before birth,”Dr. Myers said. “The information I would provide to a concerned pregnant mother is that the current weight of the evidence does not suggest an association between epidural analgesia in labor and increased likelihood of ASD in offspring, much less a causal association.”

Clay Jones, MD, a hospitalist specializing in neonatal-perinatal medicine at Newton (Mass.)–Wellesley Hospital, was not involved in the research and offered a similar assessment of the findings.

“Our understanding of autism is that it is more of a genetic condition which interferes with the organization of brain architecture, so the evidence for any environmental cause would need to be robust for it to change medical practice or our recommendations to the general public,” Dr. Jones said in an interview. Compared to the previous California study, “this new research is larger and better accounts for confounding variables that might increase the risk of a child eventually being diagnosed with autism,” he said.

While recognizing the value in conducting studies to uncover any potential environmental factors contributing to autism diagnoses, Dr. Jones also addressed science communication challenges related to this research.

“While many of these studies are valid early efforts at honing in on potential risk factors, they can be overhyped and lead to increased patient anxiety and potentially harmful changes in behavior,” Dr. Jones said. “There is already a significant amount of pressure for many women to avoid certain safe and effective pain reduction strategies during labor, such as epidural labor analgesia. This pressure is often based on misunderstandings of the risks, pseudoscientific beliefs regarding the benefits of so-called ‘natural childbirth,’ and blatant misogyny. I hope that this new study helps to reassure women that it is okay to request to be more comfortable during their labor experience with the help of epidural labor analgesia.”

The authors of the study also noted the benefits of epidural use during labor.

“It is recognized as the most effective method of providing labor analgesia,” they write. In addition, “the presence of an indwelling epidural catheter allows epidural anesthesia to be administered for an unplanned (intrapartum) cesarean delivery, thus secondarily avoiding any maternal complications or fetal exposure from general anesthesia.”

JAMA Pediatrics editor Dimitri A. Christakis, MD, MPH, wrote his second-ever Editor’s Note about this topic after the journal published two similar studies with different conclusions.

“Because there will never be experimental studies of environmental exposures, we are left with imperfect observational studies that are always at risk for residual confounding, especially when observed effect sizes are small,” Dr. Christakis writes. “Science is an imperfect and iterative process, and our responsibility as journal editors is to manage the process as best we can. Publishing two conflicting studies in such a short time frame serves as testament that we recognize the process for what it is.” His personal opinion is that any association has yet to be definitively established but that the journal will publish the study if a more definitive one is done.

In considering potentially contributing environmental risk factors to ASD, Gillian E. Hanley, PhD, of the University of British Columbia in Vancouver and two colleagues write that “meta-analyses have been unable to identify a single perinatal and neonatal factor associated with ASD risk, although some evidence suggested that exposure to a broad class of conditions such as fetal presentation, umbilical-cord complications, fetal distress, or multiple births, reflecting compromised neonatal health, may increase risk.”

Yet, they add, these studies are inconsistent in their effect size, likely because of differences in study methodology, comparison groups, sample size, diagnostic criteria, and exposure assessment.

“Thus, we continue to ask questions about whether biologically plausible associations exist or whether associations reflect residual confounding related to yet-to-be-determined maternal genetic or environmental factors,” Dr. Hanley and her colleagues write. They discuss precise differences between the California and Manitoba studies and the inevitability of selection bias since people who choose an epidural will differ in other ways from those who don’t.

“Epidural labor analgesia is an extremely effective approach to obstetric analgesia, and we have a collective responsibility to understand whether it is a safe option that sets a healthy developmental pathway well into childhood,” Dr. Hanley and her colleagues conclude. “Women have the right to make a truly informed choice about their pain relief during labor.”

The research was funded by the Canadian Institutes of Health. One author reported receiving personal fees or grants from Aetion, Alosa Foundation, Lilly, GSK, Pacira, and Takeda. No other authors had disclosures. Dr. Jones, Dr. Myers, and the editorial authors had no disclosures.