Neurology

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.

Myoclonus was diagnosed in about half of hospitalized COVID-19 patients who were evaluated for movement disorders, data from 50 cases show.

Abnormal movements often occur as complications from critical illness, and neurologic consultation can determine whether patients have experienced a seizure or stroke. However, restriction of bedside assessment in the wake of the COVID-19 pandemic increases the risk that abnormal movements will be missed, Jeffrey R. Clark and Eric M. Liotta, MD, of Northwestern University, Chicago, and colleagues wrote.

“Given the limited reports of abnormal movements in hospitalized COVID-19 patients and increased recognition of neurologic manifestations of COVID-19, we sought to examine the frequency and etiology of this finding as an indication of neurologic consultation,” they said.

In a study published in the Journal of the Neurological Sciences, the researchers reviewed data from the first 50 consecutive patients with COVID-19 symptoms who were hospitalized at a single center and underwent neurologic consultation between March 17, 2020, and May 18, 2020.

Overall, 11 patients (22.0%) of patients experienced abnormal movement, and all were admitted to the ICU within 7 days of meeting criteria for severe COVID-19. These patients included nine men and two women with an age range of 36-78 years. The most common comorbidities were obesity, hypertension, diabetes, chronic kidney disease, and coronary artery disease.

Myoclonus (generalized and focal) was the most common abnormal movement, and present in 6 of the 11 patients. Three cases were attributed to high-intensity sedation, and three to toxic-metabolic disturbances. In two patients, abnormal movements were attributed to focal seizures in the setting of encephalopathy, with focal facial twitching. An additional two patients experienced tremors; one showed an acute subdural hemorrhage on CT imaging. The second patient showed no sign of stroke or other abnormality on MRI and the tremor improved during the hospital stay. One patient who experienced abnormal high-amplitude nonrhythmic movements of the lower extremities was diagnosed with serotonin syndrome that resolved after discontinuing high-dose fentanyl.

The study findings were limited by several factors, including the small study population and limited availability of MRI, the researchers noted. Assessing severe COVID-19 cases in the ICU setting presents a challenge because of limited patient participation and the potentially confounding effects of sedation and mechanical ventilation.

However, the results highlight the importance of bedside consultation for neurologic evaluation to implement timely, directed treatments, the researchers said.

“A heightened awareness of abnormal eye movements, or subtle facial tremoring, may be the first steps in recognizing potentially dangerous neurologic manifestations,” and clinicians caring for patients with severe COVID-19 should be able to recognize abnormal movements and seek neurologic consultation when indicated, they emphasized.

The study was supported in part by grants to coauthors Nicholas J. Reish, MD, and Dr. Liotta from the National Institutes of Health. The researchers had no financial conflicts to disclose.

Myoclonus was diagnosed in about half of hospitalized COVID-19 patients who were evaluated for movement disorders, data from 50 cases show.

Abnormal movements often occur as complications from critical illness, and neurologic consultation can determine whether patients have experienced a seizure or stroke. However, restriction of bedside assessment in the wake of the COVID-19 pandemic increases the risk that abnormal movements will be missed, Jeffrey R. Clark and Eric M. Liotta, MD, of Northwestern University, Chicago, and colleagues wrote.

“Given the limited reports of abnormal movements in hospitalized COVID-19 patients and increased recognition of neurologic manifestations of COVID-19, we sought to examine the frequency and etiology of this finding as an indication of neurologic consultation,” they said.

In a study published in the Journal of the Neurological Sciences, the researchers reviewed data from the first 50 consecutive patients with COVID-19 symptoms who were hospitalized at a single center and underwent neurologic consultation between March 17, 2020, and May 18, 2020.

Overall, 11 patients (22.0%) of patients experienced abnormal movement, and all were admitted to the ICU within 7 days of meeting criteria for severe COVID-19. These patients included nine men and two women with an age range of 36-78 years. The most common comorbidities were obesity, hypertension, diabetes, chronic kidney disease, and coronary artery disease.

Myoclonus (generalized and focal) was the most common abnormal movement, and present in 6 of the 11 patients. Three cases were attributed to high-intensity sedation, and three to toxic-metabolic disturbances. In two patients, abnormal movements were attributed to focal seizures in the setting of encephalopathy, with focal facial twitching. An additional two patients experienced tremors; one showed an acute subdural hemorrhage on CT imaging. The second patient showed no sign of stroke or other abnormality on MRI and the tremor improved during the hospital stay. One patient who experienced abnormal high-amplitude nonrhythmic movements of the lower extremities was diagnosed with serotonin syndrome that resolved after discontinuing high-dose fentanyl.

The study findings were limited by several factors, including the small study population and limited availability of MRI, the researchers noted. Assessing severe COVID-19 cases in the ICU setting presents a challenge because of limited patient participation and the potentially confounding effects of sedation and mechanical ventilation.

However, the results highlight the importance of bedside consultation for neurologic evaluation to implement timely, directed treatments, the researchers said.

“A heightened awareness of abnormal eye movements, or subtle facial tremoring, may be the first steps in recognizing potentially dangerous neurologic manifestations,” and clinicians caring for patients with severe COVID-19 should be able to recognize abnormal movements and seek neurologic consultation when indicated, they emphasized.

The study was supported in part by grants to coauthors Nicholas J. Reish, MD, and Dr. Liotta from the National Institutes of Health. The researchers had no financial conflicts to disclose.

Myoclonus was diagnosed in about half of hospitalized COVID-19 patients who were evaluated for movement disorders, data from 50 cases show.

Abnormal movements often occur as complications from critical illness, and neurologic consultation can determine whether patients have experienced a seizure or stroke. However, restriction of bedside assessment in the wake of the COVID-19 pandemic increases the risk that abnormal movements will be missed, Jeffrey R. Clark and Eric M. Liotta, MD, of Northwestern University, Chicago, and colleagues wrote.

“Given the limited reports of abnormal movements in hospitalized COVID-19 patients and increased recognition of neurologic manifestations of COVID-19, we sought to examine the frequency and etiology of this finding as an indication of neurologic consultation,” they said.

In a study published in the Journal of the Neurological Sciences, the researchers reviewed data from the first 50 consecutive patients with COVID-19 symptoms who were hospitalized at a single center and underwent neurologic consultation between March 17, 2020, and May 18, 2020.

Overall, 11 patients (22.0%) of patients experienced abnormal movement, and all were admitted to the ICU within 7 days of meeting criteria for severe COVID-19. These patients included nine men and two women with an age range of 36-78 years. The most common comorbidities were obesity, hypertension, diabetes, chronic kidney disease, and coronary artery disease.

Myoclonus (generalized and focal) was the most common abnormal movement, and present in 6 of the 11 patients. Three cases were attributed to high-intensity sedation, and three to toxic-metabolic disturbances. In two patients, abnormal movements were attributed to focal seizures in the setting of encephalopathy, with focal facial twitching. An additional two patients experienced tremors; one showed an acute subdural hemorrhage on CT imaging. The second patient showed no sign of stroke or other abnormality on MRI and the tremor improved during the hospital stay. One patient who experienced abnormal high-amplitude nonrhythmic movements of the lower extremities was diagnosed with serotonin syndrome that resolved after discontinuing high-dose fentanyl.

The study findings were limited by several factors, including the small study population and limited availability of MRI, the researchers noted. Assessing severe COVID-19 cases in the ICU setting presents a challenge because of limited patient participation and the potentially confounding effects of sedation and mechanical ventilation.

However, the results highlight the importance of bedside consultation for neurologic evaluation to implement timely, directed treatments, the researchers said.

“A heightened awareness of abnormal eye movements, or subtle facial tremoring, may be the first steps in recognizing potentially dangerous neurologic manifestations,” and clinicians caring for patients with severe COVID-19 should be able to recognize abnormal movements and seek neurologic consultation when indicated, they emphasized.

The study was supported in part by grants to coauthors Nicholas J. Reish, MD, and Dr. Liotta from the National Institutes of Health. The researchers had no financial conflicts to disclose.

Cardiologists experienced in cardiac interventions can competently perform stroke thrombectomy after a short period of training, with outcomes comparable to those achieved by neuroradiology centers, a new study suggests.
 

“Using interventional cardiologists in this way will help address the huge unmet need for stroke thrombectomy that currently exists,” senior author Petr Widimsky, MD, said in an interview.

Although this may be a feasible way forward in Europe, there is strong opposition to such a proposal from U.S. neurointerventionalists.  

The study, published in the April 12 issue of JACC: Cardiovascular Interventions, describes the establishment of a stroke thrombectomy program in University Hospital Kralovske Vinohrady, a large tertiary hospital in Prague, Czech Republic.

The hospital did not have a neurointerventional program until 2012 when a joint program was started involving an experienced team of cardiologists, angiologists, and one interventional radiologist who trained the cardiologists on the thrombectomy procedure.

The current paper reports on the outcomes of the 333 patients with large vessel occlusion stroke treated under this program between October 2012 and December 2019.

The decision to perform catheter-based thrombectomy was made by a neurologist and was based on acute stroke clinical symptoms and CT angiographic findings.

Results show that functional clinical outcomes, assessed via the Modified Rankin Scale (mRS) score at 3 months, did not vary significantly across years 2012 to 2019, with a favorable outcome (mRS 0 to 2) achieved in 47.9% of patients.

Symptomatic intracerebral hemorrhage occurred in 19 patients (5.7%) and embolization in a new vascular territory occurred in 6 patients (1.8%), outcomes similar to those of neuroradiology centers.

The desired clinical results were achieved from the onset of the program, without any signs of a learning curve effect, they reported.

“These findings support the potential role of interventional cardiac cath labs in the treatment of acute stroke in regions where this therapy is not readily available due to the lack of neurointerventionalists,” the authors concluded.

“Our main message is that our results were excellent from the beginning,” Dr. Widimsky said. “When centers prepare properly, they can achieve excellent results from the beginning with cardiologists who are experienced in interventional procedures and who have spent sufficient time learning about the brain.”  

The authors noted that despite thrombectomy being an extremely beneficial treatment for severe stroke, many eligible patients remain untreated, largely because of a lack of neurointerventionalists in many regions worldwide. They estimate that about 15% of all stroke patients are eligible for thrombectomy but only around 2% of stroke patients in Europe actually receive such treatment.

Dr. Widimsky, an interventional cardiologist, first thought of the idea of using cardiologists to perform stroke thrombectomies after a good friend and colleague suffered a severe stroke in 2010.

“This made us realize that our hospital needed to be more active in the stroke field,” he said. “We decided that we needed to start doing stroke interventions.”

But the major problem was the lack of neurointerventionalists.

“There are not enough neurointerventionalists in Europe. Interventional cardiologists can perform thousands of procedures every year whereas a neurointerventionalist will at best perform hundreds a year. It is quicker and simpler to train the cardiologist to do it,” Dr. Widimsky said.  

They hired one neurointerventionalist to lead the program. “He was our tutor, he taught us his skills,” Dr. Widimsky said. “The cath lab is open 24/7, but if we only have one neurointerventionalist we cannot offer a 24/7 service for stroke thrombectomy. But if we merge with cardiology then we can,” he added.

Their hospital is a very busy center for myocardial infarction, percutaneous coronary intervention, and carotid stenting, he noted. “It is not difficult to make the step from that to stroke thrombectomy. Interventional cardiologists are used to performing carotid and coronary artery stenting. Stroke thrombectomy is a similar technique. The thrombectomy procedure is different from coronary angioplasty but it is not more difficult.  Actually, I think coronary angioplasty can be more difficult.”  

Dr. Widimsky explained that cardiologists need to learn about the brain anatomy and physiology and learn the stroke imaging techniques. “I spent 1 month in the U.S. learning stroke interventions working with simulators,” he said. “I think interventional cardiologists can learn what they need to know in about 6 months. I would recommend they should watch about 50 procedures and perform at least 25 under supervision.”

He said this model is the way forward and hopes it will become routine. Thrombectomy is “tremendously effective” in improving outcomes in severe strokes, with a number needed to treat (NNT) of just 2.6 to prevent long-term disability in one patient, he said, while other procedures can have NNTs of 50 or more.  

“But millions of patients with acute severe stroke are not getting this life-changing treatment,” he added. “We must do everything we can to make this service available to as many patients as possible.”

Dr. Widimsky acknowledges that there has been opposition to this idea from the neurointerventionalist professional bodies but this has lessened recently, at least in Europe. And a program that allows interventionalists with experience in extracranial carotid and vertebral endovascular procedures to “fast-track” technical training has now been proposed.

“There is an enormous unmet need for stroke thrombectomy in Europe, with some countries needing to increase the number of procedures done by 10 or 20 times. These include the U.K., Sweden, Italy, Spain, and Portugal. This cannot be done without cardiology,” Dr. Widimsky said.  
 

Editorial strongly supportive

An accompanying editorial strongly endorses the idea of using interdisciplinary teams to deliver high standard stroke care.

Marius Hornung, MD, and Horst Sievert, MD, from CardioVascular Center Frankfurt (Germany), point out that many experienced cardiologists are trained in performing carotid artery interventions and are therefore experienced in accessing the supra-aortic arteries.

Ted Bosworth/MDedge News

Opposition in the United States

Dr. Widimsky explained that this proposal may not be so applicable to the United States, where the need for more clinicians capable of performing stroke thrombectomies does not appear to be as critical, possibly because vascular neurosurgeons as well as neuroradiologists are qualified to undertake these procedures.

In an interview, J. Mocco, MD, director of the cerebrovascular center, department of neurological surgery, at Mount Sinai Health System, New York, confirmed that this was the case.

MDedge News

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

Cardiologists experienced in cardiac interventions can competently perform stroke thrombectomy after a short period of training, with outcomes comparable to those achieved by neuroradiology centers, a new study suggests.
 

“Using interventional cardiologists in this way will help address the huge unmet need for stroke thrombectomy that currently exists,” senior author Petr Widimsky, MD, said in an interview.

Although this may be a feasible way forward in Europe, there is strong opposition to such a proposal from U.S. neurointerventionalists.  

The study, published in the April 12 issue of JACC: Cardiovascular Interventions, describes the establishment of a stroke thrombectomy program in University Hospital Kralovske Vinohrady, a large tertiary hospital in Prague, Czech Republic.

The hospital did not have a neurointerventional program until 2012 when a joint program was started involving an experienced team of cardiologists, angiologists, and one interventional radiologist who trained the cardiologists on the thrombectomy procedure.

The current paper reports on the outcomes of the 333 patients with large vessel occlusion stroke treated under this program between October 2012 and December 2019.

The decision to perform catheter-based thrombectomy was made by a neurologist and was based on acute stroke clinical symptoms and CT angiographic findings.

Results show that functional clinical outcomes, assessed via the Modified Rankin Scale (mRS) score at 3 months, did not vary significantly across years 2012 to 2019, with a favorable outcome (mRS 0 to 2) achieved in 47.9% of patients.

Symptomatic intracerebral hemorrhage occurred in 19 patients (5.7%) and embolization in a new vascular territory occurred in 6 patients (1.8%), outcomes similar to those of neuroradiology centers.

The desired clinical results were achieved from the onset of the program, without any signs of a learning curve effect, they reported.

“These findings support the potential role of interventional cardiac cath labs in the treatment of acute stroke in regions where this therapy is not readily available due to the lack of neurointerventionalists,” the authors concluded.

“Our main message is that our results were excellent from the beginning,” Dr. Widimsky said. “When centers prepare properly, they can achieve excellent results from the beginning with cardiologists who are experienced in interventional procedures and who have spent sufficient time learning about the brain.”  

The authors noted that despite thrombectomy being an extremely beneficial treatment for severe stroke, many eligible patients remain untreated, largely because of a lack of neurointerventionalists in many regions worldwide. They estimate that about 15% of all stroke patients are eligible for thrombectomy but only around 2% of stroke patients in Europe actually receive such treatment.

Dr. Widimsky, an interventional cardiologist, first thought of the idea of using cardiologists to perform stroke thrombectomies after a good friend and colleague suffered a severe stroke in 2010.

“This made us realize that our hospital needed to be more active in the stroke field,” he said. “We decided that we needed to start doing stroke interventions.”

But the major problem was the lack of neurointerventionalists.

“There are not enough neurointerventionalists in Europe. Interventional cardiologists can perform thousands of procedures every year whereas a neurointerventionalist will at best perform hundreds a year. It is quicker and simpler to train the cardiologist to do it,” Dr. Widimsky said.  

They hired one neurointerventionalist to lead the program. “He was our tutor, he taught us his skills,” Dr. Widimsky said. “The cath lab is open 24/7, but if we only have one neurointerventionalist we cannot offer a 24/7 service for stroke thrombectomy. But if we merge with cardiology then we can,” he added.

Their hospital is a very busy center for myocardial infarction, percutaneous coronary intervention, and carotid stenting, he noted. “It is not difficult to make the step from that to stroke thrombectomy. Interventional cardiologists are used to performing carotid and coronary artery stenting. Stroke thrombectomy is a similar technique. The thrombectomy procedure is different from coronary angioplasty but it is not more difficult.  Actually, I think coronary angioplasty can be more difficult.”  

Dr. Widimsky explained that cardiologists need to learn about the brain anatomy and physiology and learn the stroke imaging techniques. “I spent 1 month in the U.S. learning stroke interventions working with simulators,” he said. “I think interventional cardiologists can learn what they need to know in about 6 months. I would recommend they should watch about 50 procedures and perform at least 25 under supervision.”

He said this model is the way forward and hopes it will become routine. Thrombectomy is “tremendously effective” in improving outcomes in severe strokes, with a number needed to treat (NNT) of just 2.6 to prevent long-term disability in one patient, he said, while other procedures can have NNTs of 50 or more.  

“But millions of patients with acute severe stroke are not getting this life-changing treatment,” he added. “We must do everything we can to make this service available to as many patients as possible.”

Dr. Widimsky acknowledges that there has been opposition to this idea from the neurointerventionalist professional bodies but this has lessened recently, at least in Europe. And a program that allows interventionalists with experience in extracranial carotid and vertebral endovascular procedures to “fast-track” technical training has now been proposed.

“There is an enormous unmet need for stroke thrombectomy in Europe, with some countries needing to increase the number of procedures done by 10 or 20 times. These include the U.K., Sweden, Italy, Spain, and Portugal. This cannot be done without cardiology,” Dr. Widimsky said.  
 

Editorial strongly supportive

An accompanying editorial strongly endorses the idea of using interdisciplinary teams to deliver high standard stroke care.

Marius Hornung, MD, and Horst Sievert, MD, from CardioVascular Center Frankfurt (Germany), point out that many experienced cardiologists are trained in performing carotid artery interventions and are therefore experienced in accessing the supra-aortic arteries.

Ted Bosworth/MDedge News

Opposition in the United States

Dr. Widimsky explained that this proposal may not be so applicable to the United States, where the need for more clinicians capable of performing stroke thrombectomies does not appear to be as critical, possibly because vascular neurosurgeons as well as neuroradiologists are qualified to undertake these procedures.

In an interview, J. Mocco, MD, director of the cerebrovascular center, department of neurological surgery, at Mount Sinai Health System, New York, confirmed that this was the case.

MDedge News

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

Cardiologists experienced in cardiac interventions can competently perform stroke thrombectomy after a short period of training, with outcomes comparable to those achieved by neuroradiology centers, a new study suggests.
 

“Using interventional cardiologists in this way will help address the huge unmet need for stroke thrombectomy that currently exists,” senior author Petr Widimsky, MD, said in an interview.

Although this may be a feasible way forward in Europe, there is strong opposition to such a proposal from U.S. neurointerventionalists.  

The study, published in the April 12 issue of JACC: Cardiovascular Interventions, describes the establishment of a stroke thrombectomy program in University Hospital Kralovske Vinohrady, a large tertiary hospital in Prague, Czech Republic.

The hospital did not have a neurointerventional program until 2012 when a joint program was started involving an experienced team of cardiologists, angiologists, and one interventional radiologist who trained the cardiologists on the thrombectomy procedure.

The current paper reports on the outcomes of the 333 patients with large vessel occlusion stroke treated under this program between October 2012 and December 2019.

The decision to perform catheter-based thrombectomy was made by a neurologist and was based on acute stroke clinical symptoms and CT angiographic findings.

Results show that functional clinical outcomes, assessed via the Modified Rankin Scale (mRS) score at 3 months, did not vary significantly across years 2012 to 2019, with a favorable outcome (mRS 0 to 2) achieved in 47.9% of patients.

Symptomatic intracerebral hemorrhage occurred in 19 patients (5.7%) and embolization in a new vascular territory occurred in 6 patients (1.8%), outcomes similar to those of neuroradiology centers.

The desired clinical results were achieved from the onset of the program, without any signs of a learning curve effect, they reported.

“These findings support the potential role of interventional cardiac cath labs in the treatment of acute stroke in regions where this therapy is not readily available due to the lack of neurointerventionalists,” the authors concluded.

“Our main message is that our results were excellent from the beginning,” Dr. Widimsky said. “When centers prepare properly, they can achieve excellent results from the beginning with cardiologists who are experienced in interventional procedures and who have spent sufficient time learning about the brain.”  

The authors noted that despite thrombectomy being an extremely beneficial treatment for severe stroke, many eligible patients remain untreated, largely because of a lack of neurointerventionalists in many regions worldwide. They estimate that about 15% of all stroke patients are eligible for thrombectomy but only around 2% of stroke patients in Europe actually receive such treatment.

Dr. Widimsky, an interventional cardiologist, first thought of the idea of using cardiologists to perform stroke thrombectomies after a good friend and colleague suffered a severe stroke in 2010.

“This made us realize that our hospital needed to be more active in the stroke field,” he said. “We decided that we needed to start doing stroke interventions.”

But the major problem was the lack of neurointerventionalists.

“There are not enough neurointerventionalists in Europe. Interventional cardiologists can perform thousands of procedures every year whereas a neurointerventionalist will at best perform hundreds a year. It is quicker and simpler to train the cardiologist to do it,” Dr. Widimsky said.  

They hired one neurointerventionalist to lead the program. “He was our tutor, he taught us his skills,” Dr. Widimsky said. “The cath lab is open 24/7, but if we only have one neurointerventionalist we cannot offer a 24/7 service for stroke thrombectomy. But if we merge with cardiology then we can,” he added.

Their hospital is a very busy center for myocardial infarction, percutaneous coronary intervention, and carotid stenting, he noted. “It is not difficult to make the step from that to stroke thrombectomy. Interventional cardiologists are used to performing carotid and coronary artery stenting. Stroke thrombectomy is a similar technique. The thrombectomy procedure is different from coronary angioplasty but it is not more difficult.  Actually, I think coronary angioplasty can be more difficult.”  

Dr. Widimsky explained that cardiologists need to learn about the brain anatomy and physiology and learn the stroke imaging techniques. “I spent 1 month in the U.S. learning stroke interventions working with simulators,” he said. “I think interventional cardiologists can learn what they need to know in about 6 months. I would recommend they should watch about 50 procedures and perform at least 25 under supervision.”

He said this model is the way forward and hopes it will become routine. Thrombectomy is “tremendously effective” in improving outcomes in severe strokes, with a number needed to treat (NNT) of just 2.6 to prevent long-term disability in one patient, he said, while other procedures can have NNTs of 50 or more.  

“But millions of patients with acute severe stroke are not getting this life-changing treatment,” he added. “We must do everything we can to make this service available to as many patients as possible.”

Dr. Widimsky acknowledges that there has been opposition to this idea from the neurointerventionalist professional bodies but this has lessened recently, at least in Europe. And a program that allows interventionalists with experience in extracranial carotid and vertebral endovascular procedures to “fast-track” technical training has now been proposed.

“There is an enormous unmet need for stroke thrombectomy in Europe, with some countries needing to increase the number of procedures done by 10 or 20 times. These include the U.K., Sweden, Italy, Spain, and Portugal. This cannot be done without cardiology,” Dr. Widimsky said.  
 

Editorial strongly supportive

An accompanying editorial strongly endorses the idea of using interdisciplinary teams to deliver high standard stroke care.

Marius Hornung, MD, and Horst Sievert, MD, from CardioVascular Center Frankfurt (Germany), point out that many experienced cardiologists are trained in performing carotid artery interventions and are therefore experienced in accessing the supra-aortic arteries.

Ted Bosworth/MDedge News

Opposition in the United States

Dr. Widimsky explained that this proposal may not be so applicable to the United States, where the need for more clinicians capable of performing stroke thrombectomies does not appear to be as critical, possibly because vascular neurosurgeons as well as neuroradiologists are qualified to undertake these procedures.

In an interview, J. Mocco, MD, director of the cerebrovascular center, department of neurological surgery, at Mount Sinai Health System, New York, confirmed that this was the case.

MDedge News

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

New Supplement to Federal Practitioner: Advances in Neurology

Read more about:

• Lumbar Fusion With PEEK Rods Use for Patients With Degenerative Disease
• Systemic Literature Review of the Use of Virtual Reality for Rehabilitation in Parkinson Disease
• COVID-19 Vaccine in Veterans With Multiple Sclerosis: Protect the Vulnerable

Click here to read the supplement or click on the image

New Supplement to Federal Practitioner: Advances in Neurology

Read more about:

• Lumbar Fusion With PEEK Rods Use for Patients With Degenerative Disease
• Systemic Literature Review of the Use of Virtual Reality for Rehabilitation in Parkinson Disease
• COVID-19 Vaccine in Veterans With Multiple Sclerosis: Protect the Vulnerable

Click here to read the supplement or click on the image

New Supplement to Federal Practitioner: Advances in Neurology

Read more about:

• Lumbar Fusion With PEEK Rods Use for Patients With Degenerative Disease
• Systemic Literature Review of the Use of Virtual Reality for Rehabilitation in Parkinson Disease
• COVID-19 Vaccine in Veterans With Multiple Sclerosis: Protect the Vulnerable

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An advisory committee to the Centers for Disease Control and Prevention is addressing the safety of the Johnson & Johnson COVID-19 vaccine on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.

This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.

According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.

On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.

In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.

“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness. 

“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.

Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.

Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria. 

This has experts questioning whether all vaccines of this type may cause these rare clots.

“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
 

Adenovirus vaccines scrutinized

Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.

Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses. 

Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system. 

The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.

There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.

The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.

Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans. 

Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.

There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.

Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport. 

But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.

The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1. 

Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.

On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.

The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.

The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.

So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.

A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.

The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.

“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
 

Studies suggest possible mechanism

On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.

The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.

These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.

It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.

The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).

It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.

“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”

No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.

Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising. 
 

Grappling with evidence

The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.

Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.

With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.

They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.

Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.

“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.

“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.

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

An advisory committee to the Centers for Disease Control and Prevention is addressing the safety of the Johnson & Johnson COVID-19 vaccine on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.

This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.

According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.

On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.

In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.

“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness. 

“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.

Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.

Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria. 

This has experts questioning whether all vaccines of this type may cause these rare clots.

“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
 

Adenovirus vaccines scrutinized

Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.

Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses. 

Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system. 

The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.

There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.

The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.

Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans. 

Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.

There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.

Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport. 

But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.

The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1. 

Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.

On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.

The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.

The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.

So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.

A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.

The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.

“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
 

Studies suggest possible mechanism

On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.

The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.

These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.

It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.

The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).

It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.

“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”

No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.

Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising. 
 

Grappling with evidence

The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.

Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.

With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.

They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.

Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.

“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.

“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.

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

An advisory committee to the Centers for Disease Control and Prevention is addressing the safety of the Johnson & Johnson COVID-19 vaccine on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.

This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.

According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.

On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.

In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.

“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness. 

“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.

Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.

Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria. 

This has experts questioning whether all vaccines of this type may cause these rare clots.

“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
 

Adenovirus vaccines scrutinized

Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.

Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses. 

Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system. 

The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.

There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.

The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.

Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans. 

Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.

There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.

Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport. 

But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.

The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1. 

Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.

On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.

The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.

The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.

So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.

A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.

The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.

“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
 

Studies suggest possible mechanism

On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.

The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.

These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.

It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.

The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).

It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.

“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”

No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.

Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising. 
 

Grappling with evidence

The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.

Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.

With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.

They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.

Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.

“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.

“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.

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