Neurology

The nootropic drug piracetam is widely available in dietary supplements marketed for cognitive enhancement, despite the lack of evidence for its efficacy and lack of approval by the U.S. Food and Drug Administration, according to an analysis of products sold online.

Sales of so-called ‘brain enhancement’ supplements exceeded $640 million in 2015 in the United States alone, but little is known about the risks of these dietary supplements, Pieter A. Cohen, MD, of the Cambridge Health Alliance in Somerville, Mass., and his coauthors wrote in a research letter published online Nov. 25 in JAMA Internal Medicine.

Piracetam is prescribed in many European countries for cognitive impairment and other disorders, the authors said. There is limited evidence for its efficacy, and the United States does not permit its sale as a dietary supplement.

Using the search terms “piracetam” and “dietary supplement,” researchers identified five brands of supplements sold online and analyzed 10 samples from these. Their chemical analysis revealed that eight samples from four brands contained piracetam, ranging from 831 mg to 1,452 mg per recommended serving size, and 85%-118% of the amount on the product’s label.

“Our findings demonstrate that, even after the FDA rejected an application to market piracetam as a new supplement ingredient, the drug was nevertheless introduced into the marketplace,” the authors wrote.

The authors calculated that, if consumers followed the recommended dosage on the labels of these products, they could be exposed to up to 11,283 mg of piracetam per day.

For comparison, prescription piracetam in Europe is commonly found in 800-mg and 1,200-mg tablets, and the recommended daily dose for cognitive disorders ranges from 2,400 to 4,800 mg per day, adjusted for renal function.

The authors commented that piracetam is associated with side effects at pharmaceutical dosages, including anxiety, insomnia, agitation, depression, drowsiness, and weight gain. However, the risk associated with higher doses, particularly in the elderly and those with renal insufficiency, are unknown.

“Until the law governing supplements is reformed such that products adulterated with drugs can be effectively removed from the market, clinicians should advise patients that supplements marketed as cognitive enhancers may contain prohibited drugs at supratherapeutic doses,” the authors wrote.

One author declared research support from two organizations unrelated to the study. No conflicts of interest were declared.

SOURCE: Cohen P et al. JAMA Int Med. 2019 Nov 25. doi: 10.1001/jamainternmed.2019.5507.

The nootropic drug piracetam is widely available in dietary supplements marketed for cognitive enhancement, despite the lack of evidence for its efficacy and lack of approval by the U.S. Food and Drug Administration, according to an analysis of products sold online.

Sales of so-called ‘brain enhancement’ supplements exceeded $640 million in 2015 in the United States alone, but little is known about the risks of these dietary supplements, Pieter A. Cohen, MD, of the Cambridge Health Alliance in Somerville, Mass., and his coauthors wrote in a research letter published online Nov. 25 in JAMA Internal Medicine.

Piracetam is prescribed in many European countries for cognitive impairment and other disorders, the authors said. There is limited evidence for its efficacy, and the United States does not permit its sale as a dietary supplement.

Using the search terms “piracetam” and “dietary supplement,” researchers identified five brands of supplements sold online and analyzed 10 samples from these. Their chemical analysis revealed that eight samples from four brands contained piracetam, ranging from 831 mg to 1,452 mg per recommended serving size, and 85%-118% of the amount on the product’s label.

“Our findings demonstrate that, even after the FDA rejected an application to market piracetam as a new supplement ingredient, the drug was nevertheless introduced into the marketplace,” the authors wrote.

The authors calculated that, if consumers followed the recommended dosage on the labels of these products, they could be exposed to up to 11,283 mg of piracetam per day.

For comparison, prescription piracetam in Europe is commonly found in 800-mg and 1,200-mg tablets, and the recommended daily dose for cognitive disorders ranges from 2,400 to 4,800 mg per day, adjusted for renal function.

The authors commented that piracetam is associated with side effects at pharmaceutical dosages, including anxiety, insomnia, agitation, depression, drowsiness, and weight gain. However, the risk associated with higher doses, particularly in the elderly and those with renal insufficiency, are unknown.

“Until the law governing supplements is reformed such that products adulterated with drugs can be effectively removed from the market, clinicians should advise patients that supplements marketed as cognitive enhancers may contain prohibited drugs at supratherapeutic doses,” the authors wrote.

One author declared research support from two organizations unrelated to the study. No conflicts of interest were declared.

SOURCE: Cohen P et al. JAMA Int Med. 2019 Nov 25. doi: 10.1001/jamainternmed.2019.5507.

The nootropic drug piracetam is widely available in dietary supplements marketed for cognitive enhancement, despite the lack of evidence for its efficacy and lack of approval by the U.S. Food and Drug Administration, according to an analysis of products sold online.

Sales of so-called ‘brain enhancement’ supplements exceeded $640 million in 2015 in the United States alone, but little is known about the risks of these dietary supplements, Pieter A. Cohen, MD, of the Cambridge Health Alliance in Somerville, Mass., and his coauthors wrote in a research letter published online Nov. 25 in JAMA Internal Medicine.

Piracetam is prescribed in many European countries for cognitive impairment and other disorders, the authors said. There is limited evidence for its efficacy, and the United States does not permit its sale as a dietary supplement.

Using the search terms “piracetam” and “dietary supplement,” researchers identified five brands of supplements sold online and analyzed 10 samples from these. Their chemical analysis revealed that eight samples from four brands contained piracetam, ranging from 831 mg to 1,452 mg per recommended serving size, and 85%-118% of the amount on the product’s label.

“Our findings demonstrate that, even after the FDA rejected an application to market piracetam as a new supplement ingredient, the drug was nevertheless introduced into the marketplace,” the authors wrote.

The authors calculated that, if consumers followed the recommended dosage on the labels of these products, they could be exposed to up to 11,283 mg of piracetam per day.

For comparison, prescription piracetam in Europe is commonly found in 800-mg and 1,200-mg tablets, and the recommended daily dose for cognitive disorders ranges from 2,400 to 4,800 mg per day, adjusted for renal function.

The authors commented that piracetam is associated with side effects at pharmaceutical dosages, including anxiety, insomnia, agitation, depression, drowsiness, and weight gain. However, the risk associated with higher doses, particularly in the elderly and those with renal insufficiency, are unknown.

“Until the law governing supplements is reformed such that products adulterated with drugs can be effectively removed from the market, clinicians should advise patients that supplements marketed as cognitive enhancers may contain prohibited drugs at supratherapeutic doses,” the authors wrote.

One author declared research support from two organizations unrelated to the study. No conflicts of interest were declared.

SOURCE: Cohen P et al. JAMA Int Med. 2019 Nov 25. doi: 10.1001/jamainternmed.2019.5507.

ST. LOUIS – Dementia and death were about four times more likely after 11 years in patients with Parkinson’s disease and cognitive or psychiatric symptoms at baseline, versus those with motor symptoms alone, according to the results of a longitudinal study of 162 patients at Washington University, St. Louis.

Parkinson’s disease is often only staged as mild, moderate, or severe, and sometimes cognitive and psychiatric symptoms are not assessed. The St. Louis team wanted to see if there are actual subtypes, and if they have clinical relevance, said lead investigator Peter Myers, PhD, a postdoctoral research associate at Washington University.

The magnitude of the findings was “surprising. ... We don’t think we are seeing stages” because the different symptom patterns were apparent at baseline. Instead, “we are seeing really distinct clinical subtypes that could inform patient prognosis and help prepare families and caregivers. It is important that you assess more than just motor symptoms,” he said at the annual meeting of the American Neurological Association.

Some of the subjects were newly diagnosed and others diagnosed years earlier. At baseline, they had symptoms for an average of 6 years, and none had dementia.

After a battery of cognitive, psychiatric, and movement tests, Dr. Myers and his colleagues found that their subjects fell into three patterns: motor symptoms only, with normal cognitive and psychiatric performance (63 subjects); motor symptoms plus prominent anxiety or depression (17); and motor symptoms plus cognitive deficits (82).

A total of 42 patients developed dementia – a score of at least 1 on the Clinical Dementia Rating evaluation – including three in the motor-only group (5%), two in the psychiatric/motor group (12%), and 37 in the cognitive/motor group (45%).

After controlling for age, sex, and symptom duration, the risk of dementia conversion was far higher in the cognitive/motor group (relative risk, 4.16, 95% confidence interval, 1.18-14.65) and psychiatric/motor group (RR, 3.08; 95% CI, 0.72-13.28), compared with motor-only subjects.

Thirty-eight patients died, the majority because of Parkinson’s disease-related causes, including five in the motor-only group (8%), two in the psychiatric/motor group (12%), and 31 in the cognitive/motor group (38%).

The risk of death, relative to motor-only patients, was higher with both the cognitive/motor (RR, 4.06; 95% CI, 1.37-12.03) and psychiatric/motor subtypes (RR, 4.17; 95% CI, 0.70-24.91).

It is unclear what leads to the progression differences, but the researchers’ hypothesis is that the broader scope of symptoms indicates a greater extent of brain pathology. The St. Louis team is looking at brain-imaging data to see if that is true, and if the subtypes can be distinguished on imaging. They are also interested in seeing if genetics plays a role in susceptibility to the different subtypes, and if the baseline subtypes are stable over time or if patients convert between them.

Subjects were, on average, 66 years old, and 62% were men. The mean levodopa-equivalent daily dose was 613 mg in the motor-only group, 1,004 mg in the psychiatric/motor group, and 783 mg in the cognitive/motor group (P = .03). Mean symptom duration was shorter in motor-only patients (5.1 years) versus the psychiatric/motor group (7.2 years) and cognitive/motor group (6.9 years, P less than .01).

Although relative risks crossed 1 in the psychiatric/motor group, it was probably because there were only 17 patients. “We do think there is a very strong likelihood that” the psychiatric/motor findings, like the cognitive/motor findings, “are valid,” Dr. Myer said.

“I think [the findings] could be real,” said Clair Henchcliffe, MD, DPhil, vice chair for clinical research in the department of neurology at Weill Cornell Medical College in New York.

“Other publications have shown that people who have cognitive symptoms at onset are more likely to go on to develop dementia down the line. This is much in line with that,” she said when asked for comment.

The field has “always been interested in finding data that help us personalize treatment, and a lot of people are looking to subtype Parkinson’s disease to help us plan with our patients.” It could also help with frequency of follow-up, trial participation, and maybe someday treatment selection. “We are always thinking a few years ahead” with Parkinson’s disease, she said.

There was no industry funding, and the investigators did not have any relevant disclosures.

[email protected]

ST. LOUIS – Dementia and death were about four times more likely after 11 years in patients with Parkinson’s disease and cognitive or psychiatric symptoms at baseline, versus those with motor symptoms alone, according to the results of a longitudinal study of 162 patients at Washington University, St. Louis.

Parkinson’s disease is often only staged as mild, moderate, or severe, and sometimes cognitive and psychiatric symptoms are not assessed. The St. Louis team wanted to see if there are actual subtypes, and if they have clinical relevance, said lead investigator Peter Myers, PhD, a postdoctoral research associate at Washington University.

The magnitude of the findings was “surprising. ... We don’t think we are seeing stages” because the different symptom patterns were apparent at baseline. Instead, “we are seeing really distinct clinical subtypes that could inform patient prognosis and help prepare families and caregivers. It is important that you assess more than just motor symptoms,” he said at the annual meeting of the American Neurological Association.

Some of the subjects were newly diagnosed and others diagnosed years earlier. At baseline, they had symptoms for an average of 6 years, and none had dementia.

After a battery of cognitive, psychiatric, and movement tests, Dr. Myers and his colleagues found that their subjects fell into three patterns: motor symptoms only, with normal cognitive and psychiatric performance (63 subjects); motor symptoms plus prominent anxiety or depression (17); and motor symptoms plus cognitive deficits (82).

A total of 42 patients developed dementia – a score of at least 1 on the Clinical Dementia Rating evaluation – including three in the motor-only group (5%), two in the psychiatric/motor group (12%), and 37 in the cognitive/motor group (45%).

After controlling for age, sex, and symptom duration, the risk of dementia conversion was far higher in the cognitive/motor group (relative risk, 4.16, 95% confidence interval, 1.18-14.65) and psychiatric/motor group (RR, 3.08; 95% CI, 0.72-13.28), compared with motor-only subjects.

Thirty-eight patients died, the majority because of Parkinson’s disease-related causes, including five in the motor-only group (8%), two in the psychiatric/motor group (12%), and 31 in the cognitive/motor group (38%).

The risk of death, relative to motor-only patients, was higher with both the cognitive/motor (RR, 4.06; 95% CI, 1.37-12.03) and psychiatric/motor subtypes (RR, 4.17; 95% CI, 0.70-24.91).

It is unclear what leads to the progression differences, but the researchers’ hypothesis is that the broader scope of symptoms indicates a greater extent of brain pathology. The St. Louis team is looking at brain-imaging data to see if that is true, and if the subtypes can be distinguished on imaging. They are also interested in seeing if genetics plays a role in susceptibility to the different subtypes, and if the baseline subtypes are stable over time or if patients convert between them.

Subjects were, on average, 66 years old, and 62% were men. The mean levodopa-equivalent daily dose was 613 mg in the motor-only group, 1,004 mg in the psychiatric/motor group, and 783 mg in the cognitive/motor group (P = .03). Mean symptom duration was shorter in motor-only patients (5.1 years) versus the psychiatric/motor group (7.2 years) and cognitive/motor group (6.9 years, P less than .01).

Although relative risks crossed 1 in the psychiatric/motor group, it was probably because there were only 17 patients. “We do think there is a very strong likelihood that” the psychiatric/motor findings, like the cognitive/motor findings, “are valid,” Dr. Myer said.

“I think [the findings] could be real,” said Clair Henchcliffe, MD, DPhil, vice chair for clinical research in the department of neurology at Weill Cornell Medical College in New York.

“Other publications have shown that people who have cognitive symptoms at onset are more likely to go on to develop dementia down the line. This is much in line with that,” she said when asked for comment.

The field has “always been interested in finding data that help us personalize treatment, and a lot of people are looking to subtype Parkinson’s disease to help us plan with our patients.” It could also help with frequency of follow-up, trial participation, and maybe someday treatment selection. “We are always thinking a few years ahead” with Parkinson’s disease, she said.

There was no industry funding, and the investigators did not have any relevant disclosures.

[email protected]

ST. LOUIS – Dementia and death were about four times more likely after 11 years in patients with Parkinson’s disease and cognitive or psychiatric symptoms at baseline, versus those with motor symptoms alone, according to the results of a longitudinal study of 162 patients at Washington University, St. Louis.

Parkinson’s disease is often only staged as mild, moderate, or severe, and sometimes cognitive and psychiatric symptoms are not assessed. The St. Louis team wanted to see if there are actual subtypes, and if they have clinical relevance, said lead investigator Peter Myers, PhD, a postdoctoral research associate at Washington University.

The magnitude of the findings was “surprising. ... We don’t think we are seeing stages” because the different symptom patterns were apparent at baseline. Instead, “we are seeing really distinct clinical subtypes that could inform patient prognosis and help prepare families and caregivers. It is important that you assess more than just motor symptoms,” he said at the annual meeting of the American Neurological Association.

Some of the subjects were newly diagnosed and others diagnosed years earlier. At baseline, they had symptoms for an average of 6 years, and none had dementia.

After a battery of cognitive, psychiatric, and movement tests, Dr. Myers and his colleagues found that their subjects fell into three patterns: motor symptoms only, with normal cognitive and psychiatric performance (63 subjects); motor symptoms plus prominent anxiety or depression (17); and motor symptoms plus cognitive deficits (82).

A total of 42 patients developed dementia – a score of at least 1 on the Clinical Dementia Rating evaluation – including three in the motor-only group (5%), two in the psychiatric/motor group (12%), and 37 in the cognitive/motor group (45%).

After controlling for age, sex, and symptom duration, the risk of dementia conversion was far higher in the cognitive/motor group (relative risk, 4.16, 95% confidence interval, 1.18-14.65) and psychiatric/motor group (RR, 3.08; 95% CI, 0.72-13.28), compared with motor-only subjects.

Thirty-eight patients died, the majority because of Parkinson’s disease-related causes, including five in the motor-only group (8%), two in the psychiatric/motor group (12%), and 31 in the cognitive/motor group (38%).

The risk of death, relative to motor-only patients, was higher with both the cognitive/motor (RR, 4.06; 95% CI, 1.37-12.03) and psychiatric/motor subtypes (RR, 4.17; 95% CI, 0.70-24.91).

It is unclear what leads to the progression differences, but the researchers’ hypothesis is that the broader scope of symptoms indicates a greater extent of brain pathology. The St. Louis team is looking at brain-imaging data to see if that is true, and if the subtypes can be distinguished on imaging. They are also interested in seeing if genetics plays a role in susceptibility to the different subtypes, and if the baseline subtypes are stable over time or if patients convert between them.

Subjects were, on average, 66 years old, and 62% were men. The mean levodopa-equivalent daily dose was 613 mg in the motor-only group, 1,004 mg in the psychiatric/motor group, and 783 mg in the cognitive/motor group (P = .03). Mean symptom duration was shorter in motor-only patients (5.1 years) versus the psychiatric/motor group (7.2 years) and cognitive/motor group (6.9 years, P less than .01).

Although relative risks crossed 1 in the psychiatric/motor group, it was probably because there were only 17 patients. “We do think there is a very strong likelihood that” the psychiatric/motor findings, like the cognitive/motor findings, “are valid,” Dr. Myer said.

“I think [the findings] could be real,” said Clair Henchcliffe, MD, DPhil, vice chair for clinical research in the department of neurology at Weill Cornell Medical College in New York.

“Other publications have shown that people who have cognitive symptoms at onset are more likely to go on to develop dementia down the line. This is much in line with that,” she said when asked for comment.

The field has “always been interested in finding data that help us personalize treatment, and a lot of people are looking to subtype Parkinson’s disease to help us plan with our patients.” It could also help with frequency of follow-up, trial participation, and maybe someday treatment selection. “We are always thinking a few years ahead” with Parkinson’s disease, she said.

There was no industry funding, and the investigators did not have any relevant disclosures.

[email protected]

The Food and Drug Administration has approved cenobamate (Xcopri) for the treatment of partial-onset seizures in adult patients with epilepsy.

The approval on Nov. 21 was based on results from two randomized controlled trials that included more than 600 patients, the agency said in a press release.

Together, the trials showed that the study drug at doses of 100, 200, and 400 mg significantly reduced the percentage of seizures, compared with placebo.

The FDA notes that, although the recommended maintenance dose of the drug is 200 mg/day after titration, some patients may need to be titrated up to 400 mg/day.

“Xcopri is a new option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life,” Billy Dunn, MD, director of the Office of Neuroscience in the Center for Drug Evaluation and Research at the FDA, said in a statement.
 

Adverse events

As reported by Medscape Medical News, results from one of the studies upon which this approval was based were published online last week in Lancet Neurology. The findings showed that both primary endpoints were met.

Although most treatment-emergent adverse events (AEs) were reported to be mild to moderate in severity, one of these participants receiving the 200 mg dose had a drug reaction with eosinophilia and systemic symptoms (DRESS).

The FDA noted that one patient in the other trial also died when the active drug was titrated rapidly.

In an open-label safety trial of 1,339 participants that was also reviewed by the FDA, there were no cases of DRESS when patients started cenobamate at 12.5 mg/day and the dose was adjusted every 2 weeks.

Because more patients who took the drug than those taking placebo had a shortening of the QT interval greater than 20 milliseconds, cenobamate shouldn’t be used in those with hypersensitivity to the drug “or any of the inactive ingredients in Xcopri or Familial Short QT syndrome,” the agency wrote, adding that QT shortening can be associated with ventricular fibrillation, a serious heart rhythm problem.

The FDA also noted that any patient taking an antiepileptic drug should be monitored for the emergence or worsening of depressive symptoms, suicidal thoughts or behaviors, or any other changes in mood.

The most common AEs reported in the trials were somnolence, dizziness, fatigue, and diplopia (double vision).
 

‘Welcome option’

“The approval of Xcopri will provide clinicians with an effective medication for our patients who are continuing to have focal [partial-onset] seizures,” Michael Sperling, MD, professor of neurology and director of the Jefferson Comprehensive Epilepsy Center, Philadelphia, and an investigator in the drug’s clinical development program, said in a press release from SK Life Science.

“It is very encouraging to see that patients receiving Xcopri saw significant reductions in frequency of seizures, with some even achieving zero seizures,” Dr. Sperling added.

“There is an urgent need to advance research and introduce new treatment options. The FDA approval of Xcopri for the treatment of partial-onset seizures is a welcome option for the epilepsy community,” Beth Lewin Dean, chief executive officer of Citizens United for Research in Epilepsy, said in the same release.

SK Life Science noted in a statement that the drug is expected to be available in the United States in the second quarter of 2020 “following scheduling review” by the Drug Enforcement Administration.
 

This story first appeared on Medscape.com.

The Food and Drug Administration has approved cenobamate (Xcopri) for the treatment of partial-onset seizures in adult patients with epilepsy.

The approval on Nov. 21 was based on results from two randomized controlled trials that included more than 600 patients, the agency said in a press release.

Together, the trials showed that the study drug at doses of 100, 200, and 400 mg significantly reduced the percentage of seizures, compared with placebo.

The FDA notes that, although the recommended maintenance dose of the drug is 200 mg/day after titration, some patients may need to be titrated up to 400 mg/day.

“Xcopri is a new option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life,” Billy Dunn, MD, director of the Office of Neuroscience in the Center for Drug Evaluation and Research at the FDA, said in a statement.
 

Adverse events

As reported by Medscape Medical News, results from one of the studies upon which this approval was based were published online last week in Lancet Neurology. The findings showed that both primary endpoints were met.

Although most treatment-emergent adverse events (AEs) were reported to be mild to moderate in severity, one of these participants receiving the 200 mg dose had a drug reaction with eosinophilia and systemic symptoms (DRESS).

The FDA noted that one patient in the other trial also died when the active drug was titrated rapidly.

In an open-label safety trial of 1,339 participants that was also reviewed by the FDA, there were no cases of DRESS when patients started cenobamate at 12.5 mg/day and the dose was adjusted every 2 weeks.

Because more patients who took the drug than those taking placebo had a shortening of the QT interval greater than 20 milliseconds, cenobamate shouldn’t be used in those with hypersensitivity to the drug “or any of the inactive ingredients in Xcopri or Familial Short QT syndrome,” the agency wrote, adding that QT shortening can be associated with ventricular fibrillation, a serious heart rhythm problem.

The FDA also noted that any patient taking an antiepileptic drug should be monitored for the emergence or worsening of depressive symptoms, suicidal thoughts or behaviors, or any other changes in mood.

The most common AEs reported in the trials were somnolence, dizziness, fatigue, and diplopia (double vision).
 

‘Welcome option’

“The approval of Xcopri will provide clinicians with an effective medication for our patients who are continuing to have focal [partial-onset] seizures,” Michael Sperling, MD, professor of neurology and director of the Jefferson Comprehensive Epilepsy Center, Philadelphia, and an investigator in the drug’s clinical development program, said in a press release from SK Life Science.

“It is very encouraging to see that patients receiving Xcopri saw significant reductions in frequency of seizures, with some even achieving zero seizures,” Dr. Sperling added.

“There is an urgent need to advance research and introduce new treatment options. The FDA approval of Xcopri for the treatment of partial-onset seizures is a welcome option for the epilepsy community,” Beth Lewin Dean, chief executive officer of Citizens United for Research in Epilepsy, said in the same release.

SK Life Science noted in a statement that the drug is expected to be available in the United States in the second quarter of 2020 “following scheduling review” by the Drug Enforcement Administration.
 

This story first appeared on Medscape.com.

The Food and Drug Administration has approved cenobamate (Xcopri) for the treatment of partial-onset seizures in adult patients with epilepsy.

The approval on Nov. 21 was based on results from two randomized controlled trials that included more than 600 patients, the agency said in a press release.

Together, the trials showed that the study drug at doses of 100, 200, and 400 mg significantly reduced the percentage of seizures, compared with placebo.

The FDA notes that, although the recommended maintenance dose of the drug is 200 mg/day after titration, some patients may need to be titrated up to 400 mg/day.

“Xcopri is a new option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life,” Billy Dunn, MD, director of the Office of Neuroscience in the Center for Drug Evaluation and Research at the FDA, said in a statement.
 

Adverse events

As reported by Medscape Medical News, results from one of the studies upon which this approval was based were published online last week in Lancet Neurology. The findings showed that both primary endpoints were met.

Although most treatment-emergent adverse events (AEs) were reported to be mild to moderate in severity, one of these participants receiving the 200 mg dose had a drug reaction with eosinophilia and systemic symptoms (DRESS).

The FDA noted that one patient in the other trial also died when the active drug was titrated rapidly.

In an open-label safety trial of 1,339 participants that was also reviewed by the FDA, there were no cases of DRESS when patients started cenobamate at 12.5 mg/day and the dose was adjusted every 2 weeks.

Because more patients who took the drug than those taking placebo had a shortening of the QT interval greater than 20 milliseconds, cenobamate shouldn’t be used in those with hypersensitivity to the drug “or any of the inactive ingredients in Xcopri or Familial Short QT syndrome,” the agency wrote, adding that QT shortening can be associated with ventricular fibrillation, a serious heart rhythm problem.

The FDA also noted that any patient taking an antiepileptic drug should be monitored for the emergence or worsening of depressive symptoms, suicidal thoughts or behaviors, or any other changes in mood.

The most common AEs reported in the trials were somnolence, dizziness, fatigue, and diplopia (double vision).
 

‘Welcome option’

“The approval of Xcopri will provide clinicians with an effective medication for our patients who are continuing to have focal [partial-onset] seizures,” Michael Sperling, MD, professor of neurology and director of the Jefferson Comprehensive Epilepsy Center, Philadelphia, and an investigator in the drug’s clinical development program, said in a press release from SK Life Science.

“It is very encouraging to see that patients receiving Xcopri saw significant reductions in frequency of seizures, with some even achieving zero seizures,” Dr. Sperling added.

“There is an urgent need to advance research and introduce new treatment options. The FDA approval of Xcopri for the treatment of partial-onset seizures is a welcome option for the epilepsy community,” Beth Lewin Dean, chief executive officer of Citizens United for Research in Epilepsy, said in the same release.

SK Life Science noted in a statement that the drug is expected to be available in the United States in the second quarter of 2020 “following scheduling review” by the Drug Enforcement Administration.
 

This story first appeared on Medscape.com.

Ubrogepant, an oral calcitonin gene–related peptide (CGRP)–receptor antagonist, may relieve patients’ migraine pain and their most bothersome associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours after acute treatment, according to phase 3 trial results published Nov. 19 in JAMA.

“Among adults with migraine, acute treatment with ubrogepant, compared with placebo, led to significantly greater rates of pain freedom at 2 hours with the 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose,” wrote first author Richard B. Lipton, MD, director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, and his colleagues. “Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations.”

A researcher who commented on the results said that the drug appears “modestly better than placebo” and called for a trial comparing ubrogepant, aspirin, and oral sumatriptan.

The Food and Drug Administration is reviewing an application for ubrogepant. Allergan, the company developing the drug, has said it expects a regulatory decision in December.
 

ACHIEVE II

To evaluate the efficacy and tolerability of ubrogepant versus placebo for the acute treatment of a migraine attack, investigators conducted ACHIEVE II, a randomized, double-blind, placebo-controlled, single-attack clinical trial. The study was conducted at 99 primary care and research clinics during 2016-2018.

The trial included adults with migraine with or without aura who experienced two to eight migraine attacks per month. Participants had a mean age of 41.5 years, and 90% were female. The safety analysis included data from 1,465 participants, and the efficacy analysis included data from 1,355 participants. The primary efficacy outcomes were pain freedom and the absence of participants’ most bothersome migraine-associated symptom at 2 hours after taking the medication. Patients received ubrogepant 50 mg, ubrogepant 25 mg, or placebo to treat a migraine attack of moderate or severe pain intensity.

At 2 hours, pain freedom was reported by 101 of 464 participants in the ubrogepant 50-mg group (21.8%), 90 of 435 in the ubrogepant 25-mg group (20.7%), and 65 of 456 in the placebo group (14.3%). Absence of the most bothersome symptom was reported by 180 of 463 participants in the ubrogepant 50-mg group (38.9%), 148 of 434 in the ubrogepant 25-mg group (34.1%), and 125 of 456 in the placebo group (27.4%).

The most common adverse events within 48 hours were nausea and dizziness. Nausea occurred in 2.0% of the 50-mg group, 2.5% of the 25-mg group, and 2.0% of the placebo group. Dizziness occurred in 1.4% of the 50-mg group, 2.1% of the 25-mg group, and 1.6% of the placebo group.

At conferences, researchers have presented results from the phase 3 ACHIEVE I trial as well as an analysis that suggests ubrogepant may be effective in patients for whom triptans have been ineffective. In addition, studies have supported the safety of “gepants” after earlier concerns about potential liver toxicity. Physicians have called the safety data reassuring.

The ACHIEVE II trial was sponsored by Allergan. Several authors are Allergan employees. Dr. Lipton is a consultant, advisory board member, or has received honoraria from Allergan and other companies.

 

Number needed to treat

“The study was large, appears to have been well conducted, is clearly reported, and used appropriate outcome measures,” said Elizabeth Loder, MD, commenting on the trial.

A year ago, Dr. Loder, chief of the division of headache at Brigham and Women’s Hospital and professor of neurology at Harvard Medical School in Boston, coauthored a paper with Peer Tfelt-Hansen, MD, DMSc, of the University of Copenhagen, that said the phase 3 trials of gepants so far have found the drugs to have small effect sizes and low efficacy (Headache. 2019 Jan;59[1]:113-7. doi: 10.1111/head.13444).

Their publication included preliminary figures from ACHIEVE II, which are consistent with those published in JAMA. “The effect size for both doses of ubrogepant is small and of debatable clinical significance,” Dr. Loder said. “The therapeutic gain over placebo is 7.5% for the 50-mg dose and 6.4% for the 25-mg dose for the outcome of pain freedom at 2 hours. That corresponds to a number needed to treat of 13 and 15.6 people, respectively, in order to have one person achieve pain freedom at 2 hours that is attributable to the active treatment.”

For a secondary outcome of pain relief at 2 hours, defined as reduction of headache pain severity from moderate or severe to mild or none, the therapeutic gain versus placebo is 14.5% for the 50-mg dose and 12.3% for the 25-mg dose. “That corresponds to a number needed to treat of 6.8 and 8.1 people, respectively, to have one person achieve pain relief at 2 hours attributable to the drug,” Dr. Loder said.

“Although there are no head to head studies comparing ubrogepant to triptans, for reference the [number needed to treat] for a 100-mg oral dose of sumatriptan is on the order of 3.5 for pain relief at 2 hours, meaning that one needs to treat just 3.5 people with sumatriptan in order to have one person achieve pain relief at 2 hours attributable to the drug,” she said (Cochrane Database Syst Rev. 2014;5:CD009108. doi: 10.1002/14651858.CD009108.pub2).

“The bottom line is that in the ACHIEVE II study, ubrogepant appears, on average, to be modestly better than placebo to treat migraine. It does not appear to be in the same league as sumatriptan. Instead, as Dr. Tfelt-Hansen and I said in our article, the results look comparable to those likely to be achieved with inexpensive nonprescription medications such as NSAIDs.”

Dr. Loder called for a trial comparing ubrogepant and other therapies. “I challenge the authors and the company to conduct a large, placebo-controlled trial comparing ubrogepant to 100 mg of oral sumatriptan and to 650 mg of aspirin,” Dr. Loder said.

Dr. Loder has no financial connections with any pharmaceutical or device companies and is paid for her work as the head of research for the British Medical Journal.

[email protected]

SOURCE: Lipton RB et al. JAMA. 2019;322(19):1887-98. doi: 10.1001/jama.2019.16711.

Ubrogepant, an oral calcitonin gene–related peptide (CGRP)–receptor antagonist, may relieve patients’ migraine pain and their most bothersome associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours after acute treatment, according to phase 3 trial results published Nov. 19 in JAMA.

“Among adults with migraine, acute treatment with ubrogepant, compared with placebo, led to significantly greater rates of pain freedom at 2 hours with the 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose,” wrote first author Richard B. Lipton, MD, director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, and his colleagues. “Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations.”

A researcher who commented on the results said that the drug appears “modestly better than placebo” and called for a trial comparing ubrogepant, aspirin, and oral sumatriptan.

The Food and Drug Administration is reviewing an application for ubrogepant. Allergan, the company developing the drug, has said it expects a regulatory decision in December.
 

ACHIEVE II

To evaluate the efficacy and tolerability of ubrogepant versus placebo for the acute treatment of a migraine attack, investigators conducted ACHIEVE II, a randomized, double-blind, placebo-controlled, single-attack clinical trial. The study was conducted at 99 primary care and research clinics during 2016-2018.

The trial included adults with migraine with or without aura who experienced two to eight migraine attacks per month. Participants had a mean age of 41.5 years, and 90% were female. The safety analysis included data from 1,465 participants, and the efficacy analysis included data from 1,355 participants. The primary efficacy outcomes were pain freedom and the absence of participants’ most bothersome migraine-associated symptom at 2 hours after taking the medication. Patients received ubrogepant 50 mg, ubrogepant 25 mg, or placebo to treat a migraine attack of moderate or severe pain intensity.

At 2 hours, pain freedom was reported by 101 of 464 participants in the ubrogepant 50-mg group (21.8%), 90 of 435 in the ubrogepant 25-mg group (20.7%), and 65 of 456 in the placebo group (14.3%). Absence of the most bothersome symptom was reported by 180 of 463 participants in the ubrogepant 50-mg group (38.9%), 148 of 434 in the ubrogepant 25-mg group (34.1%), and 125 of 456 in the placebo group (27.4%).

The most common adverse events within 48 hours were nausea and dizziness. Nausea occurred in 2.0% of the 50-mg group, 2.5% of the 25-mg group, and 2.0% of the placebo group. Dizziness occurred in 1.4% of the 50-mg group, 2.1% of the 25-mg group, and 1.6% of the placebo group.

At conferences, researchers have presented results from the phase 3 ACHIEVE I trial as well as an analysis that suggests ubrogepant may be effective in patients for whom triptans have been ineffective. In addition, studies have supported the safety of “gepants” after earlier concerns about potential liver toxicity. Physicians have called the safety data reassuring.

The ACHIEVE II trial was sponsored by Allergan. Several authors are Allergan employees. Dr. Lipton is a consultant, advisory board member, or has received honoraria from Allergan and other companies.

 

Number needed to treat

“The study was large, appears to have been well conducted, is clearly reported, and used appropriate outcome measures,” said Elizabeth Loder, MD, commenting on the trial.

A year ago, Dr. Loder, chief of the division of headache at Brigham and Women’s Hospital and professor of neurology at Harvard Medical School in Boston, coauthored a paper with Peer Tfelt-Hansen, MD, DMSc, of the University of Copenhagen, that said the phase 3 trials of gepants so far have found the drugs to have small effect sizes and low efficacy (Headache. 2019 Jan;59[1]:113-7. doi: 10.1111/head.13444).

Their publication included preliminary figures from ACHIEVE II, which are consistent with those published in JAMA. “The effect size for both doses of ubrogepant is small and of debatable clinical significance,” Dr. Loder said. “The therapeutic gain over placebo is 7.5% for the 50-mg dose and 6.4% for the 25-mg dose for the outcome of pain freedom at 2 hours. That corresponds to a number needed to treat of 13 and 15.6 people, respectively, in order to have one person achieve pain freedom at 2 hours that is attributable to the active treatment.”

For a secondary outcome of pain relief at 2 hours, defined as reduction of headache pain severity from moderate or severe to mild or none, the therapeutic gain versus placebo is 14.5% for the 50-mg dose and 12.3% for the 25-mg dose. “That corresponds to a number needed to treat of 6.8 and 8.1 people, respectively, to have one person achieve pain relief at 2 hours attributable to the drug,” Dr. Loder said.

“Although there are no head to head studies comparing ubrogepant to triptans, for reference the [number needed to treat] for a 100-mg oral dose of sumatriptan is on the order of 3.5 for pain relief at 2 hours, meaning that one needs to treat just 3.5 people with sumatriptan in order to have one person achieve pain relief at 2 hours attributable to the drug,” she said (Cochrane Database Syst Rev. 2014;5:CD009108. doi: 10.1002/14651858.CD009108.pub2).

“The bottom line is that in the ACHIEVE II study, ubrogepant appears, on average, to be modestly better than placebo to treat migraine. It does not appear to be in the same league as sumatriptan. Instead, as Dr. Tfelt-Hansen and I said in our article, the results look comparable to those likely to be achieved with inexpensive nonprescription medications such as NSAIDs.”

Dr. Loder called for a trial comparing ubrogepant and other therapies. “I challenge the authors and the company to conduct a large, placebo-controlled trial comparing ubrogepant to 100 mg of oral sumatriptan and to 650 mg of aspirin,” Dr. Loder said.

Dr. Loder has no financial connections with any pharmaceutical or device companies and is paid for her work as the head of research for the British Medical Journal.

[email protected]

SOURCE: Lipton RB et al. JAMA. 2019;322(19):1887-98. doi: 10.1001/jama.2019.16711.

Ubrogepant, an oral calcitonin gene–related peptide (CGRP)–receptor antagonist, may relieve patients’ migraine pain and their most bothersome associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours after acute treatment, according to phase 3 trial results published Nov. 19 in JAMA.

“Among adults with migraine, acute treatment with ubrogepant, compared with placebo, led to significantly greater rates of pain freedom at 2 hours with the 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose,” wrote first author Richard B. Lipton, MD, director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, and his colleagues. “Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations.”

A researcher who commented on the results said that the drug appears “modestly better than placebo” and called for a trial comparing ubrogepant, aspirin, and oral sumatriptan.

The Food and Drug Administration is reviewing an application for ubrogepant. Allergan, the company developing the drug, has said it expects a regulatory decision in December.
 

ACHIEVE II

To evaluate the efficacy and tolerability of ubrogepant versus placebo for the acute treatment of a migraine attack, investigators conducted ACHIEVE II, a randomized, double-blind, placebo-controlled, single-attack clinical trial. The study was conducted at 99 primary care and research clinics during 2016-2018.

The trial included adults with migraine with or without aura who experienced two to eight migraine attacks per month. Participants had a mean age of 41.5 years, and 90% were female. The safety analysis included data from 1,465 participants, and the efficacy analysis included data from 1,355 participants. The primary efficacy outcomes were pain freedom and the absence of participants’ most bothersome migraine-associated symptom at 2 hours after taking the medication. Patients received ubrogepant 50 mg, ubrogepant 25 mg, or placebo to treat a migraine attack of moderate or severe pain intensity.

At 2 hours, pain freedom was reported by 101 of 464 participants in the ubrogepant 50-mg group (21.8%), 90 of 435 in the ubrogepant 25-mg group (20.7%), and 65 of 456 in the placebo group (14.3%). Absence of the most bothersome symptom was reported by 180 of 463 participants in the ubrogepant 50-mg group (38.9%), 148 of 434 in the ubrogepant 25-mg group (34.1%), and 125 of 456 in the placebo group (27.4%).

The most common adverse events within 48 hours were nausea and dizziness. Nausea occurred in 2.0% of the 50-mg group, 2.5% of the 25-mg group, and 2.0% of the placebo group. Dizziness occurred in 1.4% of the 50-mg group, 2.1% of the 25-mg group, and 1.6% of the placebo group.

At conferences, researchers have presented results from the phase 3 ACHIEVE I trial as well as an analysis that suggests ubrogepant may be effective in patients for whom triptans have been ineffective. In addition, studies have supported the safety of “gepants” after earlier concerns about potential liver toxicity. Physicians have called the safety data reassuring.

The ACHIEVE II trial was sponsored by Allergan. Several authors are Allergan employees. Dr. Lipton is a consultant, advisory board member, or has received honoraria from Allergan and other companies.

 

Number needed to treat

“The study was large, appears to have been well conducted, is clearly reported, and used appropriate outcome measures,” said Elizabeth Loder, MD, commenting on the trial.

A year ago, Dr. Loder, chief of the division of headache at Brigham and Women’s Hospital and professor of neurology at Harvard Medical School in Boston, coauthored a paper with Peer Tfelt-Hansen, MD, DMSc, of the University of Copenhagen, that said the phase 3 trials of gepants so far have found the drugs to have small effect sizes and low efficacy (Headache. 2019 Jan;59[1]:113-7. doi: 10.1111/head.13444).

Their publication included preliminary figures from ACHIEVE II, which are consistent with those published in JAMA. “The effect size for both doses of ubrogepant is small and of debatable clinical significance,” Dr. Loder said. “The therapeutic gain over placebo is 7.5% for the 50-mg dose and 6.4% for the 25-mg dose for the outcome of pain freedom at 2 hours. That corresponds to a number needed to treat of 13 and 15.6 people, respectively, in order to have one person achieve pain freedom at 2 hours that is attributable to the active treatment.”

For a secondary outcome of pain relief at 2 hours, defined as reduction of headache pain severity from moderate or severe to mild or none, the therapeutic gain versus placebo is 14.5% for the 50-mg dose and 12.3% for the 25-mg dose. “That corresponds to a number needed to treat of 6.8 and 8.1 people, respectively, to have one person achieve pain relief at 2 hours attributable to the drug,” Dr. Loder said.

“Although there are no head to head studies comparing ubrogepant to triptans, for reference the [number needed to treat] for a 100-mg oral dose of sumatriptan is on the order of 3.5 for pain relief at 2 hours, meaning that one needs to treat just 3.5 people with sumatriptan in order to have one person achieve pain relief at 2 hours attributable to the drug,” she said (Cochrane Database Syst Rev. 2014;5:CD009108. doi: 10.1002/14651858.CD009108.pub2).

“The bottom line is that in the ACHIEVE II study, ubrogepant appears, on average, to be modestly better than placebo to treat migraine. It does not appear to be in the same league as sumatriptan. Instead, as Dr. Tfelt-Hansen and I said in our article, the results look comparable to those likely to be achieved with inexpensive nonprescription medications such as NSAIDs.”

Dr. Loder called for a trial comparing ubrogepant and other therapies. “I challenge the authors and the company to conduct a large, placebo-controlled trial comparing ubrogepant to 100 mg of oral sumatriptan and to 650 mg of aspirin,” Dr. Loder said.

Dr. Loder has no financial connections with any pharmaceutical or device companies and is paid for her work as the head of research for the British Medical Journal.

[email protected]

SOURCE: Lipton RB et al. JAMA. 2019;322(19):1887-98. doi: 10.1001/jama.2019.16711.

CHARLOTTE, N.C. – Children and adolescents without a history of headache may develop prolonged headaches after sustaining a concussion, according to research presented at the annual meeting of the Child Neurology Society. The headache may be migraine, chronic daily headache, tension-type headache, or a combination of these headaches.

“We strongly recommend that individuals who develop persistent headache after a concussion be evaluated and treated by a neurologist with experience in administering treatment for headache,” said Marcus Barissi, Weller Scholar at the Cleveland Clinic, and colleagues. “Using this approach, we hope that their prolonged headaches will be lessened.”
 

Few studies have examined prolonged pediatric postconcussion headache

The Centers for Disease Control and Prevention estimates that between 1.6 million and 3.8 million concussions occur annually during athletic and recreational activities in the United States. About 90% of concussions affect children or adolescents. The symptom most often reported after concussion is headache.

Few studies have focused on new persistent postconcussion headache (NPPCH) in children. Mr. Barissi and colleagues did not find any previous study that had examined prolonged headache following concussion in patients without prior chronic headache. They sought to ascertain the prognosis of patients with NPPCH and no history of prior headache, to describe this clinical entity, and to identify beneficial treatment methods.

The investigators retrospectively reviewed charts for approximately 2,000 patients who presented to the Cleveland Clinic pediatric neurology department between June 2017 and August 2018 for headaches. They identified 259 patients who received a diagnosis of concussion, 69 (27%) of whom had headaches for longer than 2 months after injury.

Mr. Barissi and colleagues emailed these patients, and 33 (48%) of them agreed to complete a questionnaire and participate in a 10-minute phone interview. Thirty-one patients (43%) could not be contacted, and eight (11%) declined to participate. All participants confirmed that they had not had consistent headache before the concussion and that chronic headache had arisen after concussion. To determine participants’ medical outcomes, the researchers compared participants’ initial assessment data with posttreatment data collected during the interview process.
 

Healthy behaviors increased after concussion

Of the 69 eligible participants, 38 (55%) were female. The population’s median age was 17. Twenty-eight (85%) of the 33 patients who completed the questionnaire considered the information and treatment that they had received to be beneficial. Twenty-five (78%) patients continued to have headache after several months, despite treatment.

Participants had withstood a mean of 1.72 concussions, and the mean age at first injury was 12.49 years. The most common cause of injury was a fall for males (36%) and an automobile accident for females (18%).

Forty-eight patients (70%) reported having two types of headache. Fifty-two patients (75%) had migraines, and 65 (94%) had chronic daily headache or tension-type headache. Forty-eight (70%) participants had a family history of headache.

In all, 64 patients (93%) had used a headache medication. The most common headache medications used were amitriptyline, topiramate, and cyproheptadine. Few patients were still taking these medications at several months after evaluation. The most common nonprescription medications used were Migravent (i.e., magnesium, riboflavin, coenzyme Q10, and butterbur), ondansetron, and melatonin. Furthermore, 61 patients (88%) participated in nonmedicinal therapy such as physical therapy, chiropractic therapy, and acupuncture.

After evaluation, patients engaged in several healthy behaviors (e.g., adequate exercise, proper use of over-the-counter medications, and drinking sufficient water) more frequently, but did not get adequate sleep. Sixty-five participants (94%) had undergone CT or MRI imaging, but the results did not improve understanding of headache etiology or treatment. Many patients missed several days of school, but average attendance improved after months of treatment.
 

Long-term outcomes

Thirty-one survey respondents (94%) reported that their emotional, cognitive, sleep, and somatic postconcussion symptoms had resolved. Nevertheless, a majority of participants still had headache. “The persistence of postconcussion symptoms is uncommon, but lasting headache is not,” said the researchers. “If patients are not properly educated, conditions may deteriorate, extending the duration of disability.” A longer study with a larger sample size could provide valuable information, said the researchers. Future work should examine objectively the efficacy of various medications used to treat NPPCH and determine the best methods of treatment for this syndrome, which “can cause prolonged pain, suffering, and lack of function,” they concluded.

The investigators did not report any study funding or disclosures.

[email protected]

SOURCE: Barissi M et al. CNS 2019, Abstract 95.

CHARLOTTE, N.C. – Children and adolescents without a history of headache may develop prolonged headaches after sustaining a concussion, according to research presented at the annual meeting of the Child Neurology Society. The headache may be migraine, chronic daily headache, tension-type headache, or a combination of these headaches.

“We strongly recommend that individuals who develop persistent headache after a concussion be evaluated and treated by a neurologist with experience in administering treatment for headache,” said Marcus Barissi, Weller Scholar at the Cleveland Clinic, and colleagues. “Using this approach, we hope that their prolonged headaches will be lessened.”
 

Few studies have examined prolonged pediatric postconcussion headache

The Centers for Disease Control and Prevention estimates that between 1.6 million and 3.8 million concussions occur annually during athletic and recreational activities in the United States. About 90% of concussions affect children or adolescents. The symptom most often reported after concussion is headache.

Few studies have focused on new persistent postconcussion headache (NPPCH) in children. Mr. Barissi and colleagues did not find any previous study that had examined prolonged headache following concussion in patients without prior chronic headache. They sought to ascertain the prognosis of patients with NPPCH and no history of prior headache, to describe this clinical entity, and to identify beneficial treatment methods.

The investigators retrospectively reviewed charts for approximately 2,000 patients who presented to the Cleveland Clinic pediatric neurology department between June 2017 and August 2018 for headaches. They identified 259 patients who received a diagnosis of concussion, 69 (27%) of whom had headaches for longer than 2 months after injury.

Mr. Barissi and colleagues emailed these patients, and 33 (48%) of them agreed to complete a questionnaire and participate in a 10-minute phone interview. Thirty-one patients (43%) could not be contacted, and eight (11%) declined to participate. All participants confirmed that they had not had consistent headache before the concussion and that chronic headache had arisen after concussion. To determine participants’ medical outcomes, the researchers compared participants’ initial assessment data with posttreatment data collected during the interview process.
 

Healthy behaviors increased after concussion

Of the 69 eligible participants, 38 (55%) were female. The population’s median age was 17. Twenty-eight (85%) of the 33 patients who completed the questionnaire considered the information and treatment that they had received to be beneficial. Twenty-five (78%) patients continued to have headache after several months, despite treatment.

Participants had withstood a mean of 1.72 concussions, and the mean age at first injury was 12.49 years. The most common cause of injury was a fall for males (36%) and an automobile accident for females (18%).

Forty-eight patients (70%) reported having two types of headache. Fifty-two patients (75%) had migraines, and 65 (94%) had chronic daily headache or tension-type headache. Forty-eight (70%) participants had a family history of headache.

In all, 64 patients (93%) had used a headache medication. The most common headache medications used were amitriptyline, topiramate, and cyproheptadine. Few patients were still taking these medications at several months after evaluation. The most common nonprescription medications used were Migravent (i.e., magnesium, riboflavin, coenzyme Q10, and butterbur), ondansetron, and melatonin. Furthermore, 61 patients (88%) participated in nonmedicinal therapy such as physical therapy, chiropractic therapy, and acupuncture.

After evaluation, patients engaged in several healthy behaviors (e.g., adequate exercise, proper use of over-the-counter medications, and drinking sufficient water) more frequently, but did not get adequate sleep. Sixty-five participants (94%) had undergone CT or MRI imaging, but the results did not improve understanding of headache etiology or treatment. Many patients missed several days of school, but average attendance improved after months of treatment.
 

Long-term outcomes

Thirty-one survey respondents (94%) reported that their emotional, cognitive, sleep, and somatic postconcussion symptoms had resolved. Nevertheless, a majority of participants still had headache. “The persistence of postconcussion symptoms is uncommon, but lasting headache is not,” said the researchers. “If patients are not properly educated, conditions may deteriorate, extending the duration of disability.” A longer study with a larger sample size could provide valuable information, said the researchers. Future work should examine objectively the efficacy of various medications used to treat NPPCH and determine the best methods of treatment for this syndrome, which “can cause prolonged pain, suffering, and lack of function,” they concluded.

The investigators did not report any study funding or disclosures.

[email protected]

SOURCE: Barissi M et al. CNS 2019, Abstract 95.

CHARLOTTE, N.C. – Children and adolescents without a history of headache may develop prolonged headaches after sustaining a concussion, according to research presented at the annual meeting of the Child Neurology Society. The headache may be migraine, chronic daily headache, tension-type headache, or a combination of these headaches.

“We strongly recommend that individuals who develop persistent headache after a concussion be evaluated and treated by a neurologist with experience in administering treatment for headache,” said Marcus Barissi, Weller Scholar at the Cleveland Clinic, and colleagues. “Using this approach, we hope that their prolonged headaches will be lessened.”
 

Few studies have examined prolonged pediatric postconcussion headache

The Centers for Disease Control and Prevention estimates that between 1.6 million and 3.8 million concussions occur annually during athletic and recreational activities in the United States. About 90% of concussions affect children or adolescents. The symptom most often reported after concussion is headache.

Few studies have focused on new persistent postconcussion headache (NPPCH) in children. Mr. Barissi and colleagues did not find any previous study that had examined prolonged headache following concussion in patients without prior chronic headache. They sought to ascertain the prognosis of patients with NPPCH and no history of prior headache, to describe this clinical entity, and to identify beneficial treatment methods.

The investigators retrospectively reviewed charts for approximately 2,000 patients who presented to the Cleveland Clinic pediatric neurology department between June 2017 and August 2018 for headaches. They identified 259 patients who received a diagnosis of concussion, 69 (27%) of whom had headaches for longer than 2 months after injury.

Mr. Barissi and colleagues emailed these patients, and 33 (48%) of them agreed to complete a questionnaire and participate in a 10-minute phone interview. Thirty-one patients (43%) could not be contacted, and eight (11%) declined to participate. All participants confirmed that they had not had consistent headache before the concussion and that chronic headache had arisen after concussion. To determine participants’ medical outcomes, the researchers compared participants’ initial assessment data with posttreatment data collected during the interview process.
 

Healthy behaviors increased after concussion

Of the 69 eligible participants, 38 (55%) were female. The population’s median age was 17. Twenty-eight (85%) of the 33 patients who completed the questionnaire considered the information and treatment that they had received to be beneficial. Twenty-five (78%) patients continued to have headache after several months, despite treatment.

Participants had withstood a mean of 1.72 concussions, and the mean age at first injury was 12.49 years. The most common cause of injury was a fall for males (36%) and an automobile accident for females (18%).

Forty-eight patients (70%) reported having two types of headache. Fifty-two patients (75%) had migraines, and 65 (94%) had chronic daily headache or tension-type headache. Forty-eight (70%) participants had a family history of headache.

In all, 64 patients (93%) had used a headache medication. The most common headache medications used were amitriptyline, topiramate, and cyproheptadine. Few patients were still taking these medications at several months after evaluation. The most common nonprescription medications used were Migravent (i.e., magnesium, riboflavin, coenzyme Q10, and butterbur), ondansetron, and melatonin. Furthermore, 61 patients (88%) participated in nonmedicinal therapy such as physical therapy, chiropractic therapy, and acupuncture.

After evaluation, patients engaged in several healthy behaviors (e.g., adequate exercise, proper use of over-the-counter medications, and drinking sufficient water) more frequently, but did not get adequate sleep. Sixty-five participants (94%) had undergone CT or MRI imaging, but the results did not improve understanding of headache etiology or treatment. Many patients missed several days of school, but average attendance improved after months of treatment.
 

Long-term outcomes

Thirty-one survey respondents (94%) reported that their emotional, cognitive, sleep, and somatic postconcussion symptoms had resolved. Nevertheless, a majority of participants still had headache. “The persistence of postconcussion symptoms is uncommon, but lasting headache is not,” said the researchers. “If patients are not properly educated, conditions may deteriorate, extending the duration of disability.” A longer study with a larger sample size could provide valuable information, said the researchers. Future work should examine objectively the efficacy of various medications used to treat NPPCH and determine the best methods of treatment for this syndrome, which “can cause prolonged pain, suffering, and lack of function,” they concluded.

The investigators did not report any study funding or disclosures.

[email protected]

SOURCE: Barissi M et al. CNS 2019, Abstract 95.

China’s National Medical Products Administration has approved a new therapy for patients with mild to moderate Alzheimer’s disease – a seaweed extract thought to alter the gut microbiome profile and subsequently decrease microbiome-driven neuroinflammation.

Sodium oligomannate – dubbed GV-971 – won approval based on a 36-week, placebo-controlled, phase 3 study of 818 patients with mild to moderate Alzheimer’s disease (AD). The study hit its primary endpoint of change on the Alzheimer’s Disease Assessment Scale cognitive portion (ADAS-cog12). It did not meet any of the trial’s other cognitive or functional secondary endpoints.

A portion of the data were presented last year at the Clinical Trials on Alzheimer’s Disease meeting in Barcelona. But the full study has never appeared in a peer-reviewed journal. A truncated version is publicly available on the website of Shanghai Green Valley Pharmaceuticals, the company developing the molecule.

Shanghai Green Valley contends that it reduces neuroinflammation by improving a proinflammatory microbiome profile that it says is characteristic of AD. However, the mechanism by which GV-971 alters intestinal bacterial composition is unclear – or at least it is not fully described in the public literature.

In the United States, some key researchers appraised the news with a cautiously optimistic eye, while others pointed noted that the AD-microbiome link is an unproven concept, and that it was evaluated in a study of questionable worth.

“The company has presented data that suggest there is a modest cognitive benefit to this treatment,” Paul S. Aisen, MD, said in an interview. “The key secondary endpoint was missed, and the other secondary endpoints showed no benefit. It’s a single trial and the mechanism is still unclear.”

“We do need to pursue all possible leads, and I’m glad the company is pursuing additional studies, but I wouldn’t draw a firm conclusion from these data. And they certainly would not be enough to win approval in the U.S.,” said Dr. Aisen, founding director Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.

Preclinical findings on GV-971

In commenting on preclinical findings of GV-971 published in Cell Research in September 2019, David Holtzman, MD, associate director of the Alzheimer’s disease research center at Washington University, St. Louis, and coauthors observed that the data support research exploring treatments that modulate the gut microbiome but leave it unclear as to whether GV-971 has AD-specific effects.

“[The company shows] that GV-971 decreases amyloid beta-related pathologies by reconditioning the gut microbiota, providing further evidence that gut-targeted interventions may serve as novel strategies to tackle AD,” Dr. Holtzman and coauthors wrote. “Whether this potential mechanism represents an AD-specific process is not clear, since there is great overlap in immunological changes and gut dysbiosis with other diseases. … In addition, although this study reveals that gut reconditioning may be one mechanism of action of the drug GV-971, it does not rule out other possible mechanisms. For example, GV-971 may attenuate AD pathogenesis by directly inhibiting neuroinflammation or amyloid-beta fibril formation. However, there is no question that [these] data further [support] the emerging idea that modulation of the gut microbiome via treatments such as GV-971 or other strategies should be further explored as novel strategies to slow the progression of AD.”

Sodium oligomannate is a long-chain saccharide extracted from brown sea algae and consists of acidic linear oligosaccharides with structures ranging from dimers to decamers. Related molecules without the sugar backbone were inactive, suggesting that the saccharides are the active portion, Xinyi Wang of Shanghai Green Valley and colleagues wrote in the Cell Research paper.

Based on these studies, the company contends that Alzheimer’s progression is accompanied by a characteristic microbiome change to a proinflammatory profile. And indeed, two transgenic Alzheimer’s mouse models – one with five familial AD mutations (5xFAD) and one with mutations of amyloid precursor protein and presenilin 1 (APP/PS1) – showed similar gradual age- and progression-related decreases of Bacteroides and Verrucomicrobia, two components of a normal microbiome. Bacteroides species perform key functions necessary for survival, including sensing and adapting to nutrient variability, expelling toxins, and stimulating the immune system). Species of the Verrucomicrobia phylum are important in glucose homeostasis. The decline in Bacteroides and Verrucomicrobia species is accompanied by an increase in concomitant proinflammatory species.

The investigators then explored the relationship between the microbiome composition and cognitive function in both transgenic models and a wild-type mouse.

First, they showed that the bacterial populations shifted as the mice aged and their AD pathology developed. This was accompanied by an uptick in activated microglia and, in turn, proinflammatory T1 helper cells that migrated through the intestinal membranes and into the periphery, then cross the blood-brain barrier to enter the brain.

Then the investigators used a cocktail of powerful antibiotics to disturb the intestinal flora in both transgenic and wild-type mice. After this, the 5xFAD mice showed fewer activated microglia and fewer infiltrating T cells. Later, they gave wild-type mice a fecal transplant from the 5xFAD mice. The wild-type mice developed more activated and infiltrating cells and their microbiome began to resemble that of the transgenic mice. Conversely, when the transgenic mice received a transplant from the wild-type mice, their microbiome changed to resemble the donors’, and their activated and infiltrating cells declined.

After this, the team gave GV-971 to the mice. The APP/PS1 mice improved cognitively, and the 5xFAD mice had fewer activated and infiltrating cells, fewer amyloid brain plaques, and less tau phosphorylation. These changes were accompanied by higher levels of two amino acids, phenylalanine and isoleucine. These proteins appear to act on T-cell proliferation and differentiation, they said.

“Taken together, these analyses suggest the idea that gut dysbiosis contributes to [phenylalanine and isoleucine] elevation, which drives the proliferation/differentiation and brain infiltration of [T1 helper] cells,” Dr. Holtzman and coauthors wrote. “These infiltrating Th1 cells may then further activate microglia and contribute to amyloid-related pathogenesis.”

The phase 3 study

The approval of GV-971 was based on the subsequent 36-week phase 3, placebo-controlled study of 818 patients with mild to moderate AD, which was reported last year. Patients were randomized to placebo or to GV-971 450 mg twice daily. Amyloid PET imaging was not required at entrance to the study, so there was no measure of baseline amyloid load. However, all patients showed MRI evidence of cortical atrophy. The Mini Mental State Exam (MMSE) ranged from 11 to 26, indicating mild to moderate AD.

Secondary endpoints included change on the Alzheimer’s Disease Cooperative Study Activities of Daily Living, the Clinician’s Interview-Based Impression of Change–Plus, and the Neuropsychiatric Index.

Patients taking GV-971 experienced a statistically significant 2.54-point difference on the ADAS-cog12, compared with placebo. The difference was apparent by week 4 and was seen at every clinical visit. When patients were grouped according to baseline MMSE (11-14, 15-19, and 20-26), the drug performed similarly.

Michele G Sullivan/MDedge News

But none of the secondary endpoints significantly favored of GV-971. And the placebo group behaved in an unexpected way, which could throw the data interpretation off-kilter somewhat, David Knopman, MD, said in an interview.

“It was a very weird and unusual-looking trajectory of the placebo and treated groups,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn., with those taking placebo staying relatively stable for some time before the cognitive scores dropped precipitously. “The data were unconvincing to me.”

He also pointed out that although the extensive preclinical data appeared in the recent peer-reviewed Cell Research paper, the phase 3 data has not appeared in any peer-reviewed forum, “even though the trial has been completed for some time now. Furthermore, the duration of the study was inadequate.”

Finally, none of the study subjects were taking the standard-of-care cholinesterase inhibitors, which virtually every AD patient in the United States does take.

“This makes it almost completely inapplicable to the U.S.,” he said. “It’s not bad news. I’m just not convinced.”

Dr. Holtzman is a cofounder of C2N Diagnostics. He is on the scientific advisory board of Genentech, Denali, and C2N Diagnostics. He consults for Idorsia. Dr. Knopman is a consultant for the Bluefield Project to Cure Frontotemporal Dementia and for Lundbeck.

China’s National Medical Products Administration has approved a new therapy for patients with mild to moderate Alzheimer’s disease – a seaweed extract thought to alter the gut microbiome profile and subsequently decrease microbiome-driven neuroinflammation.

Sodium oligomannate – dubbed GV-971 – won approval based on a 36-week, placebo-controlled, phase 3 study of 818 patients with mild to moderate Alzheimer’s disease (AD). The study hit its primary endpoint of change on the Alzheimer’s Disease Assessment Scale cognitive portion (ADAS-cog12). It did not meet any of the trial’s other cognitive or functional secondary endpoints.

A portion of the data were presented last year at the Clinical Trials on Alzheimer’s Disease meeting in Barcelona. But the full study has never appeared in a peer-reviewed journal. A truncated version is publicly available on the website of Shanghai Green Valley Pharmaceuticals, the company developing the molecule.

Shanghai Green Valley contends that it reduces neuroinflammation by improving a proinflammatory microbiome profile that it says is characteristic of AD. However, the mechanism by which GV-971 alters intestinal bacterial composition is unclear – or at least it is not fully described in the public literature.

In the United States, some key researchers appraised the news with a cautiously optimistic eye, while others pointed noted that the AD-microbiome link is an unproven concept, and that it was evaluated in a study of questionable worth.

“The company has presented data that suggest there is a modest cognitive benefit to this treatment,” Paul S. Aisen, MD, said in an interview. “The key secondary endpoint was missed, and the other secondary endpoints showed no benefit. It’s a single trial and the mechanism is still unclear.”

“We do need to pursue all possible leads, and I’m glad the company is pursuing additional studies, but I wouldn’t draw a firm conclusion from these data. And they certainly would not be enough to win approval in the U.S.,” said Dr. Aisen, founding director Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.

Preclinical findings on GV-971

In commenting on preclinical findings of GV-971 published in Cell Research in September 2019, David Holtzman, MD, associate director of the Alzheimer’s disease research center at Washington University, St. Louis, and coauthors observed that the data support research exploring treatments that modulate the gut microbiome but leave it unclear as to whether GV-971 has AD-specific effects.

“[The company shows] that GV-971 decreases amyloid beta-related pathologies by reconditioning the gut microbiota, providing further evidence that gut-targeted interventions may serve as novel strategies to tackle AD,” Dr. Holtzman and coauthors wrote. “Whether this potential mechanism represents an AD-specific process is not clear, since there is great overlap in immunological changes and gut dysbiosis with other diseases. … In addition, although this study reveals that gut reconditioning may be one mechanism of action of the drug GV-971, it does not rule out other possible mechanisms. For example, GV-971 may attenuate AD pathogenesis by directly inhibiting neuroinflammation or amyloid-beta fibril formation. However, there is no question that [these] data further [support] the emerging idea that modulation of the gut microbiome via treatments such as GV-971 or other strategies should be further explored as novel strategies to slow the progression of AD.”

Sodium oligomannate is a long-chain saccharide extracted from brown sea algae and consists of acidic linear oligosaccharides with structures ranging from dimers to decamers. Related molecules without the sugar backbone were inactive, suggesting that the saccharides are the active portion, Xinyi Wang of Shanghai Green Valley and colleagues wrote in the Cell Research paper.

Based on these studies, the company contends that Alzheimer’s progression is accompanied by a characteristic microbiome change to a proinflammatory profile. And indeed, two transgenic Alzheimer’s mouse models – one with five familial AD mutations (5xFAD) and one with mutations of amyloid precursor protein and presenilin 1 (APP/PS1) – showed similar gradual age- and progression-related decreases of Bacteroides and Verrucomicrobia, two components of a normal microbiome. Bacteroides species perform key functions necessary for survival, including sensing and adapting to nutrient variability, expelling toxins, and stimulating the immune system). Species of the Verrucomicrobia phylum are important in glucose homeostasis. The decline in Bacteroides and Verrucomicrobia species is accompanied by an increase in concomitant proinflammatory species.

The investigators then explored the relationship between the microbiome composition and cognitive function in both transgenic models and a wild-type mouse.

First, they showed that the bacterial populations shifted as the mice aged and their AD pathology developed. This was accompanied by an uptick in activated microglia and, in turn, proinflammatory T1 helper cells that migrated through the intestinal membranes and into the periphery, then cross the blood-brain barrier to enter the brain.

Then the investigators used a cocktail of powerful antibiotics to disturb the intestinal flora in both transgenic and wild-type mice. After this, the 5xFAD mice showed fewer activated microglia and fewer infiltrating T cells. Later, they gave wild-type mice a fecal transplant from the 5xFAD mice. The wild-type mice developed more activated and infiltrating cells and their microbiome began to resemble that of the transgenic mice. Conversely, when the transgenic mice received a transplant from the wild-type mice, their microbiome changed to resemble the donors’, and their activated and infiltrating cells declined.

After this, the team gave GV-971 to the mice. The APP/PS1 mice improved cognitively, and the 5xFAD mice had fewer activated and infiltrating cells, fewer amyloid brain plaques, and less tau phosphorylation. These changes were accompanied by higher levels of two amino acids, phenylalanine and isoleucine. These proteins appear to act on T-cell proliferation and differentiation, they said.

“Taken together, these analyses suggest the idea that gut dysbiosis contributes to [phenylalanine and isoleucine] elevation, which drives the proliferation/differentiation and brain infiltration of [T1 helper] cells,” Dr. Holtzman and coauthors wrote. “These infiltrating Th1 cells may then further activate microglia and contribute to amyloid-related pathogenesis.”

The phase 3 study

The approval of GV-971 was based on the subsequent 36-week phase 3, placebo-controlled study of 818 patients with mild to moderate AD, which was reported last year. Patients were randomized to placebo or to GV-971 450 mg twice daily. Amyloid PET imaging was not required at entrance to the study, so there was no measure of baseline amyloid load. However, all patients showed MRI evidence of cortical atrophy. The Mini Mental State Exam (MMSE) ranged from 11 to 26, indicating mild to moderate AD.

Secondary endpoints included change on the Alzheimer’s Disease Cooperative Study Activities of Daily Living, the Clinician’s Interview-Based Impression of Change–Plus, and the Neuropsychiatric Index.

Patients taking GV-971 experienced a statistically significant 2.54-point difference on the ADAS-cog12, compared with placebo. The difference was apparent by week 4 and was seen at every clinical visit. When patients were grouped according to baseline MMSE (11-14, 15-19, and 20-26), the drug performed similarly.

Michele G Sullivan/MDedge News

But none of the secondary endpoints significantly favored of GV-971. And the placebo group behaved in an unexpected way, which could throw the data interpretation off-kilter somewhat, David Knopman, MD, said in an interview.

“It was a very weird and unusual-looking trajectory of the placebo and treated groups,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn., with those taking placebo staying relatively stable for some time before the cognitive scores dropped precipitously. “The data were unconvincing to me.”

He also pointed out that although the extensive preclinical data appeared in the recent peer-reviewed Cell Research paper, the phase 3 data has not appeared in any peer-reviewed forum, “even though the trial has been completed for some time now. Furthermore, the duration of the study was inadequate.”

Finally, none of the study subjects were taking the standard-of-care cholinesterase inhibitors, which virtually every AD patient in the United States does take.

“This makes it almost completely inapplicable to the U.S.,” he said. “It’s not bad news. I’m just not convinced.”

Dr. Holtzman is a cofounder of C2N Diagnostics. He is on the scientific advisory board of Genentech, Denali, and C2N Diagnostics. He consults for Idorsia. Dr. Knopman is a consultant for the Bluefield Project to Cure Frontotemporal Dementia and for Lundbeck.

China’s National Medical Products Administration has approved a new therapy for patients with mild to moderate Alzheimer’s disease – a seaweed extract thought to alter the gut microbiome profile and subsequently decrease microbiome-driven neuroinflammation.

Sodium oligomannate – dubbed GV-971 – won approval based on a 36-week, placebo-controlled, phase 3 study of 818 patients with mild to moderate Alzheimer’s disease (AD). The study hit its primary endpoint of change on the Alzheimer’s Disease Assessment Scale cognitive portion (ADAS-cog12). It did not meet any of the trial’s other cognitive or functional secondary endpoints.

A portion of the data were presented last year at the Clinical Trials on Alzheimer’s Disease meeting in Barcelona. But the full study has never appeared in a peer-reviewed journal. A truncated version is publicly available on the website of Shanghai Green Valley Pharmaceuticals, the company developing the molecule.

Shanghai Green Valley contends that it reduces neuroinflammation by improving a proinflammatory microbiome profile that it says is characteristic of AD. However, the mechanism by which GV-971 alters intestinal bacterial composition is unclear – or at least it is not fully described in the public literature.

In the United States, some key researchers appraised the news with a cautiously optimistic eye, while others pointed noted that the AD-microbiome link is an unproven concept, and that it was evaluated in a study of questionable worth.

“The company has presented data that suggest there is a modest cognitive benefit to this treatment,” Paul S. Aisen, MD, said in an interview. “The key secondary endpoint was missed, and the other secondary endpoints showed no benefit. It’s a single trial and the mechanism is still unclear.”

“We do need to pursue all possible leads, and I’m glad the company is pursuing additional studies, but I wouldn’t draw a firm conclusion from these data. And they certainly would not be enough to win approval in the U.S.,” said Dr. Aisen, founding director Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.

Preclinical findings on GV-971

In commenting on preclinical findings of GV-971 published in Cell Research in September 2019, David Holtzman, MD, associate director of the Alzheimer’s disease research center at Washington University, St. Louis, and coauthors observed that the data support research exploring treatments that modulate the gut microbiome but leave it unclear as to whether GV-971 has AD-specific effects.

“[The company shows] that GV-971 decreases amyloid beta-related pathologies by reconditioning the gut microbiota, providing further evidence that gut-targeted interventions may serve as novel strategies to tackle AD,” Dr. Holtzman and coauthors wrote. “Whether this potential mechanism represents an AD-specific process is not clear, since there is great overlap in immunological changes and gut dysbiosis with other diseases. … In addition, although this study reveals that gut reconditioning may be one mechanism of action of the drug GV-971, it does not rule out other possible mechanisms. For example, GV-971 may attenuate AD pathogenesis by directly inhibiting neuroinflammation or amyloid-beta fibril formation. However, there is no question that [these] data further [support] the emerging idea that modulation of the gut microbiome via treatments such as GV-971 or other strategies should be further explored as novel strategies to slow the progression of AD.”

Sodium oligomannate is a long-chain saccharide extracted from brown sea algae and consists of acidic linear oligosaccharides with structures ranging from dimers to decamers. Related molecules without the sugar backbone were inactive, suggesting that the saccharides are the active portion, Xinyi Wang of Shanghai Green Valley and colleagues wrote in the Cell Research paper.

Based on these studies, the company contends that Alzheimer’s progression is accompanied by a characteristic microbiome change to a proinflammatory profile. And indeed, two transgenic Alzheimer’s mouse models – one with five familial AD mutations (5xFAD) and one with mutations of amyloid precursor protein and presenilin 1 (APP/PS1) – showed similar gradual age- and progression-related decreases of Bacteroides and Verrucomicrobia, two components of a normal microbiome. Bacteroides species perform key functions necessary for survival, including sensing and adapting to nutrient variability, expelling toxins, and stimulating the immune system). Species of the Verrucomicrobia phylum are important in glucose homeostasis. The decline in Bacteroides and Verrucomicrobia species is accompanied by an increase in concomitant proinflammatory species.

The investigators then explored the relationship between the microbiome composition and cognitive function in both transgenic models and a wild-type mouse.

First, they showed that the bacterial populations shifted as the mice aged and their AD pathology developed. This was accompanied by an uptick in activated microglia and, in turn, proinflammatory T1 helper cells that migrated through the intestinal membranes and into the periphery, then cross the blood-brain barrier to enter the brain.

Then the investigators used a cocktail of powerful antibiotics to disturb the intestinal flora in both transgenic and wild-type mice. After this, the 5xFAD mice showed fewer activated microglia and fewer infiltrating T cells. Later, they gave wild-type mice a fecal transplant from the 5xFAD mice. The wild-type mice developed more activated and infiltrating cells and their microbiome began to resemble that of the transgenic mice. Conversely, when the transgenic mice received a transplant from the wild-type mice, their microbiome changed to resemble the donors’, and their activated and infiltrating cells declined.

After this, the team gave GV-971 to the mice. The APP/PS1 mice improved cognitively, and the 5xFAD mice had fewer activated and infiltrating cells, fewer amyloid brain plaques, and less tau phosphorylation. These changes were accompanied by higher levels of two amino acids, phenylalanine and isoleucine. These proteins appear to act on T-cell proliferation and differentiation, they said.

“Taken together, these analyses suggest the idea that gut dysbiosis contributes to [phenylalanine and isoleucine] elevation, which drives the proliferation/differentiation and brain infiltration of [T1 helper] cells,” Dr. Holtzman and coauthors wrote. “These infiltrating Th1 cells may then further activate microglia and contribute to amyloid-related pathogenesis.”

The phase 3 study

The approval of GV-971 was based on the subsequent 36-week phase 3, placebo-controlled study of 818 patients with mild to moderate AD, which was reported last year. Patients were randomized to placebo or to GV-971 450 mg twice daily. Amyloid PET imaging was not required at entrance to the study, so there was no measure of baseline amyloid load. However, all patients showed MRI evidence of cortical atrophy. The Mini Mental State Exam (MMSE) ranged from 11 to 26, indicating mild to moderate AD.

Secondary endpoints included change on the Alzheimer’s Disease Cooperative Study Activities of Daily Living, the Clinician’s Interview-Based Impression of Change–Plus, and the Neuropsychiatric Index.

Patients taking GV-971 experienced a statistically significant 2.54-point difference on the ADAS-cog12, compared with placebo. The difference was apparent by week 4 and was seen at every clinical visit. When patients were grouped according to baseline MMSE (11-14, 15-19, and 20-26), the drug performed similarly.

Michele G Sullivan/MDedge News

But none of the secondary endpoints significantly favored of GV-971. And the placebo group behaved in an unexpected way, which could throw the data interpretation off-kilter somewhat, David Knopman, MD, said in an interview.

“It was a very weird and unusual-looking trajectory of the placebo and treated groups,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn., with those taking placebo staying relatively stable for some time before the cognitive scores dropped precipitously. “The data were unconvincing to me.”

He also pointed out that although the extensive preclinical data appeared in the recent peer-reviewed Cell Research paper, the phase 3 data has not appeared in any peer-reviewed forum, “even though the trial has been completed for some time now. Furthermore, the duration of the study was inadequate.”

Finally, none of the study subjects were taking the standard-of-care cholinesterase inhibitors, which virtually every AD patient in the United States does take.

“This makes it almost completely inapplicable to the U.S.,” he said. “It’s not bad news. I’m just not convinced.”

Dr. Holtzman is a cofounder of C2N Diagnostics. He is on the scientific advisory board of Genentech, Denali, and C2N Diagnostics. He consults for Idorsia. Dr. Knopman is a consultant for the Bluefield Project to Cure Frontotemporal Dementia and for Lundbeck.

Adults worried about dementia are far more likely to do crossword puzzles and take fish oil than they are to talk to their doctor about risk, Donovan T. Maust, MD, and colleagues reported in a research letter published in JAMA Neurology.

More than half of study participants used crossword puzzles as a memory exercise, but only 5% said they spoke to their physician about how to reduce risk. Ironically, this lack of communication was also associated with buying unproven over-the-counter memory supplements, while still remaining ignorant of proven ways to head off dementia and other contributing chronic conditions, wrote Dr. Maust of the University of Michigan, Ann Arbor, and coauthors.

Their analysis of the Michigan National Poll on Healthy Aging found that close to half of respondents (48.5%) reported that they were at least somewhat likely to develop dementia. Another 4.2% thought dementia was “very likely” in their future.

The study comprised survey responses from 1,019 adults aged 50-64 years. Most rated their physical health either excellent (445 respondents) or good (413 respondents). Most also reported excellent or very good mental health (721 respondents); 234 reported good mental health. Many (678) were affluent, with annual incomes of $60,000 or higher. They tended to be well educated; only 337 were without at least some college education. More than half were white (753); there were 101 Hispanic respondents and 93 black respondents. Other groups made up the remainder.

A multivariate analysis found that black respondents were about half as likely to believe they would develop dementia, compared with whites – an assumption contrary to epidemiologic findings that blacks are more likely than whites to develop dementia.

People who reported fair or poor mental health were more than twice as likely to feel dementia was in their future (odds ratio, 2.3). But fair or poor physical health was not significantly associated with that concern.

“Those with fair to poor physical health did not accurately perceive that their likelihood of developing dementia was potentially higher than respondents with very good or excellent physical health,” the authors wrote. “In contrast, fair to poor mental health had the largest association with perceived likelihood of dementia, even though less evidence suggests that poor mental health is causally linked with dementia.”

Despite the concerns, just 5% of respondents said that they had spoken to their physician. Those who believed they had a high likelihood of dementia were more likely to talk with their clinician (7.1%) than those who believed they had a low risk (3.6%).

Many more, however, were using non–evidence-based compounds touted as memory supporting. These included fish oil or omega-3 fatty acids (31.6%) and vitamins or supplements (32.9%). Crossword puzzles were a very popular prevention strategy, employed by about 55% in both belief groups.

“While managing chronic medical conditions, such as diabetes or cardiovascular disease, could reduce dementia risk, few respondents appear to have discussed this with their physician. Given repeated failures of disease-preventing or disease-modifying treatments for dementia, interest in treatment and prevention has shifted earlier in the disease process. Adults in middle age may not accurately estimate their risk of developing dementia, which could lead to both overuse and underuse if preclinical dementia treatments become available. Policy and physicians should emphasize current evidence-based strategies of managing lifestyle and chronic medical conditions to reduce the risk of dementia,” the investigators wrote.

Dr. Maust had no financial disclosures.

[email protected]

SOURCE: Maust D et al. JAMA Neurol. 2019 Nov 15. doi: 10.1001/jamaneurol.2019.3946

Adults worried about dementia are far more likely to do crossword puzzles and take fish oil than they are to talk to their doctor about risk, Donovan T. Maust, MD, and colleagues reported in a research letter published in JAMA Neurology.

More than half of study participants used crossword puzzles as a memory exercise, but only 5% said they spoke to their physician about how to reduce risk. Ironically, this lack of communication was also associated with buying unproven over-the-counter memory supplements, while still remaining ignorant of proven ways to head off dementia and other contributing chronic conditions, wrote Dr. Maust of the University of Michigan, Ann Arbor, and coauthors.

Their analysis of the Michigan National Poll on Healthy Aging found that close to half of respondents (48.5%) reported that they were at least somewhat likely to develop dementia. Another 4.2% thought dementia was “very likely” in their future.

The study comprised survey responses from 1,019 adults aged 50-64 years. Most rated their physical health either excellent (445 respondents) or good (413 respondents). Most also reported excellent or very good mental health (721 respondents); 234 reported good mental health. Many (678) were affluent, with annual incomes of $60,000 or higher. They tended to be well educated; only 337 were without at least some college education. More than half were white (753); there were 101 Hispanic respondents and 93 black respondents. Other groups made up the remainder.

A multivariate analysis found that black respondents were about half as likely to believe they would develop dementia, compared with whites – an assumption contrary to epidemiologic findings that blacks are more likely than whites to develop dementia.

People who reported fair or poor mental health were more than twice as likely to feel dementia was in their future (odds ratio, 2.3). But fair or poor physical health was not significantly associated with that concern.

“Those with fair to poor physical health did not accurately perceive that their likelihood of developing dementia was potentially higher than respondents with very good or excellent physical health,” the authors wrote. “In contrast, fair to poor mental health had the largest association with perceived likelihood of dementia, even though less evidence suggests that poor mental health is causally linked with dementia.”

Despite the concerns, just 5% of respondents said that they had spoken to their physician. Those who believed they had a high likelihood of dementia were more likely to talk with their clinician (7.1%) than those who believed they had a low risk (3.6%).

Many more, however, were using non–evidence-based compounds touted as memory supporting. These included fish oil or omega-3 fatty acids (31.6%) and vitamins or supplements (32.9%). Crossword puzzles were a very popular prevention strategy, employed by about 55% in both belief groups.

“While managing chronic medical conditions, such as diabetes or cardiovascular disease, could reduce dementia risk, few respondents appear to have discussed this with their physician. Given repeated failures of disease-preventing or disease-modifying treatments for dementia, interest in treatment and prevention has shifted earlier in the disease process. Adults in middle age may not accurately estimate their risk of developing dementia, which could lead to both overuse and underuse if preclinical dementia treatments become available. Policy and physicians should emphasize current evidence-based strategies of managing lifestyle and chronic medical conditions to reduce the risk of dementia,” the investigators wrote.

Dr. Maust had no financial disclosures.

[email protected]

SOURCE: Maust D et al. JAMA Neurol. 2019 Nov 15. doi: 10.1001/jamaneurol.2019.3946

Adults worried about dementia are far more likely to do crossword puzzles and take fish oil than they are to talk to their doctor about risk, Donovan T. Maust, MD, and colleagues reported in a research letter published in JAMA Neurology.

More than half of study participants used crossword puzzles as a memory exercise, but only 5% said they spoke to their physician about how to reduce risk. Ironically, this lack of communication was also associated with buying unproven over-the-counter memory supplements, while still remaining ignorant of proven ways to head off dementia and other contributing chronic conditions, wrote Dr. Maust of the University of Michigan, Ann Arbor, and coauthors.

Their analysis of the Michigan National Poll on Healthy Aging found that close to half of respondents (48.5%) reported that they were at least somewhat likely to develop dementia. Another 4.2% thought dementia was “very likely” in their future.

The study comprised survey responses from 1,019 adults aged 50-64 years. Most rated their physical health either excellent (445 respondents) or good (413 respondents). Most also reported excellent or very good mental health (721 respondents); 234 reported good mental health. Many (678) were affluent, with annual incomes of $60,000 or higher. They tended to be well educated; only 337 were without at least some college education. More than half were white (753); there were 101 Hispanic respondents and 93 black respondents. Other groups made up the remainder.

A multivariate analysis found that black respondents were about half as likely to believe they would develop dementia, compared with whites – an assumption contrary to epidemiologic findings that blacks are more likely than whites to develop dementia.

People who reported fair or poor mental health were more than twice as likely to feel dementia was in their future (odds ratio, 2.3). But fair or poor physical health was not significantly associated with that concern.

“Those with fair to poor physical health did not accurately perceive that their likelihood of developing dementia was potentially higher than respondents with very good or excellent physical health,” the authors wrote. “In contrast, fair to poor mental health had the largest association with perceived likelihood of dementia, even though less evidence suggests that poor mental health is causally linked with dementia.”

Despite the concerns, just 5% of respondents said that they had spoken to their physician. Those who believed they had a high likelihood of dementia were more likely to talk with their clinician (7.1%) than those who believed they had a low risk (3.6%).

Many more, however, were using non–evidence-based compounds touted as memory supporting. These included fish oil or omega-3 fatty acids (31.6%) and vitamins or supplements (32.9%). Crossword puzzles were a very popular prevention strategy, employed by about 55% in both belief groups.

“While managing chronic medical conditions, such as diabetes or cardiovascular disease, could reduce dementia risk, few respondents appear to have discussed this with their physician. Given repeated failures of disease-preventing or disease-modifying treatments for dementia, interest in treatment and prevention has shifted earlier in the disease process. Adults in middle age may not accurately estimate their risk of developing dementia, which could lead to both overuse and underuse if preclinical dementia treatments become available. Policy and physicians should emphasize current evidence-based strategies of managing lifestyle and chronic medical conditions to reduce the risk of dementia,” the investigators wrote.

Dr. Maust had no financial disclosures.

[email protected]

SOURCE: Maust D et al. JAMA Neurol. 2019 Nov 15. doi: 10.1001/jamaneurol.2019.3946

A few weeks ago I was at a Friday-night football game, but not to watch the game. I’ve been there and done that too many times when I used to be the team physician. I was there to listen to my granddaughter drumming in the pep band. And there was a lot of drumming because her high school’s team is having a hot year and outscoring opponents by three and four touchdowns every week.

David Peeters/iStockphoto

At half time, the field was swarmed by 45-50 early grade schoolers looking like bobblehead dolls in their oversize helmets and surprisingly professional-appearing miniature football outfits. Under the lights, on the local college’s turf field, they were in football heaven. The pep band got into it and there was more drumming as the few kids who had a clue what football was about were scampering over and around their teammates and opponents who were roughhousing with each other, rolling around on the turf having a grand time, blissfully unimpressed by such trivial concepts as the line of scrimmage or the difference between blocking and tackling or even offense and defense.

Despite all the alarming articles both lay and professional that you and I see, this was an evening on which no one seemed particularly concerned about sports-related concussions. This is class B football in Maine, not a state well known as an incubator of Division I college football players. While there were a few scrawny kids with some speed, no one in the high school game had enough size or momentum to generate the kinds of collisions one sees with frightening regularity on television.

Watching 4- and 5-year-olds in their football uniforms seemed to me to be a rather harmless exercise and certainly a more positive investment in their time on a Friday night than sitting on the couch with an electronic device clutched in their little hands. A recent report in JAMA Pediatrics suggests that my lack of concern has some validity (“Consensus statement on sports-related concussions in youth sports using a modified delphi approach.” JAMA Pediatr. 2019 Nov 11. doi: 10.1001/jamapediatrics.2019.4006). Eleven experts in sports-related injuries were surveyed with multiple rounds of questionnaires. Their anonymous responses were aggregated and shared with the group after each round until a consensus could be arrived on for each of seven broad questions about sports-related concussions. It is a paper worth reading and like most good literature surveys determined that in many situations more study needs to be done.

Among the many findings that impressed me was the group’s failure to find an “association between repetitive head impact exposure in youth and long-term neurocognitive outcomes.” In addition, “there is little evidence that age at first exposure repetitive head impacts in sports is independently associated with neurodegenerative changes.” The experts also could find “no evidence that growth or development affect the risk of sports-related concussions.”

The problem with youth football is that it is the portal that can lead to college and professional football, in which large bodies are allowed to collide after accelerating at speeds we mortals only can achieve behind the wheel of our motor vehicles. Rules to minimize those collisions do exist, but lax enforcement has failed to prevent their cumulative damage.

Whether the culture of big-time football is going to change to a point at which a conscientious parent could encourage his or her child to play after adolescence remains to be seen. However, the evidence seems to suggest that allowing young children to bang themselves around imitating the big guys seems to be reasonably safe. At least as safe as what kids used to do to each other before we adults invented television and video games.

When my son was 3 or 4 years old, he played on a hockey team he thought was called the Toronto Make-Believes (Maple Leafs). Maybe we should be telling parents it’s safe for their children to play make-believe contact sports. The challenge comes after those kids reach puberty and want to start playing the real thing.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

A few weeks ago I was at a Friday-night football game, but not to watch the game. I’ve been there and done that too many times when I used to be the team physician. I was there to listen to my granddaughter drumming in the pep band. And there was a lot of drumming because her high school’s team is having a hot year and outscoring opponents by three and four touchdowns every week.

David Peeters/iStockphoto

At half time, the field was swarmed by 45-50 early grade schoolers looking like bobblehead dolls in their oversize helmets and surprisingly professional-appearing miniature football outfits. Under the lights, on the local college’s turf field, they were in football heaven. The pep band got into it and there was more drumming as the few kids who had a clue what football was about were scampering over and around their teammates and opponents who were roughhousing with each other, rolling around on the turf having a grand time, blissfully unimpressed by such trivial concepts as the line of scrimmage or the difference between blocking and tackling or even offense and defense.

Despite all the alarming articles both lay and professional that you and I see, this was an evening on which no one seemed particularly concerned about sports-related concussions. This is class B football in Maine, not a state well known as an incubator of Division I college football players. While there were a few scrawny kids with some speed, no one in the high school game had enough size or momentum to generate the kinds of collisions one sees with frightening regularity on television.

Watching 4- and 5-year-olds in their football uniforms seemed to me to be a rather harmless exercise and certainly a more positive investment in their time on a Friday night than sitting on the couch with an electronic device clutched in their little hands. A recent report in JAMA Pediatrics suggests that my lack of concern has some validity (“Consensus statement on sports-related concussions in youth sports using a modified delphi approach.” JAMA Pediatr. 2019 Nov 11. doi: 10.1001/jamapediatrics.2019.4006). Eleven experts in sports-related injuries were surveyed with multiple rounds of questionnaires. Their anonymous responses were aggregated and shared with the group after each round until a consensus could be arrived on for each of seven broad questions about sports-related concussions. It is a paper worth reading and like most good literature surveys determined that in many situations more study needs to be done.

Among the many findings that impressed me was the group’s failure to find an “association between repetitive head impact exposure in youth and long-term neurocognitive outcomes.” In addition, “there is little evidence that age at first exposure repetitive head impacts in sports is independently associated with neurodegenerative changes.” The experts also could find “no evidence that growth or development affect the risk of sports-related concussions.”

The problem with youth football is that it is the portal that can lead to college and professional football, in which large bodies are allowed to collide after accelerating at speeds we mortals only can achieve behind the wheel of our motor vehicles. Rules to minimize those collisions do exist, but lax enforcement has failed to prevent their cumulative damage.

Whether the culture of big-time football is going to change to a point at which a conscientious parent could encourage his or her child to play after adolescence remains to be seen. However, the evidence seems to suggest that allowing young children to bang themselves around imitating the big guys seems to be reasonably safe. At least as safe as what kids used to do to each other before we adults invented television and video games.

When my son was 3 or 4 years old, he played on a hockey team he thought was called the Toronto Make-Believes (Maple Leafs). Maybe we should be telling parents it’s safe for their children to play make-believe contact sports. The challenge comes after those kids reach puberty and want to start playing the real thing.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

A few weeks ago I was at a Friday-night football game, but not to watch the game. I’ve been there and done that too many times when I used to be the team physician. I was there to listen to my granddaughter drumming in the pep band. And there was a lot of drumming because her high school’s team is having a hot year and outscoring opponents by three and four touchdowns every week.

David Peeters/iStockphoto

At half time, the field was swarmed by 45-50 early grade schoolers looking like bobblehead dolls in their oversize helmets and surprisingly professional-appearing miniature football outfits. Under the lights, on the local college’s turf field, they were in football heaven. The pep band got into it and there was more drumming as the few kids who had a clue what football was about were scampering over and around their teammates and opponents who were roughhousing with each other, rolling around on the turf having a grand time, blissfully unimpressed by such trivial concepts as the line of scrimmage or the difference between blocking and tackling or even offense and defense.

Despite all the alarming articles both lay and professional that you and I see, this was an evening on which no one seemed particularly concerned about sports-related concussions. This is class B football in Maine, not a state well known as an incubator of Division I college football players. While there were a few scrawny kids with some speed, no one in the high school game had enough size or momentum to generate the kinds of collisions one sees with frightening regularity on television.

Watching 4- and 5-year-olds in their football uniforms seemed to me to be a rather harmless exercise and certainly a more positive investment in their time on a Friday night than sitting on the couch with an electronic device clutched in their little hands. A recent report in JAMA Pediatrics suggests that my lack of concern has some validity (“Consensus statement on sports-related concussions in youth sports using a modified delphi approach.” JAMA Pediatr. 2019 Nov 11. doi: 10.1001/jamapediatrics.2019.4006). Eleven experts in sports-related injuries were surveyed with multiple rounds of questionnaires. Their anonymous responses were aggregated and shared with the group after each round until a consensus could be arrived on for each of seven broad questions about sports-related concussions. It is a paper worth reading and like most good literature surveys determined that in many situations more study needs to be done.

Among the many findings that impressed me was the group’s failure to find an “association between repetitive head impact exposure in youth and long-term neurocognitive outcomes.” In addition, “there is little evidence that age at first exposure repetitive head impacts in sports is independently associated with neurodegenerative changes.” The experts also could find “no evidence that growth or development affect the risk of sports-related concussions.”

The problem with youth football is that it is the portal that can lead to college and professional football, in which large bodies are allowed to collide after accelerating at speeds we mortals only can achieve behind the wheel of our motor vehicles. Rules to minimize those collisions do exist, but lax enforcement has failed to prevent their cumulative damage.

Whether the culture of big-time football is going to change to a point at which a conscientious parent could encourage his or her child to play after adolescence remains to be seen. However, the evidence seems to suggest that allowing young children to bang themselves around imitating the big guys seems to be reasonably safe. At least as safe as what kids used to do to each other before we adults invented television and video games.

When my son was 3 or 4 years old, he played on a hockey team he thought was called the Toronto Make-Believes (Maple Leafs). Maybe we should be telling parents it’s safe for their children to play make-believe contact sports. The challenge comes after those kids reach puberty and want to start playing the real thing.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.

CHARLOTTE, N.C. – Approximately one-fifth of pediatric stroke activations are for ischemic stroke or transient ischemic attack (TIA), according to research presented at the annual meeting of the Child Neurology Society. Ischemic stroke and TIA were the second leading diagnoses among the stroke activations examined in the study, after seizure and Todd’s paralysis. “These data, in conjunction with previous studies, highlight the importance of developing protocols for early recognition and evaluation of children who present with strokelike symptoms,” said Tiffany Barkley, DO, a child neurology resident at Children’s Mercy Hospital in Kansas City, Mo., and colleagues.

Dr. Barkley and colleagues conducted their research to describe the demographic and other characteristics of patients who present with strokelike symptoms to their hospital. They undertook a descriptive, retrospective chart review of patients who came to Children’s Mercy Hospital from Sept. 1, 2016, to August 31, 2018, with concern for acute stroke. The investigators examined only patients for whom the Stroke Alert Process and power plan were activated.

“Power plans were created at Children’s Mercy Hospital to streamline and standardize care for children,” said Dr. Barkley. “While stroke order sets tend to be common practice in many adult hospitals, stroke order sets in pediatric hospitals are new.”

In all, 61 stroke activations occurred during the study period. Twelve patients (20%) had a final diagnosis of ischemic stroke or TIA. Among the patients with a final diagnosis of ischemic stroke, the most common presenting symptom was unilateral weakness. Two of these patients were candidates for intervention with mechanical thrombectomy, and none received tissue plasminogen activator. The average age of patients in all activations was 14 years, and the average age of patients with a final diagnosis of ischemic stroke or TIA was 4 years. About 37 (61%) subjects of activations were female, and the most common racial demographic was Caucasian.

Ischemic stroke or TIA was the second most common diagnosis of all activations (12 patients; 20%). Seizure or Todd’s paralysis (14 patients; 23%) was the leading diagnosis. Other common diagnoses included migraine (18%), psychogenic or conversion disorder (15%), oncologic process (3.0%), and complications of meningitis or encephalitis (1.6%). Children who presented with ischemic stroke secondary to Moyamoya disease were classified separately (two patients or 3%). It can be difficult to distinguish between stroke and stroke mimics based on neurologic examination alone, and imaging such as MRI often is needed, said Dr. Barkley. The researchers did not identify any intracranial hemorrhages in this patient population.

These findings are consistent with current reported literature, said the researchers. “Our study is one of the first to look at the demographics of children who present with strokelike symptoms,” said Dr. Barkley. “We hope that our study will not only help identify children who present with symptoms concerning for stroke, but also help us identify children who may be at risk for ischemic stroke before the stroke happens.”

The investigators did not have funding for this study and did not report any disclosures.

[email protected]

SOURCE: Barkley T et al. CNS 2019. Abstract 235.

CHARLOTTE, N.C. – Approximately one-fifth of pediatric stroke activations are for ischemic stroke or transient ischemic attack (TIA), according to research presented at the annual meeting of the Child Neurology Society. Ischemic stroke and TIA were the second leading diagnoses among the stroke activations examined in the study, after seizure and Todd’s paralysis. “These data, in conjunction with previous studies, highlight the importance of developing protocols for early recognition and evaluation of children who present with strokelike symptoms,” said Tiffany Barkley, DO, a child neurology resident at Children’s Mercy Hospital in Kansas City, Mo., and colleagues.

Dr. Barkley and colleagues conducted their research to describe the demographic and other characteristics of patients who present with strokelike symptoms to their hospital. They undertook a descriptive, retrospective chart review of patients who came to Children’s Mercy Hospital from Sept. 1, 2016, to August 31, 2018, with concern for acute stroke. The investigators examined only patients for whom the Stroke Alert Process and power plan were activated.

“Power plans were created at Children’s Mercy Hospital to streamline and standardize care for children,” said Dr. Barkley. “While stroke order sets tend to be common practice in many adult hospitals, stroke order sets in pediatric hospitals are new.”

In all, 61 stroke activations occurred during the study period. Twelve patients (20%) had a final diagnosis of ischemic stroke or TIA. Among the patients with a final diagnosis of ischemic stroke, the most common presenting symptom was unilateral weakness. Two of these patients were candidates for intervention with mechanical thrombectomy, and none received tissue plasminogen activator. The average age of patients in all activations was 14 years, and the average age of patients with a final diagnosis of ischemic stroke or TIA was 4 years. About 37 (61%) subjects of activations were female, and the most common racial demographic was Caucasian.

Ischemic stroke or TIA was the second most common diagnosis of all activations (12 patients; 20%). Seizure or Todd’s paralysis (14 patients; 23%) was the leading diagnosis. Other common diagnoses included migraine (18%), psychogenic or conversion disorder (15%), oncologic process (3.0%), and complications of meningitis or encephalitis (1.6%). Children who presented with ischemic stroke secondary to Moyamoya disease were classified separately (two patients or 3%). It can be difficult to distinguish between stroke and stroke mimics based on neurologic examination alone, and imaging such as MRI often is needed, said Dr. Barkley. The researchers did not identify any intracranial hemorrhages in this patient population.

These findings are consistent with current reported literature, said the researchers. “Our study is one of the first to look at the demographics of children who present with strokelike symptoms,” said Dr. Barkley. “We hope that our study will not only help identify children who present with symptoms concerning for stroke, but also help us identify children who may be at risk for ischemic stroke before the stroke happens.”

The investigators did not have funding for this study and did not report any disclosures.

[email protected]

SOURCE: Barkley T et al. CNS 2019. Abstract 235.

CHARLOTTE, N.C. – Approximately one-fifth of pediatric stroke activations are for ischemic stroke or transient ischemic attack (TIA), according to research presented at the annual meeting of the Child Neurology Society. Ischemic stroke and TIA were the second leading diagnoses among the stroke activations examined in the study, after seizure and Todd’s paralysis. “These data, in conjunction with previous studies, highlight the importance of developing protocols for early recognition and evaluation of children who present with strokelike symptoms,” said Tiffany Barkley, DO, a child neurology resident at Children’s Mercy Hospital in Kansas City, Mo., and colleagues.

Dr. Barkley and colleagues conducted their research to describe the demographic and other characteristics of patients who present with strokelike symptoms to their hospital. They undertook a descriptive, retrospective chart review of patients who came to Children’s Mercy Hospital from Sept. 1, 2016, to August 31, 2018, with concern for acute stroke. The investigators examined only patients for whom the Stroke Alert Process and power plan were activated.

“Power plans were created at Children’s Mercy Hospital to streamline and standardize care for children,” said Dr. Barkley. “While stroke order sets tend to be common practice in many adult hospitals, stroke order sets in pediatric hospitals are new.”

In all, 61 stroke activations occurred during the study period. Twelve patients (20%) had a final diagnosis of ischemic stroke or TIA. Among the patients with a final diagnosis of ischemic stroke, the most common presenting symptom was unilateral weakness. Two of these patients were candidates for intervention with mechanical thrombectomy, and none received tissue plasminogen activator. The average age of patients in all activations was 14 years, and the average age of patients with a final diagnosis of ischemic stroke or TIA was 4 years. About 37 (61%) subjects of activations were female, and the most common racial demographic was Caucasian.

Ischemic stroke or TIA was the second most common diagnosis of all activations (12 patients; 20%). Seizure or Todd’s paralysis (14 patients; 23%) was the leading diagnosis. Other common diagnoses included migraine (18%), psychogenic or conversion disorder (15%), oncologic process (3.0%), and complications of meningitis or encephalitis (1.6%). Children who presented with ischemic stroke secondary to Moyamoya disease were classified separately (two patients or 3%). It can be difficult to distinguish between stroke and stroke mimics based on neurologic examination alone, and imaging such as MRI often is needed, said Dr. Barkley. The researchers did not identify any intracranial hemorrhages in this patient population.

These findings are consistent with current reported literature, said the researchers. “Our study is one of the first to look at the demographics of children who present with strokelike symptoms,” said Dr. Barkley. “We hope that our study will not only help identify children who present with symptoms concerning for stroke, but also help us identify children who may be at risk for ischemic stroke before the stroke happens.”

The investigators did not have funding for this study and did not report any disclosures.

[email protected]

SOURCE: Barkley T et al. CNS 2019. Abstract 235.