Neurology

In patients with acute ischemic stroke who have not received thrombolysis or thrombectomy, early antihypertensive treatment compared with delayed antihypertensive treatment did not reduce the likelihood of death and major disability at 3 months in the CATIS-2 trial.

The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.

But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.

Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”

But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”

Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.

“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.

In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.

In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.

Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.

The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.

Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).

The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.

BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).

At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).

The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).

There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).

There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.

Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.

Dr. Liu has disclosed no relevant financial relationships.

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

In patients with acute ischemic stroke who have not received thrombolysis or thrombectomy, early antihypertensive treatment compared with delayed antihypertensive treatment did not reduce the likelihood of death and major disability at 3 months in the CATIS-2 trial.

The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.

But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.

Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”

But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”

Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.

“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.

In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.

In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.

Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.

The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.

Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).

The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.

BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).

At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).

The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).

There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).

There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.

Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.

Dr. Liu has disclosed no relevant financial relationships.

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

In patients with acute ischemic stroke who have not received thrombolysis or thrombectomy, early antihypertensive treatment compared with delayed antihypertensive treatment did not reduce the likelihood of death and major disability at 3 months in the CATIS-2 trial.

The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.

But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.

Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”

But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”

Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.

“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.

In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.

In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.

Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.

The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.

Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).

The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.

BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).

At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).

The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).

There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).

There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.

Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.

Dr. Liu has disclosed no relevant financial relationships.

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

Among Chinese patients with minor nondisabling stroke who presented within 4.5 hours of symptom onset, dual antiplatelet treatment was noninferior to thrombolysis with intravenous alteplase with regard to functional outcome at 90 days in the ARAMIS trial.

The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.

In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.

Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”

She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”

Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.

A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.

This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.

In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.

In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.

The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.

The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).

The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.

In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).

“Therefore, this was a positive trial,” Dr. Nguyen stated.

About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.

Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.

In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.

Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).

Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.

Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.

In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.

“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.

“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.

In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”

But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”

The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.

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

Among Chinese patients with minor nondisabling stroke who presented within 4.5 hours of symptom onset, dual antiplatelet treatment was noninferior to thrombolysis with intravenous alteplase with regard to functional outcome at 90 days in the ARAMIS trial.

The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.

In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.

Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”

She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”

Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.

A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.

This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.

In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.

In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.

The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.

The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).

The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.

In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).

“Therefore, this was a positive trial,” Dr. Nguyen stated.

About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.

Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.

In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.

Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).

Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.

Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.

In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.

“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.

“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.

In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”

But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”

The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.

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

Among Chinese patients with minor nondisabling stroke who presented within 4.5 hours of symptom onset, dual antiplatelet treatment was noninferior to thrombolysis with intravenous alteplase with regard to functional outcome at 90 days in the ARAMIS trial.

The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.

In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.

Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”

She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”

Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.

A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.

This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.

In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.

In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.

The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.

The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).

The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.

In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).

“Therefore, this was a positive trial,” Dr. Nguyen stated.

About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.

Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.

In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.

Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).

Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.

Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.

In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.

“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.

“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.

In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”

But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”

The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.

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

Treatment with the thiazolidinedione pioglitazone may offer the greatest protection against dementia for older adults with newly diagnosed type 2 diabetes mellitus (T2DM) who have a history of stroke or ischemic heart disease, new research suggests.

Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.

However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.

“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.

However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.

This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.

The results were published online in Neurology.
 

Dose-response relationship

Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.

This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.

Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.

Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.

Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.

There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).

A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
 

Several limitations

The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).

The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.

The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.

However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.

The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.

There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
 

More data needed

In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”

However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.

They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.

They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.

“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.

For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.

The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.

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

Treatment with the thiazolidinedione pioglitazone may offer the greatest protection against dementia for older adults with newly diagnosed type 2 diabetes mellitus (T2DM) who have a history of stroke or ischemic heart disease, new research suggests.

Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.

However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.

“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.

However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.

This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.

The results were published online in Neurology.
 

Dose-response relationship

Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.

This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.

Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.

Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.

Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.

There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).

A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
 

Several limitations

The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).

The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.

The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.

However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.

The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.

There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
 

More data needed

In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”

However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.

They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.

They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.

“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.

For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.

The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.

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

Treatment with the thiazolidinedione pioglitazone may offer the greatest protection against dementia for older adults with newly diagnosed type 2 diabetes mellitus (T2DM) who have a history of stroke or ischemic heart disease, new research suggests.

Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.

However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.

“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.

However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.

This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.

The results were published online in Neurology.
 

Dose-response relationship

Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.

This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.

Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.

Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.

Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.

There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).

A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
 

Several limitations

The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).

The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.

The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.

However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.

The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.

There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
 

More data needed

In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”

However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.

They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.

They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.

“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.

For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.

The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.

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

Maternal primary antibody immunodeficiencies (PIDs) are tied to increased risk for psychiatric disorders and suicidality in offspring, new research suggests.

Results from a cohort study of more than 4.2 million individuals showed that offspring of mothers with PIDs had a 17% increased risk for a psychiatric disorder and a 20% increased risk for suicidal behavior, compared with their peers with mothers who did not have PIDs.

The risk was more pronounced in offspring of mothers with both PIDs and autoimmune diseases. These risks remained after strictly controlling for different covariates, such as the parents’ psychiatric history, offspring PIDs, and offspring autoimmune diseases.

The investigators, led by Josef Isung, MD, PhD, Centre for Psychiatry Research, department of clinical neuroscience, Karolinska Institutet, Stockholm, noted that they could not “pinpoint a precise causal mechanism” underlying these findings.

Still, “the results add to the existing literature suggesting that the intrauterine immune environment may have implications for fetal neurodevelopment and that a compromised maternal immune system during pregnancy may be a risk factor for psychiatric disorders and suicidal behavior in their offspring in the long term,” they wrote.

The findings were published online in JAMA Psychiatry.
 

‘Natural experiment’

Maternal immune activation (MIA) is “an overarching term for aberrant and disrupted immune activity in the mother during gestation [and] has long been of interest in relation to adverse health outcomes in the offspring,” Dr. Isung noted.

“In relation to negative psychiatric outcomes, there is an abundance of preclinical evidence that has shown a negative impact on offspring secondary to MIA. And in humans, there are several observational studies supporting this link,” he said in an interview.

Dr. Isung added that PIDs are “rare conditions” known to be associated with repeated infections and high rates of autoimmune diseases, causing substantial disability.

“PIDs represent an interesting ‘natural experiment’ for researchers to understand more about the association between immune system dysfunctions and mental health,” he said.

Dr. Isung’s group previously showed that individuals with PIDs have increased odds of psychiatric disorders and suicidal behavior. The link was more pronounced in women with PIDs – and was even more pronounced in those with both PIDs and autoimmune diseases.

In the current study, “we wanted to see whether offspring of individuals were differentially at risk of psychiatric disorders and suicidal behavior, depending on being offspring of mothers or fathers with PIDs,” Dr. Isung said.

“Our hypothesis was that mothers with PIDs would have an increased risk of having offspring with neuropsychiatric outcomes, and that this risk could be due to MIA,” he added.

The researchers turned to Swedish nationwide health and administrative registers. They analyzed data on all individuals with diagnoses of PIDs identified between 1973 and 2013. Offspring born prior to 2003 were included, and parent-offspring pairs in which both parents had a history of PIDs were excluded.

The final study sample consisted of 4,294,169 offspring (51.4% boys). Of these participants, 7,270 (0.17%) had a parent with PIDs.

The researchers identified lifetime records of 10 psychiatric disorders: obsessive-compulsive disorder, ADHD, autism spectrum disorders, schizophrenia and other psychotic disorders, bipolar disorders, major depressive disorder and other mood disorders, anxiety and stress-related disorders, eating disorders, substance use disorders, and Tourette syndrome and chronic tic disorders.

The investigators included parental birth year, psychopathology, suicide attempts, suicide deaths, and autoimmune diseases as covariates, as well as offsprings’ birth year and gender.
 

Elucidation needed

Results showed that, of the 4,676 offspring of mothers with PID, 17.1% had a psychiatric disorder versus 12.7% of offspring of mothers without PIDs. This translated “into a 17% increased risk for offspring of mothers with PIDs in the fully adjusted model,” the investigators reported.

The risk was even higher for offspring of mothers who had not only PIDs but also one of six of the individual psychiatric disorders, with incident rate ratios ranging from 1.15 to 1.71.

Important piece of the puzzle?

In a comment, Michael Eriksen Benros, MD, PhD, professor of immunopsychiatry, department of immunology and microbiology, health, and medical sciences, University of Copenhagen, said this was a “high-quality study” that used a “rich data source.”

Dr. Benros, who is also head of research (biological and precision psychiatry) at the Copenhagen Research Centre for Mental Health, Copenhagen University Hospital, was not involved with the current study.

He noted that prior studies, including some conducted by his own group, have shown that maternal infections overall did not seem to be “specifically linked to mental disorders in the offspring.”

However, “specific maternal infections or specific brain-reactive antibodies during the pregnancy period have been shown to be associated with neurodevelopmental outcomes among the children,” such as intellectual disability, he said.

Regarding direct clinical implications of the study, “it is important to note that the increased risk of psychiatric disorders and suicidality in the offspring of mothers with PID were small,” Dr. Benros said.

“However, it adds an important part to the scientific puzzle regarding the role of maternal immune activation during pregnancy and the risk of mental disorders,” he added.

The study was funded by the Söderström König Foundation and the Fredrik and Ingrid Thuring Foundation. Neither Dr. Isung nor Dr. Benros reported no relevant financial relationships.

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

Maternal primary antibody immunodeficiencies (PIDs) are tied to increased risk for psychiatric disorders and suicidality in offspring, new research suggests.

Results from a cohort study of more than 4.2 million individuals showed that offspring of mothers with PIDs had a 17% increased risk for a psychiatric disorder and a 20% increased risk for suicidal behavior, compared with their peers with mothers who did not have PIDs.

The risk was more pronounced in offspring of mothers with both PIDs and autoimmune diseases. These risks remained after strictly controlling for different covariates, such as the parents’ psychiatric history, offspring PIDs, and offspring autoimmune diseases.

The investigators, led by Josef Isung, MD, PhD, Centre for Psychiatry Research, department of clinical neuroscience, Karolinska Institutet, Stockholm, noted that they could not “pinpoint a precise causal mechanism” underlying these findings.

Still, “the results add to the existing literature suggesting that the intrauterine immune environment may have implications for fetal neurodevelopment and that a compromised maternal immune system during pregnancy may be a risk factor for psychiatric disorders and suicidal behavior in their offspring in the long term,” they wrote.

The findings were published online in JAMA Psychiatry.
 

‘Natural experiment’

Maternal immune activation (MIA) is “an overarching term for aberrant and disrupted immune activity in the mother during gestation [and] has long been of interest in relation to adverse health outcomes in the offspring,” Dr. Isung noted.

“In relation to negative psychiatric outcomes, there is an abundance of preclinical evidence that has shown a negative impact on offspring secondary to MIA. And in humans, there are several observational studies supporting this link,” he said in an interview.

Dr. Isung added that PIDs are “rare conditions” known to be associated with repeated infections and high rates of autoimmune diseases, causing substantial disability.

“PIDs represent an interesting ‘natural experiment’ for researchers to understand more about the association between immune system dysfunctions and mental health,” he said.

Dr. Isung’s group previously showed that individuals with PIDs have increased odds of psychiatric disorders and suicidal behavior. The link was more pronounced in women with PIDs – and was even more pronounced in those with both PIDs and autoimmune diseases.

In the current study, “we wanted to see whether offspring of individuals were differentially at risk of psychiatric disorders and suicidal behavior, depending on being offspring of mothers or fathers with PIDs,” Dr. Isung said.

“Our hypothesis was that mothers with PIDs would have an increased risk of having offspring with neuropsychiatric outcomes, and that this risk could be due to MIA,” he added.

The researchers turned to Swedish nationwide health and administrative registers. They analyzed data on all individuals with diagnoses of PIDs identified between 1973 and 2013. Offspring born prior to 2003 were included, and parent-offspring pairs in which both parents had a history of PIDs were excluded.

The final study sample consisted of 4,294,169 offspring (51.4% boys). Of these participants, 7,270 (0.17%) had a parent with PIDs.

The researchers identified lifetime records of 10 psychiatric disorders: obsessive-compulsive disorder, ADHD, autism spectrum disorders, schizophrenia and other psychotic disorders, bipolar disorders, major depressive disorder and other mood disorders, anxiety and stress-related disorders, eating disorders, substance use disorders, and Tourette syndrome and chronic tic disorders.

The investigators included parental birth year, psychopathology, suicide attempts, suicide deaths, and autoimmune diseases as covariates, as well as offsprings’ birth year and gender.
 

Elucidation needed

Results showed that, of the 4,676 offspring of mothers with PID, 17.1% had a psychiatric disorder versus 12.7% of offspring of mothers without PIDs. This translated “into a 17% increased risk for offspring of mothers with PIDs in the fully adjusted model,” the investigators reported.

The risk was even higher for offspring of mothers who had not only PIDs but also one of six of the individual psychiatric disorders, with incident rate ratios ranging from 1.15 to 1.71.

Important piece of the puzzle?

In a comment, Michael Eriksen Benros, MD, PhD, professor of immunopsychiatry, department of immunology and microbiology, health, and medical sciences, University of Copenhagen, said this was a “high-quality study” that used a “rich data source.”

Dr. Benros, who is also head of research (biological and precision psychiatry) at the Copenhagen Research Centre for Mental Health, Copenhagen University Hospital, was not involved with the current study.

He noted that prior studies, including some conducted by his own group, have shown that maternal infections overall did not seem to be “specifically linked to mental disorders in the offspring.”

However, “specific maternal infections or specific brain-reactive antibodies during the pregnancy period have been shown to be associated with neurodevelopmental outcomes among the children,” such as intellectual disability, he said.

Regarding direct clinical implications of the study, “it is important to note that the increased risk of psychiatric disorders and suicidality in the offspring of mothers with PID were small,” Dr. Benros said.

“However, it adds an important part to the scientific puzzle regarding the role of maternal immune activation during pregnancy and the risk of mental disorders,” he added.

The study was funded by the Söderström König Foundation and the Fredrik and Ingrid Thuring Foundation. Neither Dr. Isung nor Dr. Benros reported no relevant financial relationships.

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

Maternal primary antibody immunodeficiencies (PIDs) are tied to increased risk for psychiatric disorders and suicidality in offspring, new research suggests.

Results from a cohort study of more than 4.2 million individuals showed that offspring of mothers with PIDs had a 17% increased risk for a psychiatric disorder and a 20% increased risk for suicidal behavior, compared with their peers with mothers who did not have PIDs.

The risk was more pronounced in offspring of mothers with both PIDs and autoimmune diseases. These risks remained after strictly controlling for different covariates, such as the parents’ psychiatric history, offspring PIDs, and offspring autoimmune diseases.

The investigators, led by Josef Isung, MD, PhD, Centre for Psychiatry Research, department of clinical neuroscience, Karolinska Institutet, Stockholm, noted that they could not “pinpoint a precise causal mechanism” underlying these findings.

Still, “the results add to the existing literature suggesting that the intrauterine immune environment may have implications for fetal neurodevelopment and that a compromised maternal immune system during pregnancy may be a risk factor for psychiatric disorders and suicidal behavior in their offspring in the long term,” they wrote.

The findings were published online in JAMA Psychiatry.
 

‘Natural experiment’

Maternal immune activation (MIA) is “an overarching term for aberrant and disrupted immune activity in the mother during gestation [and] has long been of interest in relation to adverse health outcomes in the offspring,” Dr. Isung noted.

“In relation to negative psychiatric outcomes, there is an abundance of preclinical evidence that has shown a negative impact on offspring secondary to MIA. And in humans, there are several observational studies supporting this link,” he said in an interview.

Dr. Isung added that PIDs are “rare conditions” known to be associated with repeated infections and high rates of autoimmune diseases, causing substantial disability.

“PIDs represent an interesting ‘natural experiment’ for researchers to understand more about the association between immune system dysfunctions and mental health,” he said.

Dr. Isung’s group previously showed that individuals with PIDs have increased odds of psychiatric disorders and suicidal behavior. The link was more pronounced in women with PIDs – and was even more pronounced in those with both PIDs and autoimmune diseases.

In the current study, “we wanted to see whether offspring of individuals were differentially at risk of psychiatric disorders and suicidal behavior, depending on being offspring of mothers or fathers with PIDs,” Dr. Isung said.

“Our hypothesis was that mothers with PIDs would have an increased risk of having offspring with neuropsychiatric outcomes, and that this risk could be due to MIA,” he added.

The researchers turned to Swedish nationwide health and administrative registers. They analyzed data on all individuals with diagnoses of PIDs identified between 1973 and 2013. Offspring born prior to 2003 were included, and parent-offspring pairs in which both parents had a history of PIDs were excluded.

The final study sample consisted of 4,294,169 offspring (51.4% boys). Of these participants, 7,270 (0.17%) had a parent with PIDs.

The researchers identified lifetime records of 10 psychiatric disorders: obsessive-compulsive disorder, ADHD, autism spectrum disorders, schizophrenia and other psychotic disorders, bipolar disorders, major depressive disorder and other mood disorders, anxiety and stress-related disorders, eating disorders, substance use disorders, and Tourette syndrome and chronic tic disorders.

The investigators included parental birth year, psychopathology, suicide attempts, suicide deaths, and autoimmune diseases as covariates, as well as offsprings’ birth year and gender.
 

Elucidation needed

Results showed that, of the 4,676 offspring of mothers with PID, 17.1% had a psychiatric disorder versus 12.7% of offspring of mothers without PIDs. This translated “into a 17% increased risk for offspring of mothers with PIDs in the fully adjusted model,” the investigators reported.

The risk was even higher for offspring of mothers who had not only PIDs but also one of six of the individual psychiatric disorders, with incident rate ratios ranging from 1.15 to 1.71.

Important piece of the puzzle?

In a comment, Michael Eriksen Benros, MD, PhD, professor of immunopsychiatry, department of immunology and microbiology, health, and medical sciences, University of Copenhagen, said this was a “high-quality study” that used a “rich data source.”

Dr. Benros, who is also head of research (biological and precision psychiatry) at the Copenhagen Research Centre for Mental Health, Copenhagen University Hospital, was not involved with the current study.

He noted that prior studies, including some conducted by his own group, have shown that maternal infections overall did not seem to be “specifically linked to mental disorders in the offspring.”

However, “specific maternal infections or specific brain-reactive antibodies during the pregnancy period have been shown to be associated with neurodevelopmental outcomes among the children,” such as intellectual disability, he said.

Regarding direct clinical implications of the study, “it is important to note that the increased risk of psychiatric disorders and suicidality in the offspring of mothers with PID were small,” Dr. Benros said.

“However, it adds an important part to the scientific puzzle regarding the role of maternal immune activation during pregnancy and the risk of mental disorders,” he added.

The study was funded by the Söderström König Foundation and the Fredrik and Ingrid Thuring Foundation. Neither Dr. Isung nor Dr. Benros reported no relevant financial relationships.

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

Slowing progression of, rather than stopping, Alzheimer’s disease (AD) has measurable benefits for patients and families and may be a more realistic goal for clinical AD drug trials, a new report suggests.

The report is a yearlong undertaking by an expert work group convened by the Alzheimer’s Association and was prompted, in part, by the fallout from the U.S. Food and Drug Administration’s controversial decision to grant aducanumab (Aduhelm) accelerated approval, which came over the objection of an advisory panel that found the drug was ineffective.

The report’s authors call for a “reframing” of how researchers define “clinically meaningful” in randomized controlled trials (RCTs), noting that it’s time to adjust expectations of outcomes from relatively short clinical trials.

“Without lowering the bar, are we expecting too much from a clinical trial by expecting that unless the disease is halted in its tracks and there’s no progression, we failed at treatment?” the report’s lead author and group leader Ronald C. Petersen, MD, PhD, lead author, chair of the work group, and professor of neurology at the Mayo Clinic, Rochester, Minn., told this news organization.

Interpretations of clinical meaningfulness are used in the drug approval process and in decisions about whether an insurer will cover the cost of treatment, the authors note.

While the report doesn’t provide a consensus definition of clinically meaningful benefit, it does offer a starting point for a conversation about how the phrase should be defined in the context of RCTs for disease-modifying therapies (DMTs) in AD, Dr. Petersen said.

“What we tried to do was to put it into some kind of perspective and at least have people reflect on this: If you’re going to design the perfect drug trial in Alzheimer’s disease, what would it be? We wanted to get people to think about it without digging in their heels for or against,” he added.

The report was published online  in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
 

A proactive measure

The expert group began its work in January 2022, less than a year after the FDA approved aducanumab. Since the panel began its work, the FDA has approved a second AD drug, lecanemab (Leqembi), and denied accelerated approval of a third medication, donanemab.

“At the time we started this group, we had one approved treatment, and we just knew that there were others on the way, and we needed to be prepared to have this conversation and be more proactive than reactive,” Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association and co-author of the report, said in an interview.

The work group suggests that simply slowing disease progression might be a desired goal for drug trials, especially early on, before cognition and memory are affected.

They also note that a benefit identified during an 18-month clinical trial may ultimately lead to even more meaningful changes over coming years, well beyond the trial’s end.

In addition, the report authors call for the development of better research tools to more accurately assess meaningful change. The Clinical Dementia Rating (CDR) scale is currently the key instrument used as a primary outcome measure in RCTs. However, the report’s authors note that it may not be adequate to measure meaningful change in early-stage disease.

“Developing better tools certainly should be on the radar screen for all of us, because I think we can do better,” Dr. Petersen said. “The CDR, as good as it is and as long as it’s been used in the field, is a pretty blunt instrument, and it’s the result of subjective ratings.”
 

‘Quality of mind’

Jason Karlawish, MD, professor of medicine, medical ethics, health policy, and neurology at the University of Pennsylvania, Philadelphia, said measuring the actual impact of a drug on a patient’s disease and quality of life has been a hot topic in the AD field for some time, but settling on a definition of “clinically meaningful” that everyone agrees upon will be a challenge.

“I think the idea of ‘clinically meaningful’ is truly a socially constructed idea,” said Dr. Karlawish, co-director of Penn’s Memory Center, who did not work on the report.

“You can come up with objective measures of cognition, but a measure to call something ‘clinically meaningful’ ultimately requires some sort of negotiated social order among clinicians and patients and others who have immediate interest in the health and well-being of the patient.”

Dr. Karlawish added that he’s interested in the conversations the report might prompt and the challenges it could highlight, especially when it comes to how meaningful clinical benefit can be measured, regardless of how it’s defined.

“Hidden in this conversation about clinically meaningful treatments in Alzheimer’s disease is, frankly, not quality of life, but quality of mind,” said Dr. Karlawish. “No measure captures acceptably the very thing that everyone actually cares a lot about and why we view this disease as so dreadful, which is damage to our mind.”
 

More evidence needed

The development of such tools will take time. What does that mean for drugs already in the pipeline? Members of the work group argue that those trials must move forward at the same time new tools are being created.

“We need to continue to refine, develop better instruments, [and] develop tools that are going to assess the disease in its more subtle features early on, even in the so-called ‘pre-symptomatic’ stage of the disease,” said lead author Dr. Petersen. “We shouldn’t wait for the development of that before intervening if we have a drug that seems to work.”

However, not everyone who agrees with the premise of the report agrees with this position, including Joel S. Perlmutter, MD, professor of neurology, Washington University School of Medicine, St. Louis, who also commented on the report.

As reported by this news organization, Dr. Perlmutter was one of three physicians who resigned from the FDA advisory panel that voted against approving aducanumab after the agency moved forward anyway.

“We have to be careful not to recommend DMTs that we hope will help without strong evidence, especially when potential side effects are not trivial,” Dr. Perlmutter said. “We have to have evidence before making these recommendations so we don’t end up harming people more than helping them.”

The report received no specific funding. Dr. Petersen received consulting fees from Roche, Nestle, Merck, Biogen, Eisai, and Genentech. Full disclosures are included in the original article. Dr. Perlmutter and Dr. Karlawish report no relevant financial relationships.

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

Slowing progression of, rather than stopping, Alzheimer’s disease (AD) has measurable benefits for patients and families and may be a more realistic goal for clinical AD drug trials, a new report suggests.

The report is a yearlong undertaking by an expert work group convened by the Alzheimer’s Association and was prompted, in part, by the fallout from the U.S. Food and Drug Administration’s controversial decision to grant aducanumab (Aduhelm) accelerated approval, which came over the objection of an advisory panel that found the drug was ineffective.

The report’s authors call for a “reframing” of how researchers define “clinically meaningful” in randomized controlled trials (RCTs), noting that it’s time to adjust expectations of outcomes from relatively short clinical trials.

“Without lowering the bar, are we expecting too much from a clinical trial by expecting that unless the disease is halted in its tracks and there’s no progression, we failed at treatment?” the report’s lead author and group leader Ronald C. Petersen, MD, PhD, lead author, chair of the work group, and professor of neurology at the Mayo Clinic, Rochester, Minn., told this news organization.

Interpretations of clinical meaningfulness are used in the drug approval process and in decisions about whether an insurer will cover the cost of treatment, the authors note.

While the report doesn’t provide a consensus definition of clinically meaningful benefit, it does offer a starting point for a conversation about how the phrase should be defined in the context of RCTs for disease-modifying therapies (DMTs) in AD, Dr. Petersen said.

“What we tried to do was to put it into some kind of perspective and at least have people reflect on this: If you’re going to design the perfect drug trial in Alzheimer’s disease, what would it be? We wanted to get people to think about it without digging in their heels for or against,” he added.

The report was published online  in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
 

A proactive measure

The expert group began its work in January 2022, less than a year after the FDA approved aducanumab. Since the panel began its work, the FDA has approved a second AD drug, lecanemab (Leqembi), and denied accelerated approval of a third medication, donanemab.

“At the time we started this group, we had one approved treatment, and we just knew that there were others on the way, and we needed to be prepared to have this conversation and be more proactive than reactive,” Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association and co-author of the report, said in an interview.

The work group suggests that simply slowing disease progression might be a desired goal for drug trials, especially early on, before cognition and memory are affected.

They also note that a benefit identified during an 18-month clinical trial may ultimately lead to even more meaningful changes over coming years, well beyond the trial’s end.

In addition, the report authors call for the development of better research tools to more accurately assess meaningful change. The Clinical Dementia Rating (CDR) scale is currently the key instrument used as a primary outcome measure in RCTs. However, the report’s authors note that it may not be adequate to measure meaningful change in early-stage disease.

“Developing better tools certainly should be on the radar screen for all of us, because I think we can do better,” Dr. Petersen said. “The CDR, as good as it is and as long as it’s been used in the field, is a pretty blunt instrument, and it’s the result of subjective ratings.”
 

‘Quality of mind’

Jason Karlawish, MD, professor of medicine, medical ethics, health policy, and neurology at the University of Pennsylvania, Philadelphia, said measuring the actual impact of a drug on a patient’s disease and quality of life has been a hot topic in the AD field for some time, but settling on a definition of “clinically meaningful” that everyone agrees upon will be a challenge.

“I think the idea of ‘clinically meaningful’ is truly a socially constructed idea,” said Dr. Karlawish, co-director of Penn’s Memory Center, who did not work on the report.

“You can come up with objective measures of cognition, but a measure to call something ‘clinically meaningful’ ultimately requires some sort of negotiated social order among clinicians and patients and others who have immediate interest in the health and well-being of the patient.”

Dr. Karlawish added that he’s interested in the conversations the report might prompt and the challenges it could highlight, especially when it comes to how meaningful clinical benefit can be measured, regardless of how it’s defined.

“Hidden in this conversation about clinically meaningful treatments in Alzheimer’s disease is, frankly, not quality of life, but quality of mind,” said Dr. Karlawish. “No measure captures acceptably the very thing that everyone actually cares a lot about and why we view this disease as so dreadful, which is damage to our mind.”
 

More evidence needed

The development of such tools will take time. What does that mean for drugs already in the pipeline? Members of the work group argue that those trials must move forward at the same time new tools are being created.

“We need to continue to refine, develop better instruments, [and] develop tools that are going to assess the disease in its more subtle features early on, even in the so-called ‘pre-symptomatic’ stage of the disease,” said lead author Dr. Petersen. “We shouldn’t wait for the development of that before intervening if we have a drug that seems to work.”

However, not everyone who agrees with the premise of the report agrees with this position, including Joel S. Perlmutter, MD, professor of neurology, Washington University School of Medicine, St. Louis, who also commented on the report.

As reported by this news organization, Dr. Perlmutter was one of three physicians who resigned from the FDA advisory panel that voted against approving aducanumab after the agency moved forward anyway.

“We have to be careful not to recommend DMTs that we hope will help without strong evidence, especially when potential side effects are not trivial,” Dr. Perlmutter said. “We have to have evidence before making these recommendations so we don’t end up harming people more than helping them.”

The report received no specific funding. Dr. Petersen received consulting fees from Roche, Nestle, Merck, Biogen, Eisai, and Genentech. Full disclosures are included in the original article. Dr. Perlmutter and Dr. Karlawish report no relevant financial relationships.

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

Slowing progression of, rather than stopping, Alzheimer’s disease (AD) has measurable benefits for patients and families and may be a more realistic goal for clinical AD drug trials, a new report suggests.

The report is a yearlong undertaking by an expert work group convened by the Alzheimer’s Association and was prompted, in part, by the fallout from the U.S. Food and Drug Administration’s controversial decision to grant aducanumab (Aduhelm) accelerated approval, which came over the objection of an advisory panel that found the drug was ineffective.

The report’s authors call for a “reframing” of how researchers define “clinically meaningful” in randomized controlled trials (RCTs), noting that it’s time to adjust expectations of outcomes from relatively short clinical trials.

“Without lowering the bar, are we expecting too much from a clinical trial by expecting that unless the disease is halted in its tracks and there’s no progression, we failed at treatment?” the report’s lead author and group leader Ronald C. Petersen, MD, PhD, lead author, chair of the work group, and professor of neurology at the Mayo Clinic, Rochester, Minn., told this news organization.

Interpretations of clinical meaningfulness are used in the drug approval process and in decisions about whether an insurer will cover the cost of treatment, the authors note.

While the report doesn’t provide a consensus definition of clinically meaningful benefit, it does offer a starting point for a conversation about how the phrase should be defined in the context of RCTs for disease-modifying therapies (DMTs) in AD, Dr. Petersen said.

“What we tried to do was to put it into some kind of perspective and at least have people reflect on this: If you’re going to design the perfect drug trial in Alzheimer’s disease, what would it be? We wanted to get people to think about it without digging in their heels for or against,” he added.

The report was published online  in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
 

A proactive measure

The expert group began its work in January 2022, less than a year after the FDA approved aducanumab. Since the panel began its work, the FDA has approved a second AD drug, lecanemab (Leqembi), and denied accelerated approval of a third medication, donanemab.

“At the time we started this group, we had one approved treatment, and we just knew that there were others on the way, and we needed to be prepared to have this conversation and be more proactive than reactive,” Christopher Weber, PhD, director of global science initiatives for the Alzheimer’s Association and co-author of the report, said in an interview.

The work group suggests that simply slowing disease progression might be a desired goal for drug trials, especially early on, before cognition and memory are affected.

They also note that a benefit identified during an 18-month clinical trial may ultimately lead to even more meaningful changes over coming years, well beyond the trial’s end.

In addition, the report authors call for the development of better research tools to more accurately assess meaningful change. The Clinical Dementia Rating (CDR) scale is currently the key instrument used as a primary outcome measure in RCTs. However, the report’s authors note that it may not be adequate to measure meaningful change in early-stage disease.

“Developing better tools certainly should be on the radar screen for all of us, because I think we can do better,” Dr. Petersen said. “The CDR, as good as it is and as long as it’s been used in the field, is a pretty blunt instrument, and it’s the result of subjective ratings.”
 

‘Quality of mind’

Jason Karlawish, MD, professor of medicine, medical ethics, health policy, and neurology at the University of Pennsylvania, Philadelphia, said measuring the actual impact of a drug on a patient’s disease and quality of life has been a hot topic in the AD field for some time, but settling on a definition of “clinically meaningful” that everyone agrees upon will be a challenge.

“I think the idea of ‘clinically meaningful’ is truly a socially constructed idea,” said Dr. Karlawish, co-director of Penn’s Memory Center, who did not work on the report.

“You can come up with objective measures of cognition, but a measure to call something ‘clinically meaningful’ ultimately requires some sort of negotiated social order among clinicians and patients and others who have immediate interest in the health and well-being of the patient.”

Dr. Karlawish added that he’s interested in the conversations the report might prompt and the challenges it could highlight, especially when it comes to how meaningful clinical benefit can be measured, regardless of how it’s defined.

“Hidden in this conversation about clinically meaningful treatments in Alzheimer’s disease is, frankly, not quality of life, but quality of mind,” said Dr. Karlawish. “No measure captures acceptably the very thing that everyone actually cares a lot about and why we view this disease as so dreadful, which is damage to our mind.”
 

More evidence needed

The development of such tools will take time. What does that mean for drugs already in the pipeline? Members of the work group argue that those trials must move forward at the same time new tools are being created.

“We need to continue to refine, develop better instruments, [and] develop tools that are going to assess the disease in its more subtle features early on, even in the so-called ‘pre-symptomatic’ stage of the disease,” said lead author Dr. Petersen. “We shouldn’t wait for the development of that before intervening if we have a drug that seems to work.”

However, not everyone who agrees with the premise of the report agrees with this position, including Joel S. Perlmutter, MD, professor of neurology, Washington University School of Medicine, St. Louis, who also commented on the report.

As reported by this news organization, Dr. Perlmutter was one of three physicians who resigned from the FDA advisory panel that voted against approving aducanumab after the agency moved forward anyway.

“We have to be careful not to recommend DMTs that we hope will help without strong evidence, especially when potential side effects are not trivial,” Dr. Perlmutter said. “We have to have evidence before making these recommendations so we don’t end up harming people more than helping them.”

The report received no specific funding. Dr. Petersen received consulting fees from Roche, Nestle, Merck, Biogen, Eisai, and Genentech. Full disclosures are included in the original article. Dr. Perlmutter and Dr. Karlawish report no relevant financial relationships.

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

Butylphthalide, a medication derived from celery seed, may improve outcomes after an acute ischemic stroke when given in addition to thrombolysis or endovascular treatment, a new report suggests.

Patients treated with butylphthalide had fewer severe neurologic symptoms and better function 90 days after the stroke, compared with those receiving placebo.

Butylphthalide is approved and available for use in China, where the study was conducted. However, the medication hasn’t been approved for use by the U.S. Food and Drug Administration.

“Patients who received butylphthalide had less severe neurological symptoms and a better living status at 90 days post stroke, compared to those who received the placebo,” said coauthor Baixue Jia, MD, an attending physician in interventional neuroradiology at the Beijing Tiantan Hospital of Capital Medical University and a faculty member at the China National Clinical Research Center for Neurological Diseases in Beijing. “If the results are confirmed in other trials, this may lead to more options to treat strokes caused by clots.”

The study was presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
 

Studying stroke outcomes

The researchers described butylphthalide as a cerebroprotective drug that was originally extracted from seeds of Apium graveolens. In China, previous studies have shown that the drug has cerebroprotective effects in animal models of ischemia-reperfusion, they noted.

In this randomized, double-blind, placebo-controlled trial, Dr. Jia and colleagues evaluated whether treatment with butylphthalide could improve 90-day outcomes for adults with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator (tPA), endovascular treatment, or both.

The participants were treated at one of 59 medical centers in China between July 2018 and February 2022. Those who had minimal stroke symptoms on their initial exam, defined as a score of 0-3 on the National Institutes of Health Stroke Scale, or had severe stroke symptoms, defined as having a score of 26 or higher on the NIHSS, were excluded from the study.

Along with an initial revascularization intervention chosen by their physician, participants were randomly selected to receive either butylphthalide or a placebo daily for 90 days. The drug was administered through daily intravenous injections for the first 14 days, after which patients received oral capsules for 76 days.

The research team defined the outcomes as “favorable” if a patient fell into one of the following categories 90 days after the stroke: an initially mild to moderate stroke (NIHSS, 4-7) and no symptoms after treatment, defined as a score of 0 on the Modified Rankin Scale (mRS), which measures disability and dependence; an initially moderate to serious stroke (NIHSS, 8-14) and no residual symptoms or mild symptoms that don’t impair the ability to perform routine activities of daily living without assistance (mRS, 0-1); or an initially serious to severe stroke (NIHSS, 15-25) and no remaining symptoms or a slight disability that impairs some activities but allows one to conduct daily living without assistance (mRS, 0-2).

Secondary outcomes included symptomatic intracranial hemorrhage, recurrent stroke, and mortality.

Among the 1,216 participants, 607 were assigned to the treatment group, and 609 were assigned to the placebo group. The average age was 66 years, and 68% were men.

Overall, participants in the butylphthalide group were 70% more likely to have a favorable 90-day outcome, compared with the placebo group. Favorable outcomes occurred in 344 patients (56.7%) in the butylphthalide group, compared with 268 patients (44%) in the placebo group (odds ratio, 1.70; 95% confidence interval, 1.35-2.14; P < .001).

In addition, butylphthalide improved function equally well for the patients who initially received tPA, those who received endovascular treatment, and those who received both tPA and endovascular treatment.

Secondary events, such as recurrent stroke and intracranial hemorrhage, weren’t significantly different between the butylphthalide and placebo groups.
 

Ongoing questions

Dr. Jia and colleagues noted the need to understand how butylphthalide works in the brain. Animal studies have suggested several possible mechanisms, but it remains unclear.

“The next step should be investigating the exact mechanisms of butylphthalide in humans,” Dr. Jia said.

Additional research should assess the medication in other populations, the authors noted, particularly because the study involved participants who received initial treatment with tPA, endovascular treatment, or both. The results may not be generalizable to stroke patients who receive other treatments or to populations outside of China.

“While these are interesting results, this is only one relatively small study on a fairly select population in China. Butylphthalide, a medication initially compounded from celery seed, is not ready for use in standard stroke treatment,” said Daniel Lackland, DrPH, professor of neurology and director of the division of translational neurosciences and population studies at the Medical University of South Carolina, Charleston.

Dr. Lackland, who wasn’t involved with the study, is a member of the American Stroke Association’s Stroke Council. Although butylphthalide was originally extracted from seeds, he noted, it’s not what patients would find commercially available.

“The medication used in this study is not the same as celery seed or celery seed extract supplements,” he said. “Stroke survivors should always consult with their neurologist or healthcare professional regarding diet after a stroke.”

The study was funded by the National Key Technology Research and Development Program of the Ministry of Science and Technology of the People’s Republic of China and Shijiazhuang Pharmaceutical Group dl-3-butylphthalide Pharmaceutical. Several authors are employed with Beijing Tiantan Hospital and the Beijing Institute of Brain Disorders. Dr. Lackland reported no relevant financial relationships.

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

Butylphthalide, a medication derived from celery seed, may improve outcomes after an acute ischemic stroke when given in addition to thrombolysis or endovascular treatment, a new report suggests.

Patients treated with butylphthalide had fewer severe neurologic symptoms and better function 90 days after the stroke, compared with those receiving placebo.

Butylphthalide is approved and available for use in China, where the study was conducted. However, the medication hasn’t been approved for use by the U.S. Food and Drug Administration.

“Patients who received butylphthalide had less severe neurological symptoms and a better living status at 90 days post stroke, compared to those who received the placebo,” said coauthor Baixue Jia, MD, an attending physician in interventional neuroradiology at the Beijing Tiantan Hospital of Capital Medical University and a faculty member at the China National Clinical Research Center for Neurological Diseases in Beijing. “If the results are confirmed in other trials, this may lead to more options to treat strokes caused by clots.”

The study was presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
 

Studying stroke outcomes

The researchers described butylphthalide as a cerebroprotective drug that was originally extracted from seeds of Apium graveolens. In China, previous studies have shown that the drug has cerebroprotective effects in animal models of ischemia-reperfusion, they noted.

In this randomized, double-blind, placebo-controlled trial, Dr. Jia and colleagues evaluated whether treatment with butylphthalide could improve 90-day outcomes for adults with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator (tPA), endovascular treatment, or both.

The participants were treated at one of 59 medical centers in China between July 2018 and February 2022. Those who had minimal stroke symptoms on their initial exam, defined as a score of 0-3 on the National Institutes of Health Stroke Scale, or had severe stroke symptoms, defined as having a score of 26 or higher on the NIHSS, were excluded from the study.

Along with an initial revascularization intervention chosen by their physician, participants were randomly selected to receive either butylphthalide or a placebo daily for 90 days. The drug was administered through daily intravenous injections for the first 14 days, after which patients received oral capsules for 76 days.

The research team defined the outcomes as “favorable” if a patient fell into one of the following categories 90 days after the stroke: an initially mild to moderate stroke (NIHSS, 4-7) and no symptoms after treatment, defined as a score of 0 on the Modified Rankin Scale (mRS), which measures disability and dependence; an initially moderate to serious stroke (NIHSS, 8-14) and no residual symptoms or mild symptoms that don’t impair the ability to perform routine activities of daily living without assistance (mRS, 0-1); or an initially serious to severe stroke (NIHSS, 15-25) and no remaining symptoms or a slight disability that impairs some activities but allows one to conduct daily living without assistance (mRS, 0-2).

Secondary outcomes included symptomatic intracranial hemorrhage, recurrent stroke, and mortality.

Among the 1,216 participants, 607 were assigned to the treatment group, and 609 were assigned to the placebo group. The average age was 66 years, and 68% were men.

Overall, participants in the butylphthalide group were 70% more likely to have a favorable 90-day outcome, compared with the placebo group. Favorable outcomes occurred in 344 patients (56.7%) in the butylphthalide group, compared with 268 patients (44%) in the placebo group (odds ratio, 1.70; 95% confidence interval, 1.35-2.14; P < .001).

In addition, butylphthalide improved function equally well for the patients who initially received tPA, those who received endovascular treatment, and those who received both tPA and endovascular treatment.

Secondary events, such as recurrent stroke and intracranial hemorrhage, weren’t significantly different between the butylphthalide and placebo groups.
 

Ongoing questions

Dr. Jia and colleagues noted the need to understand how butylphthalide works in the brain. Animal studies have suggested several possible mechanisms, but it remains unclear.

“The next step should be investigating the exact mechanisms of butylphthalide in humans,” Dr. Jia said.

Additional research should assess the medication in other populations, the authors noted, particularly because the study involved participants who received initial treatment with tPA, endovascular treatment, or both. The results may not be generalizable to stroke patients who receive other treatments or to populations outside of China.

“While these are interesting results, this is only one relatively small study on a fairly select population in China. Butylphthalide, a medication initially compounded from celery seed, is not ready for use in standard stroke treatment,” said Daniel Lackland, DrPH, professor of neurology and director of the division of translational neurosciences and population studies at the Medical University of South Carolina, Charleston.

Dr. Lackland, who wasn’t involved with the study, is a member of the American Stroke Association’s Stroke Council. Although butylphthalide was originally extracted from seeds, he noted, it’s not what patients would find commercially available.

“The medication used in this study is not the same as celery seed or celery seed extract supplements,” he said. “Stroke survivors should always consult with their neurologist or healthcare professional regarding diet after a stroke.”

The study was funded by the National Key Technology Research and Development Program of the Ministry of Science and Technology of the People’s Republic of China and Shijiazhuang Pharmaceutical Group dl-3-butylphthalide Pharmaceutical. Several authors are employed with Beijing Tiantan Hospital and the Beijing Institute of Brain Disorders. Dr. Lackland reported no relevant financial relationships.

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

Butylphthalide, a medication derived from celery seed, may improve outcomes after an acute ischemic stroke when given in addition to thrombolysis or endovascular treatment, a new report suggests.

Patients treated with butylphthalide had fewer severe neurologic symptoms and better function 90 days after the stroke, compared with those receiving placebo.

Butylphthalide is approved and available for use in China, where the study was conducted. However, the medication hasn’t been approved for use by the U.S. Food and Drug Administration.

“Patients who received butylphthalide had less severe neurological symptoms and a better living status at 90 days post stroke, compared to those who received the placebo,” said coauthor Baixue Jia, MD, an attending physician in interventional neuroradiology at the Beijing Tiantan Hospital of Capital Medical University and a faculty member at the China National Clinical Research Center for Neurological Diseases in Beijing. “If the results are confirmed in other trials, this may lead to more options to treat strokes caused by clots.”

The study was presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
 

Studying stroke outcomes

The researchers described butylphthalide as a cerebroprotective drug that was originally extracted from seeds of Apium graveolens. In China, previous studies have shown that the drug has cerebroprotective effects in animal models of ischemia-reperfusion, they noted.

In this randomized, double-blind, placebo-controlled trial, Dr. Jia and colleagues evaluated whether treatment with butylphthalide could improve 90-day outcomes for adults with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator (tPA), endovascular treatment, or both.

The participants were treated at one of 59 medical centers in China between July 2018 and February 2022. Those who had minimal stroke symptoms on their initial exam, defined as a score of 0-3 on the National Institutes of Health Stroke Scale, or had severe stroke symptoms, defined as having a score of 26 or higher on the NIHSS, were excluded from the study.

Along with an initial revascularization intervention chosen by their physician, participants were randomly selected to receive either butylphthalide or a placebo daily for 90 days. The drug was administered through daily intravenous injections for the first 14 days, after which patients received oral capsules for 76 days.

The research team defined the outcomes as “favorable” if a patient fell into one of the following categories 90 days after the stroke: an initially mild to moderate stroke (NIHSS, 4-7) and no symptoms after treatment, defined as a score of 0 on the Modified Rankin Scale (mRS), which measures disability and dependence; an initially moderate to serious stroke (NIHSS, 8-14) and no residual symptoms or mild symptoms that don’t impair the ability to perform routine activities of daily living without assistance (mRS, 0-1); or an initially serious to severe stroke (NIHSS, 15-25) and no remaining symptoms or a slight disability that impairs some activities but allows one to conduct daily living without assistance (mRS, 0-2).

Secondary outcomes included symptomatic intracranial hemorrhage, recurrent stroke, and mortality.

Among the 1,216 participants, 607 were assigned to the treatment group, and 609 were assigned to the placebo group. The average age was 66 years, and 68% were men.

Overall, participants in the butylphthalide group were 70% more likely to have a favorable 90-day outcome, compared with the placebo group. Favorable outcomes occurred in 344 patients (56.7%) in the butylphthalide group, compared with 268 patients (44%) in the placebo group (odds ratio, 1.70; 95% confidence interval, 1.35-2.14; P < .001).

In addition, butylphthalide improved function equally well for the patients who initially received tPA, those who received endovascular treatment, and those who received both tPA and endovascular treatment.

Secondary events, such as recurrent stroke and intracranial hemorrhage, weren’t significantly different between the butylphthalide and placebo groups.
 

Ongoing questions

Dr. Jia and colleagues noted the need to understand how butylphthalide works in the brain. Animal studies have suggested several possible mechanisms, but it remains unclear.

“The next step should be investigating the exact mechanisms of butylphthalide in humans,” Dr. Jia said.

Additional research should assess the medication in other populations, the authors noted, particularly because the study involved participants who received initial treatment with tPA, endovascular treatment, or both. The results may not be generalizable to stroke patients who receive other treatments or to populations outside of China.

“While these are interesting results, this is only one relatively small study on a fairly select population in China. Butylphthalide, a medication initially compounded from celery seed, is not ready for use in standard stroke treatment,” said Daniel Lackland, DrPH, professor of neurology and director of the division of translational neurosciences and population studies at the Medical University of South Carolina, Charleston.

Dr. Lackland, who wasn’t involved with the study, is a member of the American Stroke Association’s Stroke Council. Although butylphthalide was originally extracted from seeds, he noted, it’s not what patients would find commercially available.

“The medication used in this study is not the same as celery seed or celery seed extract supplements,” he said. “Stroke survivors should always consult with their neurologist or healthcare professional regarding diet after a stroke.”

The study was funded by the National Key Technology Research and Development Program of the Ministry of Science and Technology of the People’s Republic of China and Shijiazhuang Pharmaceutical Group dl-3-butylphthalide Pharmaceutical. Several authors are employed with Beijing Tiantan Hospital and the Beijing Institute of Brain Disorders. Dr. Lackland reported no relevant financial relationships.

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

This transcript has been edited for clarity.

Dear colleagues, I am Christoph Diener from the medical faculty of the University of Duisburg-Essen in Germany. Today, I would like to discuss what happened in neurology in the past month.
 

Treatment of tension-type headache

I would like to start with headache. You are all aware that we have several new studies regarding the prevention of migraine, but very few studies involving nondrug treatments for tension-type headache.

A working group in Göttingen, Germany, conducted a study in people with frequent episodic and chronic tension-type headache. The first of the four randomized groups received traditional Chinese acupuncture for 3 months. The second group received physical therapy and exercise for 1 hour per week for 12 weeks. The third group received a combination of acupuncture and exercise. The last was a control group that received only standard care.

The outcome parameters of tension-type headache were evaluated after 6 months and again after 12 months. Previously, these same researchers published that the intensity but not the frequency of tension-type headache was reduced by active therapy.

In Cephalalgia, they published the outcome for the endpoints of depression, anxiety, and quality of life. Acupuncture, exercise, and the combination of the two improved depression, anxiety, and quality of life. This shows that nonmedical treatment is effective in people with frequent episodic and chronic tension-type headache.
 

Headache after COVID-19

The next study was published in Headache and discusses headache after COVID-19. In this review of published studies, more than 50% of people with COVID-19 develop headache. It is more frequent in young patients and people with preexisting primary headaches, such as migraine and tension-type headache. Prognosis is usually good, but some patients develop new, daily persistent headache, which is a major problem because treatment is unclear. We desperately need studies investigating how to treat this new, daily persistent headache after COVID-19.

SSRIs during COVID-19 infection

The next study also focuses on COVID-19. We have conflicting results from several studies suggesting that selective serotonin reuptake inhibitors might be effective in people with mild COVID-19 infection. This hypothesis was tested in a study in Brazil and was published in JAMA, The study included 1,288 outpatients with mild COVID-19 who either received 50 mg of fluvoxamine twice daily for 10 days or placebo. There was no benefit of the treatment for any outcome.

Preventing dementia with antihypertensive treatment

The next study was published in the European Heart Journal and addresses the question of whether effective antihypertensive treatment in elderly persons can prevent dementia. This is a meta-analysis of five placebo-controlled trials with more than 28,000 patients. The meta-analysis clearly shows that treating hypertension in elderly patients does prevent dementia. The benefit is higher if the blood pressure is lowered by a larger amount which also stays true for elderly patients. There is no negative impact of lowering blood pressure in this population.

Antiplatelet therapy

The next study was published in Stroke and reexamines whether resumption of antiplatelet therapy should be early or late in people who had an intracerebral hemorrhage while on antiplatelet therapy. In the Taiwanese Health Registry, this was studied in 1,584 patients. The researchers divided participants into groups based on whether antiplatelet therapy was resumed within 30 days or after 30 days. In 1 year, the rate of recurrent intracerebral hemorrhage was 3.2%. There was no difference whether antiplatelet therapy was resumed early or late.

Regular exercise in Parkinson’s disease

The final study is a review of nonmedical therapy. This meta-analysis of 19 randomized trials looked at the benefit of regular exercise in patients with Parkinson’s disease and depression. The analysis clearly showed that rigorous and moderate exercise improved depression in patients with Parkinson’s disease. This is very important because exercise improves not only the symptoms of Parkinson’s disease but also comorbid depression while presenting no serious adverse events or side effects.

Dr. Diener is a professor in the department of neurology at Stroke Center–Headache Center, University Duisburg-Essen, Germany. He disclosed ties with Abbott, Addex Pharma, Alder, Allergan, Almirall, Amgen, Autonomic Technology, AstraZeneca, Bayer Vital, Berlin Chemie, Bristol-Myers Squibb, Boehringer Ingelheim, Chordate, CoAxia, Corimmun, Covidien, Coherex, CoLucid, Daiichi Sankyo, D-Pharm, Electrocore, Fresenius, GlaxoSmithKline, Grunenthal, Janssen-Cilag, Labrys Biologics Lilly, La Roche, Lundbeck, 3M Medica, MSD, Medtronic, Menarini, MindFrame, Minster, Neuroscore, Neurobiological Technologies, Novartis, Novo Nordisk, Johnson & Johnson, Knoll, Paion, Parke-Davis, Pierre Fabre, Pfizer Inc, Schaper and Brummer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St. Jude, Talecris, Thrombogenics, WebMD Global, Weber and Weber, Wyeth, and Yamanouchi. Dr. Diener has served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerz News, Stroke News, and the Treatment Guidelines of the German Neurological Society; as co-editor of Cephalalgia; and on the editorial board of The Lancet Neurology, Stroke, European Neurology, and Cerebrovascular Disorders. The department of neurology in Essen is supported by the German Research Council, the German Ministry of Education and Research, European Union, National Institutes of Health, Bertelsmann Foundation, and Heinz Nixdorf Foundation. Dr. Diener has no ownership interest and does not own stocks in any pharmaceutical company. A version of this article originally appeared on Medscape.com.

This transcript has been edited for clarity.

Dear colleagues, I am Christoph Diener from the medical faculty of the University of Duisburg-Essen in Germany. Today, I would like to discuss what happened in neurology in the past month.
 

Treatment of tension-type headache

I would like to start with headache. You are all aware that we have several new studies regarding the prevention of migraine, but very few studies involving nondrug treatments for tension-type headache.

A working group in Göttingen, Germany, conducted a study in people with frequent episodic and chronic tension-type headache. The first of the four randomized groups received traditional Chinese acupuncture for 3 months. The second group received physical therapy and exercise for 1 hour per week for 12 weeks. The third group received a combination of acupuncture and exercise. The last was a control group that received only standard care.

The outcome parameters of tension-type headache were evaluated after 6 months and again after 12 months. Previously, these same researchers published that the intensity but not the frequency of tension-type headache was reduced by active therapy.

In Cephalalgia, they published the outcome for the endpoints of depression, anxiety, and quality of life. Acupuncture, exercise, and the combination of the two improved depression, anxiety, and quality of life. This shows that nonmedical treatment is effective in people with frequent episodic and chronic tension-type headache.
 

Headache after COVID-19

The next study was published in Headache and discusses headache after COVID-19. In this review of published studies, more than 50% of people with COVID-19 develop headache. It is more frequent in young patients and people with preexisting primary headaches, such as migraine and tension-type headache. Prognosis is usually good, but some patients develop new, daily persistent headache, which is a major problem because treatment is unclear. We desperately need studies investigating how to treat this new, daily persistent headache after COVID-19.

SSRIs during COVID-19 infection

The next study also focuses on COVID-19. We have conflicting results from several studies suggesting that selective serotonin reuptake inhibitors might be effective in people with mild COVID-19 infection. This hypothesis was tested in a study in Brazil and was published in JAMA, The study included 1,288 outpatients with mild COVID-19 who either received 50 mg of fluvoxamine twice daily for 10 days or placebo. There was no benefit of the treatment for any outcome.

Preventing dementia with antihypertensive treatment

The next study was published in the European Heart Journal and addresses the question of whether effective antihypertensive treatment in elderly persons can prevent dementia. This is a meta-analysis of five placebo-controlled trials with more than 28,000 patients. The meta-analysis clearly shows that treating hypertension in elderly patients does prevent dementia. The benefit is higher if the blood pressure is lowered by a larger amount which also stays true for elderly patients. There is no negative impact of lowering blood pressure in this population.

Antiplatelet therapy

The next study was published in Stroke and reexamines whether resumption of antiplatelet therapy should be early or late in people who had an intracerebral hemorrhage while on antiplatelet therapy. In the Taiwanese Health Registry, this was studied in 1,584 patients. The researchers divided participants into groups based on whether antiplatelet therapy was resumed within 30 days or after 30 days. In 1 year, the rate of recurrent intracerebral hemorrhage was 3.2%. There was no difference whether antiplatelet therapy was resumed early or late.

Regular exercise in Parkinson’s disease

The final study is a review of nonmedical therapy. This meta-analysis of 19 randomized trials looked at the benefit of regular exercise in patients with Parkinson’s disease and depression. The analysis clearly showed that rigorous and moderate exercise improved depression in patients with Parkinson’s disease. This is very important because exercise improves not only the symptoms of Parkinson’s disease but also comorbid depression while presenting no serious adverse events or side effects.

Dr. Diener is a professor in the department of neurology at Stroke Center–Headache Center, University Duisburg-Essen, Germany. He disclosed ties with Abbott, Addex Pharma, Alder, Allergan, Almirall, Amgen, Autonomic Technology, AstraZeneca, Bayer Vital, Berlin Chemie, Bristol-Myers Squibb, Boehringer Ingelheim, Chordate, CoAxia, Corimmun, Covidien, Coherex, CoLucid, Daiichi Sankyo, D-Pharm, Electrocore, Fresenius, GlaxoSmithKline, Grunenthal, Janssen-Cilag, Labrys Biologics Lilly, La Roche, Lundbeck, 3M Medica, MSD, Medtronic, Menarini, MindFrame, Minster, Neuroscore, Neurobiological Technologies, Novartis, Novo Nordisk, Johnson & Johnson, Knoll, Paion, Parke-Davis, Pierre Fabre, Pfizer Inc, Schaper and Brummer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St. Jude, Talecris, Thrombogenics, WebMD Global, Weber and Weber, Wyeth, and Yamanouchi. Dr. Diener has served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerz News, Stroke News, and the Treatment Guidelines of the German Neurological Society; as co-editor of Cephalalgia; and on the editorial board of The Lancet Neurology, Stroke, European Neurology, and Cerebrovascular Disorders. The department of neurology in Essen is supported by the German Research Council, the German Ministry of Education and Research, European Union, National Institutes of Health, Bertelsmann Foundation, and Heinz Nixdorf Foundation. Dr. Diener has no ownership interest and does not own stocks in any pharmaceutical company. A version of this article originally appeared on Medscape.com.

This transcript has been edited for clarity.

Dear colleagues, I am Christoph Diener from the medical faculty of the University of Duisburg-Essen in Germany. Today, I would like to discuss what happened in neurology in the past month.
 

Treatment of tension-type headache

I would like to start with headache. You are all aware that we have several new studies regarding the prevention of migraine, but very few studies involving nondrug treatments for tension-type headache.

A working group in Göttingen, Germany, conducted a study in people with frequent episodic and chronic tension-type headache. The first of the four randomized groups received traditional Chinese acupuncture for 3 months. The second group received physical therapy and exercise for 1 hour per week for 12 weeks. The third group received a combination of acupuncture and exercise. The last was a control group that received only standard care.

The outcome parameters of tension-type headache were evaluated after 6 months and again after 12 months. Previously, these same researchers published that the intensity but not the frequency of tension-type headache was reduced by active therapy.

In Cephalalgia, they published the outcome for the endpoints of depression, anxiety, and quality of life. Acupuncture, exercise, and the combination of the two improved depression, anxiety, and quality of life. This shows that nonmedical treatment is effective in people with frequent episodic and chronic tension-type headache.
 

Headache after COVID-19

The next study was published in Headache and discusses headache after COVID-19. In this review of published studies, more than 50% of people with COVID-19 develop headache. It is more frequent in young patients and people with preexisting primary headaches, such as migraine and tension-type headache. Prognosis is usually good, but some patients develop new, daily persistent headache, which is a major problem because treatment is unclear. We desperately need studies investigating how to treat this new, daily persistent headache after COVID-19.

SSRIs during COVID-19 infection

The next study also focuses on COVID-19. We have conflicting results from several studies suggesting that selective serotonin reuptake inhibitors might be effective in people with mild COVID-19 infection. This hypothesis was tested in a study in Brazil and was published in JAMA, The study included 1,288 outpatients with mild COVID-19 who either received 50 mg of fluvoxamine twice daily for 10 days or placebo. There was no benefit of the treatment for any outcome.

Preventing dementia with antihypertensive treatment

The next study was published in the European Heart Journal and addresses the question of whether effective antihypertensive treatment in elderly persons can prevent dementia. This is a meta-analysis of five placebo-controlled trials with more than 28,000 patients. The meta-analysis clearly shows that treating hypertension in elderly patients does prevent dementia. The benefit is higher if the blood pressure is lowered by a larger amount which also stays true for elderly patients. There is no negative impact of lowering blood pressure in this population.

Antiplatelet therapy

The next study was published in Stroke and reexamines whether resumption of antiplatelet therapy should be early or late in people who had an intracerebral hemorrhage while on antiplatelet therapy. In the Taiwanese Health Registry, this was studied in 1,584 patients. The researchers divided participants into groups based on whether antiplatelet therapy was resumed within 30 days or after 30 days. In 1 year, the rate of recurrent intracerebral hemorrhage was 3.2%. There was no difference whether antiplatelet therapy was resumed early or late.

Regular exercise in Parkinson’s disease

The final study is a review of nonmedical therapy. This meta-analysis of 19 randomized trials looked at the benefit of regular exercise in patients with Parkinson’s disease and depression. The analysis clearly showed that rigorous and moderate exercise improved depression in patients with Parkinson’s disease. This is very important because exercise improves not only the symptoms of Parkinson’s disease but also comorbid depression while presenting no serious adverse events or side effects.

Dr. Diener is a professor in the department of neurology at Stroke Center–Headache Center, University Duisburg-Essen, Germany. He disclosed ties with Abbott, Addex Pharma, Alder, Allergan, Almirall, Amgen, Autonomic Technology, AstraZeneca, Bayer Vital, Berlin Chemie, Bristol-Myers Squibb, Boehringer Ingelheim, Chordate, CoAxia, Corimmun, Covidien, Coherex, CoLucid, Daiichi Sankyo, D-Pharm, Electrocore, Fresenius, GlaxoSmithKline, Grunenthal, Janssen-Cilag, Labrys Biologics Lilly, La Roche, Lundbeck, 3M Medica, MSD, Medtronic, Menarini, MindFrame, Minster, Neuroscore, Neurobiological Technologies, Novartis, Novo Nordisk, Johnson & Johnson, Knoll, Paion, Parke-Davis, Pierre Fabre, Pfizer Inc, Schaper and Brummer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St. Jude, Talecris, Thrombogenics, WebMD Global, Weber and Weber, Wyeth, and Yamanouchi. Dr. Diener has served as editor of Aktuelle Neurologie, Arzneimitteltherapie, Kopfschmerz News, Stroke News, and the Treatment Guidelines of the German Neurological Society; as co-editor of Cephalalgia; and on the editorial board of The Lancet Neurology, Stroke, European Neurology, and Cerebrovascular Disorders. The department of neurology in Essen is supported by the German Research Council, the German Ministry of Education and Research, European Union, National Institutes of Health, Bertelsmann Foundation, and Heinz Nixdorf Foundation. Dr. Diener has no ownership interest and does not own stocks in any pharmaceutical company. A version of this article originally appeared on Medscape.com.

Tenecteplase is as effective as alteplase with respect to disability outcomes and safety in Chinese patients with ischemic stroke, a new study has found. “This was a pivotal trial in establishing the safety and efficacy of tenecteplase as an alternative to alteplase in the thrombolytic treatment of acute ischemic stroke within 4.5 hours in Asian patients,” said study author Shuya Li, MD, associate chief physician, department of neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing.

The findings in this all-Chinese population should have an impact on the use of tenecteplase going forward, said Dr. Li. “The results provide further evidence to support a worldwide switch to tenecteplase as the preferred thrombolytic for acute ischemic stroke.”

The findings were presented at the 2023 International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
 

Single bolus

Use of alteplase (tissue plasminogen activator [tPA]) has for years been the main approach to thrombolytic reperfusion therapy for patients with acute stroke, but tenecteplase has recently emerged as a potential successor.

Tenecteplase is a tPA produced by recombinant DNA technology. It has a relatively long half-life and can be delivered in a single bolus instead of requiring an hour-long infusion, as is the case with alteplase.

The phase 3 noninferiority Tenecteplase Reperfusion Therapy in Acute ischemic Cerebrovascular Events (TRACE-2) trial – the first of its kind in an Asian population – included 1,430 adult ischemic stroke patients at 53 Chinese centers. Patients had to have a National Institutes of Health Stroke Scale (NIHSS) score of 5-25 and either not be eligible for or have refused endovascular therapy.

The mean age of study participants was about 66 years, and the percentage of women was about 31%. The mean baseline NIHSS score was 7 in both groups, and the symptom-onset-to-needle time was similar at 180 minutes for the tenecteplase group and 178.5 minutes for the alteplase group.

Researchers randomly assigned patients to receive tenecteplase or alteplase within 4.5 hours of symptom onset.

Those in the tenecteplase group received 0.25 mg/kg of the drug in a single IV bolus (maximum dose, 25 mg). Control group members who were treated with alteplase were given the drug as a 10% bolus, with the remainder given as a 1-hour infusion (0.9 mg/kg with a maximum dose of 90 mg).
 

Showed noninferiority

The primary efficacy outcome was a modified Rankins scale (mRS) score of 0-1 at 90 days, which is considered excellent function. About 62% of tenecteplase patients and 58% of alteplase patients attained this outcome (risk ratio, 1.09; 95% confidence interval, 1.00-1.18).

The P value was .001 for noninferiority and .06 for superiority, but Dr. Li explained that these values may change when considering the site effect.

There were no statistically significant differences between the two drugs on secondary outcomes of favorable function. For example, 73% of tenecteplase patients and 72% of alteplase patients had an mRS score of 0-2 at 3 months, and 50% in the tenecteplase and 49% in the alteplase group improved by 4 or more points on the NIHSS, or had a score of 1 or less, at 24 hours.

The groups also had comparable scores on the European quality-of-life visual analogue scale and on the Barthel index, which measures functional independence related to personal care and mobility.

Tenecteplase also turned out to be as safe at alteplase. About 2% in both groups had symptomatic intracranial hemorrhage within 36 hours, and both groups had that same percentage for such hemorrhages within 90 days. As well, the groups had a similar rate of any intracranial hemorrhage within 90 days (6% and 7%).

The mortality rate was 7% in the tenecteplase group, compared with 5% in the alteplase group.

Adverse events (AEs) occurred in 86% and 87%, and serious AEs in 16% and 15%, of the tenecteplase and alteplase groups, respectively, again with no statistically significant differences.

The research team aims to test the effectiveness of tenecteplase in other stroke patients, including those with minor strokes, those receiving thrombolysis in a later window, and those receiving endovascular therapy, said Dr. Li.
 

Strong evidence

Commenting on the study findings, Larry B. Goldstein, MD, professor and chair of neurology, University of Kentucky, Lexington, said it is important to determine the efficacy of tenecteplase among Asians, as they represent “an entirely different population” with unique concerns, such as bleeding complications from anticoagulants.

He noted an advantage of tenecteplase is ease of administration. “You don’t have to go through the loading dose and then the 1-hour infusion,” which poses an “additional hassle” when transferring patients between institutions, he said.

However, he noted that a possible “downside” to having both drugs available in the emergency department is “using the wrong drug at the wrong dose” because of their similar sounding names.

Also commenting on the study, Tudor G. Jovin, MD, professor and chair, department of neurology, Rowan University, Camden, N.J., said he welcomes another trial that confirms that these two drugs are biologically similar.

“I’m very glad this trial was done because it adds another very strong piece of evidence of equivalency.”

But the two drugs are not the same in some important respects, said Dr. Jovin, whose center switched to using tenecteplase almost 3 years ago. That switch has resulted in cutting 17 minutes from the door-to-needle time “which is quite significant,” he said.

“There’s no question that once we used tenecteplase in lieu of tPA, it’s been just so much easier to administer and affects the interhospital transfer protocols, because you’re not transferring the patient with a critical care IV. It’s a win-win situation for everyone.”

The study received funding from the National Science and Technology Major Project, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the National Natural Science Foundation of China, and the China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou). Dr. Li, Dr. Goldstein, and Dr. Jovin report no relevant financial relationships.

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

Tenecteplase is as effective as alteplase with respect to disability outcomes and safety in Chinese patients with ischemic stroke, a new study has found. “This was a pivotal trial in establishing the safety and efficacy of tenecteplase as an alternative to alteplase in the thrombolytic treatment of acute ischemic stroke within 4.5 hours in Asian patients,” said study author Shuya Li, MD, associate chief physician, department of neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing.

The findings in this all-Chinese population should have an impact on the use of tenecteplase going forward, said Dr. Li. “The results provide further evidence to support a worldwide switch to tenecteplase as the preferred thrombolytic for acute ischemic stroke.”

The findings were presented at the 2023 International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
 

Single bolus

Use of alteplase (tissue plasminogen activator [tPA]) has for years been the main approach to thrombolytic reperfusion therapy for patients with acute stroke, but tenecteplase has recently emerged as a potential successor.

Tenecteplase is a tPA produced by recombinant DNA technology. It has a relatively long half-life and can be delivered in a single bolus instead of requiring an hour-long infusion, as is the case with alteplase.

The phase 3 noninferiority Tenecteplase Reperfusion Therapy in Acute ischemic Cerebrovascular Events (TRACE-2) trial – the first of its kind in an Asian population – included 1,430 adult ischemic stroke patients at 53 Chinese centers. Patients had to have a National Institutes of Health Stroke Scale (NIHSS) score of 5-25 and either not be eligible for or have refused endovascular therapy.

The mean age of study participants was about 66 years, and the percentage of women was about 31%. The mean baseline NIHSS score was 7 in both groups, and the symptom-onset-to-needle time was similar at 180 minutes for the tenecteplase group and 178.5 minutes for the alteplase group.

Researchers randomly assigned patients to receive tenecteplase or alteplase within 4.5 hours of symptom onset.

Those in the tenecteplase group received 0.25 mg/kg of the drug in a single IV bolus (maximum dose, 25 mg). Control group members who were treated with alteplase were given the drug as a 10% bolus, with the remainder given as a 1-hour infusion (0.9 mg/kg with a maximum dose of 90 mg).
 

Showed noninferiority

The primary efficacy outcome was a modified Rankins scale (mRS) score of 0-1 at 90 days, which is considered excellent function. About 62% of tenecteplase patients and 58% of alteplase patients attained this outcome (risk ratio, 1.09; 95% confidence interval, 1.00-1.18).

The P value was .001 for noninferiority and .06 for superiority, but Dr. Li explained that these values may change when considering the site effect.

There were no statistically significant differences between the two drugs on secondary outcomes of favorable function. For example, 73% of tenecteplase patients and 72% of alteplase patients had an mRS score of 0-2 at 3 months, and 50% in the tenecteplase and 49% in the alteplase group improved by 4 or more points on the NIHSS, or had a score of 1 or less, at 24 hours.

The groups also had comparable scores on the European quality-of-life visual analogue scale and on the Barthel index, which measures functional independence related to personal care and mobility.

Tenecteplase also turned out to be as safe at alteplase. About 2% in both groups had symptomatic intracranial hemorrhage within 36 hours, and both groups had that same percentage for such hemorrhages within 90 days. As well, the groups had a similar rate of any intracranial hemorrhage within 90 days (6% and 7%).

The mortality rate was 7% in the tenecteplase group, compared with 5% in the alteplase group.

Adverse events (AEs) occurred in 86% and 87%, and serious AEs in 16% and 15%, of the tenecteplase and alteplase groups, respectively, again with no statistically significant differences.

The research team aims to test the effectiveness of tenecteplase in other stroke patients, including those with minor strokes, those receiving thrombolysis in a later window, and those receiving endovascular therapy, said Dr. Li.
 

Strong evidence

Commenting on the study findings, Larry B. Goldstein, MD, professor and chair of neurology, University of Kentucky, Lexington, said it is important to determine the efficacy of tenecteplase among Asians, as they represent “an entirely different population” with unique concerns, such as bleeding complications from anticoagulants.

He noted an advantage of tenecteplase is ease of administration. “You don’t have to go through the loading dose and then the 1-hour infusion,” which poses an “additional hassle” when transferring patients between institutions, he said.

However, he noted that a possible “downside” to having both drugs available in the emergency department is “using the wrong drug at the wrong dose” because of their similar sounding names.

Also commenting on the study, Tudor G. Jovin, MD, professor and chair, department of neurology, Rowan University, Camden, N.J., said he welcomes another trial that confirms that these two drugs are biologically similar.

“I’m very glad this trial was done because it adds another very strong piece of evidence of equivalency.”

But the two drugs are not the same in some important respects, said Dr. Jovin, whose center switched to using tenecteplase almost 3 years ago. That switch has resulted in cutting 17 minutes from the door-to-needle time “which is quite significant,” he said.

“There’s no question that once we used tenecteplase in lieu of tPA, it’s been just so much easier to administer and affects the interhospital transfer protocols, because you’re not transferring the patient with a critical care IV. It’s a win-win situation for everyone.”

The study received funding from the National Science and Technology Major Project, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the National Natural Science Foundation of China, and the China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou). Dr. Li, Dr. Goldstein, and Dr. Jovin report no relevant financial relationships.

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

Tenecteplase is as effective as alteplase with respect to disability outcomes and safety in Chinese patients with ischemic stroke, a new study has found. “This was a pivotal trial in establishing the safety and efficacy of tenecteplase as an alternative to alteplase in the thrombolytic treatment of acute ischemic stroke within 4.5 hours in Asian patients,” said study author Shuya Li, MD, associate chief physician, department of neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing.

The findings in this all-Chinese population should have an impact on the use of tenecteplase going forward, said Dr. Li. “The results provide further evidence to support a worldwide switch to tenecteplase as the preferred thrombolytic for acute ischemic stroke.”

The findings were presented at the 2023 International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
 

Single bolus

Use of alteplase (tissue plasminogen activator [tPA]) has for years been the main approach to thrombolytic reperfusion therapy for patients with acute stroke, but tenecteplase has recently emerged as a potential successor.

Tenecteplase is a tPA produced by recombinant DNA technology. It has a relatively long half-life and can be delivered in a single bolus instead of requiring an hour-long infusion, as is the case with alteplase.

The phase 3 noninferiority Tenecteplase Reperfusion Therapy in Acute ischemic Cerebrovascular Events (TRACE-2) trial – the first of its kind in an Asian population – included 1,430 adult ischemic stroke patients at 53 Chinese centers. Patients had to have a National Institutes of Health Stroke Scale (NIHSS) score of 5-25 and either not be eligible for or have refused endovascular therapy.

The mean age of study participants was about 66 years, and the percentage of women was about 31%. The mean baseline NIHSS score was 7 in both groups, and the symptom-onset-to-needle time was similar at 180 minutes for the tenecteplase group and 178.5 minutes for the alteplase group.

Researchers randomly assigned patients to receive tenecteplase or alteplase within 4.5 hours of symptom onset.

Those in the tenecteplase group received 0.25 mg/kg of the drug in a single IV bolus (maximum dose, 25 mg). Control group members who were treated with alteplase were given the drug as a 10% bolus, with the remainder given as a 1-hour infusion (0.9 mg/kg with a maximum dose of 90 mg).
 

Showed noninferiority

The primary efficacy outcome was a modified Rankins scale (mRS) score of 0-1 at 90 days, which is considered excellent function. About 62% of tenecteplase patients and 58% of alteplase patients attained this outcome (risk ratio, 1.09; 95% confidence interval, 1.00-1.18).

The P value was .001 for noninferiority and .06 for superiority, but Dr. Li explained that these values may change when considering the site effect.

There were no statistically significant differences between the two drugs on secondary outcomes of favorable function. For example, 73% of tenecteplase patients and 72% of alteplase patients had an mRS score of 0-2 at 3 months, and 50% in the tenecteplase and 49% in the alteplase group improved by 4 or more points on the NIHSS, or had a score of 1 or less, at 24 hours.

The groups also had comparable scores on the European quality-of-life visual analogue scale and on the Barthel index, which measures functional independence related to personal care and mobility.

Tenecteplase also turned out to be as safe at alteplase. About 2% in both groups had symptomatic intracranial hemorrhage within 36 hours, and both groups had that same percentage for such hemorrhages within 90 days. As well, the groups had a similar rate of any intracranial hemorrhage within 90 days (6% and 7%).

The mortality rate was 7% in the tenecteplase group, compared with 5% in the alteplase group.

Adverse events (AEs) occurred in 86% and 87%, and serious AEs in 16% and 15%, of the tenecteplase and alteplase groups, respectively, again with no statistically significant differences.

The research team aims to test the effectiveness of tenecteplase in other stroke patients, including those with minor strokes, those receiving thrombolysis in a later window, and those receiving endovascular therapy, said Dr. Li.
 

Strong evidence

Commenting on the study findings, Larry B. Goldstein, MD, professor and chair of neurology, University of Kentucky, Lexington, said it is important to determine the efficacy of tenecteplase among Asians, as they represent “an entirely different population” with unique concerns, such as bleeding complications from anticoagulants.

He noted an advantage of tenecteplase is ease of administration. “You don’t have to go through the loading dose and then the 1-hour infusion,” which poses an “additional hassle” when transferring patients between institutions, he said.

However, he noted that a possible “downside” to having both drugs available in the emergency department is “using the wrong drug at the wrong dose” because of their similar sounding names.

Also commenting on the study, Tudor G. Jovin, MD, professor and chair, department of neurology, Rowan University, Camden, N.J., said he welcomes another trial that confirms that these two drugs are biologically similar.

“I’m very glad this trial was done because it adds another very strong piece of evidence of equivalency.”

But the two drugs are not the same in some important respects, said Dr. Jovin, whose center switched to using tenecteplase almost 3 years ago. That switch has resulted in cutting 17 minutes from the door-to-needle time “which is quite significant,” he said.

“There’s no question that once we used tenecteplase in lieu of tPA, it’s been just so much easier to administer and affects the interhospital transfer protocols, because you’re not transferring the patient with a critical care IV. It’s a win-win situation for everyone.”

The study received funding from the National Science and Technology Major Project, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the National Natural Science Foundation of China, and the China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou). Dr. Li, Dr. Goldstein, and Dr. Jovin report no relevant financial relationships.

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

Dilating eye drops may delay – and perhaps even prevent – the onset of myopia in children, according to findings from a study published in JAMA. The study was conducted by researchers in Hong Kong.

Myopia is irreversible once it takes root and can contribute to other vision problems, such as macular degeneration, retinal detachment, glaucoma, and cataracts. The incidence of nearsightedness has nearly doubled since the 1970s, rising from 25% of the U.S. population to nearly 42%. Children have been particularly affected by the increase; reasons may include spending more time indoors looking at screens, experts say.

“Myopia is an ongoing and growing worldwide concern. This is of particular importance because of the change in children’s lifestyle, such as decreased outdoor time and increased screen time during and after the COVID-19 pandemic,” Jason C. Yam, MPH, of the department of ophthalmology and visual services at the Chinese University of Hong Kong, said in an interview.

Mr. Yam said that, while encouraging children to engage more in outdoor activity and spend less time using screens would help delay myopia, pharmaceutical interventions are needed, given myopia’s potential lifelong effects.
 

Putting eye drops to the test

In 2020, Mr. Yam and colleagues reported results of the Low-Concentration Atropine for Myopia Progression (LAMP) study, which showed that eye drops containing a solution of 0.05% atropine worked best at slowing the progression of myopia in 4- to 12-year-olds who already had the condition. Atropine relaxes eye muscles, causing dilation.

In that study, Mr. Yam and colleagues measured the rate of change in the eye’s ability to see at a great distance using a unit of measure known as the diopter. The higher the diopter, the more myopic a person’s vision. The 0.05% atropine solution was better at slowing this decline than placebo or solutions that contained a lower concentration of the substance.

The new study enrolled 474 children who were evenly divided by sex. None of the children had myopia when the trial began. Of that starting group, 353 children (age, 4-9 years) completed the study, which involved receiving eye drops once nightly in both eyes for 2 years.

Some children (n = 116) received 0.05% atropine, others (n = 122) received 0.01% atropine, and the rest (n = 115) received placebo drops. Mr. Yam and colleagues assessed how many children in each group had myopia after 2 years, as measured by a decline of at least a half diopter in one eye.

At the 2-year mark, more than half of children who received the placebo drops (61/115) had developed myopia, as had nearly half of those given 0.01% atropine (56/122). But fewer than one-third of children (33/116, 28.4%) who had received the drops with 0.05% atropine developed myopia during that period, the researchers reported.

The percentage of children with myopia in the placebo group (39/128, 30.5%) was larger by the end of the first year of the study than was the share of children in the 0.05% atropine group by the end of the trial. (Between 12 months and 24 months, 13 children in the placebo group left the study.) The main adverse event, in all treatment groups, was discomfort when exposed to bright light, according to the researchers.

“We are continuing the current study with the total intended follow-up duration of at least 6years,” added Mr. Yam, who hopes to determine whether the 0.05% atropine solution not only delays myopia but also prevents it altogether. While myopia is a concern worldwide, the condition is particularly prevalent in East Asia.

Mark A. Bullimore, MCOptom, PhD, FAAO, an adjunct professor at the University of Houston, and a consultant to ophthalmologic companies, called the trial “a landmark study. Finding children who are eligible and parents who are willing to deal with 2 years of drops is no small feat.

“The 0.05% atropine, on average, delays onset of myopia by a year,” Dr. Bullimore noted. He pointed to the similar percentages of myopia with placebo at 12 months, compared with 0.05% atropine 1 year later. He added that few clinicians in the United States use higher than 0.05% atropine for control of myopia because doing so can lead to excessive dilation and difficulty focusing.

While preventing myopia altogether would be ideal, simply delaying its onset can also be of tangible benefit, Bullimore said. In an article published in January, Dr. Bullimore and Noel A. Brennan of Johnson & Johnson Vision showed that delaying the onset of myopia reduces its severity.

“Optometrists prescribe low-concentration atropine already for myopia control, and there’s no reason now – in the light of this study – that they wouldn’t also do it to delay onset,” Dr. Bullimore said.

But in an editorial accompanying the journal article David A. Berntsen, OD, PhD, and Jeffrey J. Walline, OD, PhD, both of the University of Houston, wrote that a change in practice would be premature.

“The evidence presented does not yet warrant a change in the standard care of children because we do not yet know the long-term effects of delaying the onset of myopia with low-concentration atropine,” they wrote.

Identifying which children to consider for treatment is “a challenge,” they noted, because those who are not nearsighted typically do not undergo routine examination unless they have failed a vision test.

“Ultimately, the implementation of vision screenings that include determining a child’s prescription will likely be needed to identify children most likely to become myopic who may benefit from low-concentration atropine,” Dr. Berntsen and Dr. Walline wrote.

Mr. Yam and coinvestigators have applied for a patent on a 0.05% atropine solution. Dr. Bullimore reported relationships with Alcon Research,CooperVision, CorneaGen, EssilorLuxottica, Eyenovia, Genentech, Johnson & Johnson Vision, Lentechs, Novartis, and Vyluma, and is the sole owner of Ridgevue Publishing and Ridgevue Vision.

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

Dilating eye drops may delay – and perhaps even prevent – the onset of myopia in children, according to findings from a study published in JAMA. The study was conducted by researchers in Hong Kong.

Myopia is irreversible once it takes root and can contribute to other vision problems, such as macular degeneration, retinal detachment, glaucoma, and cataracts. The incidence of nearsightedness has nearly doubled since the 1970s, rising from 25% of the U.S. population to nearly 42%. Children have been particularly affected by the increase; reasons may include spending more time indoors looking at screens, experts say.

“Myopia is an ongoing and growing worldwide concern. This is of particular importance because of the change in children’s lifestyle, such as decreased outdoor time and increased screen time during and after the COVID-19 pandemic,” Jason C. Yam, MPH, of the department of ophthalmology and visual services at the Chinese University of Hong Kong, said in an interview.

Mr. Yam said that, while encouraging children to engage more in outdoor activity and spend less time using screens would help delay myopia, pharmaceutical interventions are needed, given myopia’s potential lifelong effects.
 

Putting eye drops to the test

In 2020, Mr. Yam and colleagues reported results of the Low-Concentration Atropine for Myopia Progression (LAMP) study, which showed that eye drops containing a solution of 0.05% atropine worked best at slowing the progression of myopia in 4- to 12-year-olds who already had the condition. Atropine relaxes eye muscles, causing dilation.

In that study, Mr. Yam and colleagues measured the rate of change in the eye’s ability to see at a great distance using a unit of measure known as the diopter. The higher the diopter, the more myopic a person’s vision. The 0.05% atropine solution was better at slowing this decline than placebo or solutions that contained a lower concentration of the substance.

The new study enrolled 474 children who were evenly divided by sex. None of the children had myopia when the trial began. Of that starting group, 353 children (age, 4-9 years) completed the study, which involved receiving eye drops once nightly in both eyes for 2 years.

Some children (n = 116) received 0.05% atropine, others (n = 122) received 0.01% atropine, and the rest (n = 115) received placebo drops. Mr. Yam and colleagues assessed how many children in each group had myopia after 2 years, as measured by a decline of at least a half diopter in one eye.

At the 2-year mark, more than half of children who received the placebo drops (61/115) had developed myopia, as had nearly half of those given 0.01% atropine (56/122). But fewer than one-third of children (33/116, 28.4%) who had received the drops with 0.05% atropine developed myopia during that period, the researchers reported.

The percentage of children with myopia in the placebo group (39/128, 30.5%) was larger by the end of the first year of the study than was the share of children in the 0.05% atropine group by the end of the trial. (Between 12 months and 24 months, 13 children in the placebo group left the study.) The main adverse event, in all treatment groups, was discomfort when exposed to bright light, according to the researchers.

“We are continuing the current study with the total intended follow-up duration of at least 6years,” added Mr. Yam, who hopes to determine whether the 0.05% atropine solution not only delays myopia but also prevents it altogether. While myopia is a concern worldwide, the condition is particularly prevalent in East Asia.

Mark A. Bullimore, MCOptom, PhD, FAAO, an adjunct professor at the University of Houston, and a consultant to ophthalmologic companies, called the trial “a landmark study. Finding children who are eligible and parents who are willing to deal with 2 years of drops is no small feat.

“The 0.05% atropine, on average, delays onset of myopia by a year,” Dr. Bullimore noted. He pointed to the similar percentages of myopia with placebo at 12 months, compared with 0.05% atropine 1 year later. He added that few clinicians in the United States use higher than 0.05% atropine for control of myopia because doing so can lead to excessive dilation and difficulty focusing.

While preventing myopia altogether would be ideal, simply delaying its onset can also be of tangible benefit, Bullimore said. In an article published in January, Dr. Bullimore and Noel A. Brennan of Johnson & Johnson Vision showed that delaying the onset of myopia reduces its severity.

“Optometrists prescribe low-concentration atropine already for myopia control, and there’s no reason now – in the light of this study – that they wouldn’t also do it to delay onset,” Dr. Bullimore said.

But in an editorial accompanying the journal article David A. Berntsen, OD, PhD, and Jeffrey J. Walline, OD, PhD, both of the University of Houston, wrote that a change in practice would be premature.

“The evidence presented does not yet warrant a change in the standard care of children because we do not yet know the long-term effects of delaying the onset of myopia with low-concentration atropine,” they wrote.

Identifying which children to consider for treatment is “a challenge,” they noted, because those who are not nearsighted typically do not undergo routine examination unless they have failed a vision test.

“Ultimately, the implementation of vision screenings that include determining a child’s prescription will likely be needed to identify children most likely to become myopic who may benefit from low-concentration atropine,” Dr. Berntsen and Dr. Walline wrote.

Mr. Yam and coinvestigators have applied for a patent on a 0.05% atropine solution. Dr. Bullimore reported relationships with Alcon Research,CooperVision, CorneaGen, EssilorLuxottica, Eyenovia, Genentech, Johnson & Johnson Vision, Lentechs, Novartis, and Vyluma, and is the sole owner of Ridgevue Publishing and Ridgevue Vision.

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

Dilating eye drops may delay – and perhaps even prevent – the onset of myopia in children, according to findings from a study published in JAMA. The study was conducted by researchers in Hong Kong.

Myopia is irreversible once it takes root and can contribute to other vision problems, such as macular degeneration, retinal detachment, glaucoma, and cataracts. The incidence of nearsightedness has nearly doubled since the 1970s, rising from 25% of the U.S. population to nearly 42%. Children have been particularly affected by the increase; reasons may include spending more time indoors looking at screens, experts say.

“Myopia is an ongoing and growing worldwide concern. This is of particular importance because of the change in children’s lifestyle, such as decreased outdoor time and increased screen time during and after the COVID-19 pandemic,” Jason C. Yam, MPH, of the department of ophthalmology and visual services at the Chinese University of Hong Kong, said in an interview.

Mr. Yam said that, while encouraging children to engage more in outdoor activity and spend less time using screens would help delay myopia, pharmaceutical interventions are needed, given myopia’s potential lifelong effects.
 

Putting eye drops to the test

In 2020, Mr. Yam and colleagues reported results of the Low-Concentration Atropine for Myopia Progression (LAMP) study, which showed that eye drops containing a solution of 0.05% atropine worked best at slowing the progression of myopia in 4- to 12-year-olds who already had the condition. Atropine relaxes eye muscles, causing dilation.

In that study, Mr. Yam and colleagues measured the rate of change in the eye’s ability to see at a great distance using a unit of measure known as the diopter. The higher the diopter, the more myopic a person’s vision. The 0.05% atropine solution was better at slowing this decline than placebo or solutions that contained a lower concentration of the substance.

The new study enrolled 474 children who were evenly divided by sex. None of the children had myopia when the trial began. Of that starting group, 353 children (age, 4-9 years) completed the study, which involved receiving eye drops once nightly in both eyes for 2 years.

Some children (n = 116) received 0.05% atropine, others (n = 122) received 0.01% atropine, and the rest (n = 115) received placebo drops. Mr. Yam and colleagues assessed how many children in each group had myopia after 2 years, as measured by a decline of at least a half diopter in one eye.

At the 2-year mark, more than half of children who received the placebo drops (61/115) had developed myopia, as had nearly half of those given 0.01% atropine (56/122). But fewer than one-third of children (33/116, 28.4%) who had received the drops with 0.05% atropine developed myopia during that period, the researchers reported.

The percentage of children with myopia in the placebo group (39/128, 30.5%) was larger by the end of the first year of the study than was the share of children in the 0.05% atropine group by the end of the trial. (Between 12 months and 24 months, 13 children in the placebo group left the study.) The main adverse event, in all treatment groups, was discomfort when exposed to bright light, according to the researchers.

“We are continuing the current study with the total intended follow-up duration of at least 6years,” added Mr. Yam, who hopes to determine whether the 0.05% atropine solution not only delays myopia but also prevents it altogether. While myopia is a concern worldwide, the condition is particularly prevalent in East Asia.

Mark A. Bullimore, MCOptom, PhD, FAAO, an adjunct professor at the University of Houston, and a consultant to ophthalmologic companies, called the trial “a landmark study. Finding children who are eligible and parents who are willing to deal with 2 years of drops is no small feat.

“The 0.05% atropine, on average, delays onset of myopia by a year,” Dr. Bullimore noted. He pointed to the similar percentages of myopia with placebo at 12 months, compared with 0.05% atropine 1 year later. He added that few clinicians in the United States use higher than 0.05% atropine for control of myopia because doing so can lead to excessive dilation and difficulty focusing.

While preventing myopia altogether would be ideal, simply delaying its onset can also be of tangible benefit, Bullimore said. In an article published in January, Dr. Bullimore and Noel A. Brennan of Johnson & Johnson Vision showed that delaying the onset of myopia reduces its severity.

“Optometrists prescribe low-concentration atropine already for myopia control, and there’s no reason now – in the light of this study – that they wouldn’t also do it to delay onset,” Dr. Bullimore said.

But in an editorial accompanying the journal article David A. Berntsen, OD, PhD, and Jeffrey J. Walline, OD, PhD, both of the University of Houston, wrote that a change in practice would be premature.

“The evidence presented does not yet warrant a change in the standard care of children because we do not yet know the long-term effects of delaying the onset of myopia with low-concentration atropine,” they wrote.

Identifying which children to consider for treatment is “a challenge,” they noted, because those who are not nearsighted typically do not undergo routine examination unless they have failed a vision test.

“Ultimately, the implementation of vision screenings that include determining a child’s prescription will likely be needed to identify children most likely to become myopic who may benefit from low-concentration atropine,” Dr. Berntsen and Dr. Walline wrote.

Mr. Yam and coinvestigators have applied for a patent on a 0.05% atropine solution. Dr. Bullimore reported relationships with Alcon Research,CooperVision, CorneaGen, EssilorLuxottica, Eyenovia, Genentech, Johnson & Johnson Vision, Lentechs, Novartis, and Vyluma, and is the sole owner of Ridgevue Publishing and Ridgevue Vision.

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

Caring for a child with autism is a long haul for families and not often a smooth ride. Medications can help improve child functioning and family quality of life but the evidence may require our careful consideration.

Although I am discussing medication treatment here, the best evidence-based treatments for autism symptoms such as poor social communication and repetitive restricted behavior (RRB) are behavioral (for example, applied behavior analysis), cognitive-behavioral therapy (CBT), and parent training. These modalities also augment the effectiveness of medications in many cases. Educational adjustments and specific therapies, when indicated, such as speech-language, occupational, and physical therapy are also beneficial.

Autism symptoms change with age from early regression, later to RRB, then depression, and they are complicated by coexisting conditions. Not surprisingly then, studying the effectiveness and side effects of medications is complex and guidance is in flux as reliable data emerge.

Because of the shortage of specialists and increasing prevalence of autism, we need to be prepared to manage, monitor, and sometimes start medications for our autistic patients. With great individual differences and the hopes and fears of distressed parents making them desperate for help, we need to be as evidence-based as possible to avoid serious side effects or delay effective behavioral treatments.

Our assistance is mainly to address the many co-occurring symptoms in autism: 37%-85% ADHD, 50% anxiety, 7.3% bipolar disorder, and 54.1% depression (by age 30). Many autistic children have problematic irritability, explosive episodes, repetitive or rigid routines, difficulty with social engagement, or trouble sleeping.

We need to be clear with families about the evidence and, whenever possible, use our own time-limited trials with placebos and objective measures that target symptoms and goals for improvement. This is complicated by that fact that the child may have trouble communicating about how they feel, have hypo- or hypersensitivity to feelings, as well as confounding coexisting conditions.

The Food and Drug Administration has approved the atypical antipsychotics risperidone (ages 5-16) and aripiprazole (ages 6-17) for reducing symptoms of irritability by 25%-50% – such as agitation, stereotypy, anger outbursts, self-injurious behavior, and hyperactivity within 8 weeks. The Aberrant Behavior Checklist can be used for monitoring. These benefits are largest with behavior therapy and at doses of 1.25-1.75  mg/day (risperidone) or 2-15 mg/day (aripiprazole). Unfortunately, side effects of these medications include somnolence, increased appetite and weight gain (average of 5.1 kg), abnormal blood lipids and glucose, dyskinesia, and elevated prolactin (sometimes galactorrhea). Aripiprazole is equivalent to risperidone for irritability, has less prolactin and fewer metabolic effects, but sometimes has extrapyramidal symptoms. Other second-generation atypical antipsychotics have less evidence but may have fewer side effects. With careful monitoring, these medications can make a major difference in child behavior.

ADHD symptoms often respond to methylphenidate within 4 weeks but at a lower dose and with more side effects of irritability, social withdrawal, and emotional outbursts than for children with ADHD without autism. Formulations such as liquid (short or long acting) or dermal patch may facilitate the important small-dose adjustments and slow ramp-up we should use with checklist monitoring (for example, Vanderbilt Assessment). Atomoxetine also reduces hyperactivity, especially when used with parent training, but has associated nausea, anorexia, early awakening, and rare unpredictable liver failure. Mixed amphetamine salts have not been studied. Clonidine (oral or patch) and guanfacine extended release have also shown some effectiveness for hyperarousal, social interaction, and sleep although they can cause drowsiness/hypotension.

Sleep issues such as sleep onset, duration, and disruptions can improve with melatonin, especially combined with CBT, and it can even sometimes help with anxiety, rigidity, and communication. Use a certified brand and prevent accidental ingestion of gummy forms. Note that obstructive sleep apnea is significantly more common in children with autism spectrum disorder (ASD) and should be evaluated if there are signs. The Childhood Sleep Questionnaire can be used to monitor.

There aren’t data available for selective serotonin reuptake inhibitors in treating depression and anxiety in autistic children but CBT may help. Buspirone improved RRB (at 2.5 mg b.i.d.) but did not help mood. Mood-stabilizing antiepileptics have had mixed results (valproate reduced irritability but with serious side effects), no benefits (lamotrigine and levetiracetam), or no trials (lithium, oxcarbazepine, and topiramate). In spite of this, a Cochrane report recommends antidepressants “on a case by case basis” for children with ASD, keeping in mind the higher risks of behavioral activation (consider comorbid bipolar disorder), irritability, akathisia, and sleep disturbance. We can monitor with Short Moods and Feelings Questionnaire and Problem Behavior Checklist.

NMDA and GABA receptors are implicated in the genesis of ASD. Bumetanide, a GABA modulator, at 1 mg b.i.d., improved social communication and restricted interests, but had dose-related hypokalemia, increased urination, dehydration, loss of appetite, and asthenia. Donepezil (cholinesterase inhibitor) in small studies improved autism scores and expressive/receptive language. N-acetylcysteine, D-cycloserine, and arbaclofen did not show efficacy.

Currently, 64% of children with ASD are prescribed one psychotropic medication, 35% more than two classes, and 15% more than three. While we may look askance at polypharmacy, several medications not effective as monotherapy for children with ASD have significant effects in combination with risperidone; notably memantine, riluzole, N-acetylcysteine, amantadine, topiramate, and buspirone, compared with placebo. Memantine alone has shown benefits in 60% of autistic patients on social, language, and self-stimulatory behaviors at 2.5-30 mg; effective enough that 80% chose continuation.

Families often use complementary or alternative medicines (CAM) so we need to ask about them because CAM may interact with prescribed drugs or complicate determining the source of side effects or benefits. Oxytocin has promising but inconclusive data for improving social cognition but only for 3-8 year olds. Omega-3 fatty acid had benefits for young child stereotypy and lethargy but only by parent report. Vitamin B12, folinic acid, vitamin D3, and digestive enzymes may help but lack data. It is important that families not replace evidence-based treatments with CAM when there are significant symptoms needing treatment.

Being a person with autism, beyond the stress of rigid routines and social difficulties, may include being a target of physical or sexual abuse or bullying, which are risks for suicide. Suicide is eightfold greater in people with autism, especially those who are high functioning; thus, we need to include children with ASD in our routine suicide screening.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

References

Goel R et al. Int Rev Psychiatry. 2018;30(1):78-95.

Stepanova E et al. Dialogues Clin Neurosci. 2017;19(4):395-402.

Caring for a child with autism is a long haul for families and not often a smooth ride. Medications can help improve child functioning and family quality of life but the evidence may require our careful consideration.

Although I am discussing medication treatment here, the best evidence-based treatments for autism symptoms such as poor social communication and repetitive restricted behavior (RRB) are behavioral (for example, applied behavior analysis), cognitive-behavioral therapy (CBT), and parent training. These modalities also augment the effectiveness of medications in many cases. Educational adjustments and specific therapies, when indicated, such as speech-language, occupational, and physical therapy are also beneficial.

Autism symptoms change with age from early regression, later to RRB, then depression, and they are complicated by coexisting conditions. Not surprisingly then, studying the effectiveness and side effects of medications is complex and guidance is in flux as reliable data emerge.

Because of the shortage of specialists and increasing prevalence of autism, we need to be prepared to manage, monitor, and sometimes start medications for our autistic patients. With great individual differences and the hopes and fears of distressed parents making them desperate for help, we need to be as evidence-based as possible to avoid serious side effects or delay effective behavioral treatments.

Our assistance is mainly to address the many co-occurring symptoms in autism: 37%-85% ADHD, 50% anxiety, 7.3% bipolar disorder, and 54.1% depression (by age 30). Many autistic children have problematic irritability, explosive episodes, repetitive or rigid routines, difficulty with social engagement, or trouble sleeping.

We need to be clear with families about the evidence and, whenever possible, use our own time-limited trials with placebos and objective measures that target symptoms and goals for improvement. This is complicated by that fact that the child may have trouble communicating about how they feel, have hypo- or hypersensitivity to feelings, as well as confounding coexisting conditions.

The Food and Drug Administration has approved the atypical antipsychotics risperidone (ages 5-16) and aripiprazole (ages 6-17) for reducing symptoms of irritability by 25%-50% – such as agitation, stereotypy, anger outbursts, self-injurious behavior, and hyperactivity within 8 weeks. The Aberrant Behavior Checklist can be used for monitoring. These benefits are largest with behavior therapy and at doses of 1.25-1.75  mg/day (risperidone) or 2-15 mg/day (aripiprazole). Unfortunately, side effects of these medications include somnolence, increased appetite and weight gain (average of 5.1 kg), abnormal blood lipids and glucose, dyskinesia, and elevated prolactin (sometimes galactorrhea). Aripiprazole is equivalent to risperidone for irritability, has less prolactin and fewer metabolic effects, but sometimes has extrapyramidal symptoms. Other second-generation atypical antipsychotics have less evidence but may have fewer side effects. With careful monitoring, these medications can make a major difference in child behavior.

ADHD symptoms often respond to methylphenidate within 4 weeks but at a lower dose and with more side effects of irritability, social withdrawal, and emotional outbursts than for children with ADHD without autism. Formulations such as liquid (short or long acting) or dermal patch may facilitate the important small-dose adjustments and slow ramp-up we should use with checklist monitoring (for example, Vanderbilt Assessment). Atomoxetine also reduces hyperactivity, especially when used with parent training, but has associated nausea, anorexia, early awakening, and rare unpredictable liver failure. Mixed amphetamine salts have not been studied. Clonidine (oral or patch) and guanfacine extended release have also shown some effectiveness for hyperarousal, social interaction, and sleep although they can cause drowsiness/hypotension.

Sleep issues such as sleep onset, duration, and disruptions can improve with melatonin, especially combined with CBT, and it can even sometimes help with anxiety, rigidity, and communication. Use a certified brand and prevent accidental ingestion of gummy forms. Note that obstructive sleep apnea is significantly more common in children with autism spectrum disorder (ASD) and should be evaluated if there are signs. The Childhood Sleep Questionnaire can be used to monitor.

There aren’t data available for selective serotonin reuptake inhibitors in treating depression and anxiety in autistic children but CBT may help. Buspirone improved RRB (at 2.5 mg b.i.d.) but did not help mood. Mood-stabilizing antiepileptics have had mixed results (valproate reduced irritability but with serious side effects), no benefits (lamotrigine and levetiracetam), or no trials (lithium, oxcarbazepine, and topiramate). In spite of this, a Cochrane report recommends antidepressants “on a case by case basis” for children with ASD, keeping in mind the higher risks of behavioral activation (consider comorbid bipolar disorder), irritability, akathisia, and sleep disturbance. We can monitor with Short Moods and Feelings Questionnaire and Problem Behavior Checklist.

NMDA and GABA receptors are implicated in the genesis of ASD. Bumetanide, a GABA modulator, at 1 mg b.i.d., improved social communication and restricted interests, but had dose-related hypokalemia, increased urination, dehydration, loss of appetite, and asthenia. Donepezil (cholinesterase inhibitor) in small studies improved autism scores and expressive/receptive language. N-acetylcysteine, D-cycloserine, and arbaclofen did not show efficacy.

Currently, 64% of children with ASD are prescribed one psychotropic medication, 35% more than two classes, and 15% more than three. While we may look askance at polypharmacy, several medications not effective as monotherapy for children with ASD have significant effects in combination with risperidone; notably memantine, riluzole, N-acetylcysteine, amantadine, topiramate, and buspirone, compared with placebo. Memantine alone has shown benefits in 60% of autistic patients on social, language, and self-stimulatory behaviors at 2.5-30 mg; effective enough that 80% chose continuation.

Families often use complementary or alternative medicines (CAM) so we need to ask about them because CAM may interact with prescribed drugs or complicate determining the source of side effects or benefits. Oxytocin has promising but inconclusive data for improving social cognition but only for 3-8 year olds. Omega-3 fatty acid had benefits for young child stereotypy and lethargy but only by parent report. Vitamin B12, folinic acid, vitamin D3, and digestive enzymes may help but lack data. It is important that families not replace evidence-based treatments with CAM when there are significant symptoms needing treatment.

Being a person with autism, beyond the stress of rigid routines and social difficulties, may include being a target of physical or sexual abuse or bullying, which are risks for suicide. Suicide is eightfold greater in people with autism, especially those who are high functioning; thus, we need to include children with ASD in our routine suicide screening.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

References

Goel R et al. Int Rev Psychiatry. 2018;30(1):78-95.

Stepanova E et al. Dialogues Clin Neurosci. 2017;19(4):395-402.

Caring for a child with autism is a long haul for families and not often a smooth ride. Medications can help improve child functioning and family quality of life but the evidence may require our careful consideration.

Although I am discussing medication treatment here, the best evidence-based treatments for autism symptoms such as poor social communication and repetitive restricted behavior (RRB) are behavioral (for example, applied behavior analysis), cognitive-behavioral therapy (CBT), and parent training. These modalities also augment the effectiveness of medications in many cases. Educational adjustments and specific therapies, when indicated, such as speech-language, occupational, and physical therapy are also beneficial.

Autism symptoms change with age from early regression, later to RRB, then depression, and they are complicated by coexisting conditions. Not surprisingly then, studying the effectiveness and side effects of medications is complex and guidance is in flux as reliable data emerge.

Because of the shortage of specialists and increasing prevalence of autism, we need to be prepared to manage, monitor, and sometimes start medications for our autistic patients. With great individual differences and the hopes and fears of distressed parents making them desperate for help, we need to be as evidence-based as possible to avoid serious side effects or delay effective behavioral treatments.

Our assistance is mainly to address the many co-occurring symptoms in autism: 37%-85% ADHD, 50% anxiety, 7.3% bipolar disorder, and 54.1% depression (by age 30). Many autistic children have problematic irritability, explosive episodes, repetitive or rigid routines, difficulty with social engagement, or trouble sleeping.

We need to be clear with families about the evidence and, whenever possible, use our own time-limited trials with placebos and objective measures that target symptoms and goals for improvement. This is complicated by that fact that the child may have trouble communicating about how they feel, have hypo- or hypersensitivity to feelings, as well as confounding coexisting conditions.

The Food and Drug Administration has approved the atypical antipsychotics risperidone (ages 5-16) and aripiprazole (ages 6-17) for reducing symptoms of irritability by 25%-50% – such as agitation, stereotypy, anger outbursts, self-injurious behavior, and hyperactivity within 8 weeks. The Aberrant Behavior Checklist can be used for monitoring. These benefits are largest with behavior therapy and at doses of 1.25-1.75  mg/day (risperidone) or 2-15 mg/day (aripiprazole). Unfortunately, side effects of these medications include somnolence, increased appetite and weight gain (average of 5.1 kg), abnormal blood lipids and glucose, dyskinesia, and elevated prolactin (sometimes galactorrhea). Aripiprazole is equivalent to risperidone for irritability, has less prolactin and fewer metabolic effects, but sometimes has extrapyramidal symptoms. Other second-generation atypical antipsychotics have less evidence but may have fewer side effects. With careful monitoring, these medications can make a major difference in child behavior.

ADHD symptoms often respond to methylphenidate within 4 weeks but at a lower dose and with more side effects of irritability, social withdrawal, and emotional outbursts than for children with ADHD without autism. Formulations such as liquid (short or long acting) or dermal patch may facilitate the important small-dose adjustments and slow ramp-up we should use with checklist monitoring (for example, Vanderbilt Assessment). Atomoxetine also reduces hyperactivity, especially when used with parent training, but has associated nausea, anorexia, early awakening, and rare unpredictable liver failure. Mixed amphetamine salts have not been studied. Clonidine (oral or patch) and guanfacine extended release have also shown some effectiveness for hyperarousal, social interaction, and sleep although they can cause drowsiness/hypotension.

Sleep issues such as sleep onset, duration, and disruptions can improve with melatonin, especially combined with CBT, and it can even sometimes help with anxiety, rigidity, and communication. Use a certified brand and prevent accidental ingestion of gummy forms. Note that obstructive sleep apnea is significantly more common in children with autism spectrum disorder (ASD) and should be evaluated if there are signs. The Childhood Sleep Questionnaire can be used to monitor.

There aren’t data available for selective serotonin reuptake inhibitors in treating depression and anxiety in autistic children but CBT may help. Buspirone improved RRB (at 2.5 mg b.i.d.) but did not help mood. Mood-stabilizing antiepileptics have had mixed results (valproate reduced irritability but with serious side effects), no benefits (lamotrigine and levetiracetam), or no trials (lithium, oxcarbazepine, and topiramate). In spite of this, a Cochrane report recommends antidepressants “on a case by case basis” for children with ASD, keeping in mind the higher risks of behavioral activation (consider comorbid bipolar disorder), irritability, akathisia, and sleep disturbance. We can monitor with Short Moods and Feelings Questionnaire and Problem Behavior Checklist.

NMDA and GABA receptors are implicated in the genesis of ASD. Bumetanide, a GABA modulator, at 1 mg b.i.d., improved social communication and restricted interests, but had dose-related hypokalemia, increased urination, dehydration, loss of appetite, and asthenia. Donepezil (cholinesterase inhibitor) in small studies improved autism scores and expressive/receptive language. N-acetylcysteine, D-cycloserine, and arbaclofen did not show efficacy.

Currently, 64% of children with ASD are prescribed one psychotropic medication, 35% more than two classes, and 15% more than three. While we may look askance at polypharmacy, several medications not effective as monotherapy for children with ASD have significant effects in combination with risperidone; notably memantine, riluzole, N-acetylcysteine, amantadine, topiramate, and buspirone, compared with placebo. Memantine alone has shown benefits in 60% of autistic patients on social, language, and self-stimulatory behaviors at 2.5-30 mg; effective enough that 80% chose continuation.

Families often use complementary or alternative medicines (CAM) so we need to ask about them because CAM may interact with prescribed drugs or complicate determining the source of side effects or benefits. Oxytocin has promising but inconclusive data for improving social cognition but only for 3-8 year olds. Omega-3 fatty acid had benefits for young child stereotypy and lethargy but only by parent report. Vitamin B12, folinic acid, vitamin D3, and digestive enzymes may help but lack data. It is important that families not replace evidence-based treatments with CAM when there are significant symptoms needing treatment.

Being a person with autism, beyond the stress of rigid routines and social difficulties, may include being a target of physical or sexual abuse or bullying, which are risks for suicide. Suicide is eightfold greater in people with autism, especially those who are high functioning; thus, we need to include children with ASD in our routine suicide screening.

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

References

Goel R et al. Int Rev Psychiatry. 2018;30(1):78-95.

Stepanova E et al. Dialogues Clin Neurosci. 2017;19(4):395-402.