Neurology

Adults with bipolar disorder showed a decline in total white matter volume, but stability in other brain features over time compared to healthy controls, based on data from 88 individuals.

Patients with bipolar disorder demonstrate cognitive impairment and brain structure abnormalities, including global white matter loss, that have been associated with poor outcomes, but data on the stability or progression of neuroanatomical changes are limited, wrote Julian Macoveanu, PhD, of Copenhagen University Hospital, Denmark, and colleagues.

In a study published in The Journal of Affective Disorders, the researchers identified 97 adults aged 18 to 60 years with recently diagnosed bipolar disorder and matched them with 66 healthy controls. Participants were enrolled in the larger Bipolar Illness Onset (BIO) study. All participants underwent structural MRI and neuropsychological testing at baseline and were in full or partial remission based on total scores of 14 or less on the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Approximately half of the participants (50 bipolar patients and 38 controls) participated in follow-up scans and testing after 6-27 months (mean 16 months), because of limited resources, according to the researchers.

The researchers compared changes in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning over time. In addition, they examined within-patient associations between baseline brain structure abnormalities and later mood episodes.

Overall, bipolar patients (BD) showed a significant decrease in total cerebral white matter from baseline, compared with healthy controls (HC) in mixed models (P = .006). “This effect was driven by BD patients showing a decrease in WM volume over time compared to HC who remained stable,” the researchers wrote, and the effect persisted in a post hoc analysis adjusting for subsyndromal symptoms and body mass index.

BD patients also had a larger amygdala volume at baseline and follow-up than HC, but no changes were noted between the groups. Changes in hippocampal volume also remained similar between the groups.

Analysis of cognitive data showed no significant differences in trajectories between BD patients and controls across cognitive domains or globally; although BD patients performed worse than controls at both time points.

BD patients in general experienced lower functioning and worse quality of life, compared with controls, but the trajectories of each group were similar for both functional and quality of life.

The researchers found no significant differences over time in total white matter, hippocampus, or amygdala volumes between BD patients who experienced at least one mood episode during the study period and those who remained in remission.

The findings were limited by several factors including the small sample size and limited generalizability of the findings because of the restriction to patients in full or partial remission, the researchers noted. Other limitations included the variation in follow-up time and the potential impact of psychotropic medication use.

However, the results were strengthened by the use of neuropsychiatric testing in addition to MRI to compare brain structure and cognitive function, the researchers said. The data suggest that both amygdala volume and cognitive impairment may be stable markers of BD soon after diagnosis, but that decreases in white matter may stem from disease progression.

The BIO study is funded by the Mental Health Services, Capital Region of Denmark, the Danish Council for Independent Research, Medical Sciences, Weimans Fund, Markedsmodningsfonden, Gangstedfonden, Læge Sofus Carl Emil og hustru Olga Boris Friis’ legat, Helsefonden, Innovation Fund Denmark, Copenhagen Center for Health Technology (CACHET), EU H2020 ITN, Augustinusfonden, and The Capital Region of Denmark. Macoveanu had no financial conflicts to disclose.

Adults with bipolar disorder showed a decline in total white matter volume, but stability in other brain features over time compared to healthy controls, based on data from 88 individuals.

Patients with bipolar disorder demonstrate cognitive impairment and brain structure abnormalities, including global white matter loss, that have been associated with poor outcomes, but data on the stability or progression of neuroanatomical changes are limited, wrote Julian Macoveanu, PhD, of Copenhagen University Hospital, Denmark, and colleagues.

In a study published in The Journal of Affective Disorders, the researchers identified 97 adults aged 18 to 60 years with recently diagnosed bipolar disorder and matched them with 66 healthy controls. Participants were enrolled in the larger Bipolar Illness Onset (BIO) study. All participants underwent structural MRI and neuropsychological testing at baseline and were in full or partial remission based on total scores of 14 or less on the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Approximately half of the participants (50 bipolar patients and 38 controls) participated in follow-up scans and testing after 6-27 months (mean 16 months), because of limited resources, according to the researchers.

The researchers compared changes in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning over time. In addition, they examined within-patient associations between baseline brain structure abnormalities and later mood episodes.

Overall, bipolar patients (BD) showed a significant decrease in total cerebral white matter from baseline, compared with healthy controls (HC) in mixed models (P = .006). “This effect was driven by BD patients showing a decrease in WM volume over time compared to HC who remained stable,” the researchers wrote, and the effect persisted in a post hoc analysis adjusting for subsyndromal symptoms and body mass index.

BD patients also had a larger amygdala volume at baseline and follow-up than HC, but no changes were noted between the groups. Changes in hippocampal volume also remained similar between the groups.

Analysis of cognitive data showed no significant differences in trajectories between BD patients and controls across cognitive domains or globally; although BD patients performed worse than controls at both time points.

BD patients in general experienced lower functioning and worse quality of life, compared with controls, but the trajectories of each group were similar for both functional and quality of life.

The researchers found no significant differences over time in total white matter, hippocampus, or amygdala volumes between BD patients who experienced at least one mood episode during the study period and those who remained in remission.

The findings were limited by several factors including the small sample size and limited generalizability of the findings because of the restriction to patients in full or partial remission, the researchers noted. Other limitations included the variation in follow-up time and the potential impact of psychotropic medication use.

However, the results were strengthened by the use of neuropsychiatric testing in addition to MRI to compare brain structure and cognitive function, the researchers said. The data suggest that both amygdala volume and cognitive impairment may be stable markers of BD soon after diagnosis, but that decreases in white matter may stem from disease progression.

The BIO study is funded by the Mental Health Services, Capital Region of Denmark, the Danish Council for Independent Research, Medical Sciences, Weimans Fund, Markedsmodningsfonden, Gangstedfonden, Læge Sofus Carl Emil og hustru Olga Boris Friis’ legat, Helsefonden, Innovation Fund Denmark, Copenhagen Center for Health Technology (CACHET), EU H2020 ITN, Augustinusfonden, and The Capital Region of Denmark. Macoveanu had no financial conflicts to disclose.

Adults with bipolar disorder showed a decline in total white matter volume, but stability in other brain features over time compared to healthy controls, based on data from 88 individuals.

Patients with bipolar disorder demonstrate cognitive impairment and brain structure abnormalities, including global white matter loss, that have been associated with poor outcomes, but data on the stability or progression of neuroanatomical changes are limited, wrote Julian Macoveanu, PhD, of Copenhagen University Hospital, Denmark, and colleagues.

In a study published in The Journal of Affective Disorders, the researchers identified 97 adults aged 18 to 60 years with recently diagnosed bipolar disorder and matched them with 66 healthy controls. Participants were enrolled in the larger Bipolar Illness Onset (BIO) study. All participants underwent structural MRI and neuropsychological testing at baseline and were in full or partial remission based on total scores of 14 or less on the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Approximately half of the participants (50 bipolar patients and 38 controls) participated in follow-up scans and testing after 6-27 months (mean 16 months), because of limited resources, according to the researchers.

The researchers compared changes in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning over time. In addition, they examined within-patient associations between baseline brain structure abnormalities and later mood episodes.

Overall, bipolar patients (BD) showed a significant decrease in total cerebral white matter from baseline, compared with healthy controls (HC) in mixed models (P = .006). “This effect was driven by BD patients showing a decrease in WM volume over time compared to HC who remained stable,” the researchers wrote, and the effect persisted in a post hoc analysis adjusting for subsyndromal symptoms and body mass index.

BD patients also had a larger amygdala volume at baseline and follow-up than HC, but no changes were noted between the groups. Changes in hippocampal volume also remained similar between the groups.

Analysis of cognitive data showed no significant differences in trajectories between BD patients and controls across cognitive domains or globally; although BD patients performed worse than controls at both time points.

BD patients in general experienced lower functioning and worse quality of life, compared with controls, but the trajectories of each group were similar for both functional and quality of life.

The researchers found no significant differences over time in total white matter, hippocampus, or amygdala volumes between BD patients who experienced at least one mood episode during the study period and those who remained in remission.

The findings were limited by several factors including the small sample size and limited generalizability of the findings because of the restriction to patients in full or partial remission, the researchers noted. Other limitations included the variation in follow-up time and the potential impact of psychotropic medication use.

However, the results were strengthened by the use of neuropsychiatric testing in addition to MRI to compare brain structure and cognitive function, the researchers said. The data suggest that both amygdala volume and cognitive impairment may be stable markers of BD soon after diagnosis, but that decreases in white matter may stem from disease progression.

The BIO study is funded by the Mental Health Services, Capital Region of Denmark, the Danish Council for Independent Research, Medical Sciences, Weimans Fund, Markedsmodningsfonden, Gangstedfonden, Læge Sofus Carl Emil og hustru Olga Boris Friis’ legat, Helsefonden, Innovation Fund Denmark, Copenhagen Center for Health Technology (CACHET), EU H2020 ITN, Augustinusfonden, and The Capital Region of Denmark. Macoveanu had no financial conflicts to disclose.

A first stroke in older adults is associated with substantial immediate and accelerated long-term cognitive decline, suggested a new study that underscores the need for continuous cognitive monitoring in this patient population.

Results from the study, which included 14 international cohorts of older adults, showed that stroke was associated with a significant acute decline in global cognition and a small, but significant, acceleration in the rate of cognitive decline over time.

Cognitive assessments in primary care are “crucial, especially since cognitive impairment is frequently missed or undiagnosed in hospitals,” lead author Jessica Lo, MSc, biostatistician and research associate with the Center for Healthy Brain Aging, University of New South Wales, Sydney, Australia, told this news organization.

She suggested clinicians incorporate long-term cognitive assessments into care plans, using more sensitive neuropsychological tests in primary care to detect early signs of cognitive impairment. “Early detection would enable timely interventions to improve outcomes,” Lo said.

She also noted that poststroke care typically includes physical rehabilitation but not cognitive rehabilitation, which many rehabilitation centers aren’t equipped to provide.

The study was published online in JAMA Network Open.
 

Mapping Cognitive Decline Trajectory

Cognitive impairment after stroke is common, but the trajectory of cognitive decline following a first stroke, relative to prestroke cognitive function, remains unclear.

The investigators leveraged data from 14 population-based cohort studies of 20,860 adults (mean age, 73 years; 59% women) to map the trajectory of cognitive function before and after a first stroke.

The primary outcome was global cognition, defined as the standardized average of four cognitive domains (language, memory, processing speed, and executive function).

During a mean follow-up of 7.5 years, 1041 (5%) adults (mean age, 79 years) experienced a first stroke, a mean of 4.5 years after study entry.

In adjusted analyses, stroke was associated with a significant acute decline of 0.25 SD in global cognition and a “small but significant” acceleration in the rate of decline of −0.038 SD per year, the authors reported.

Stroke was also associated with acute decline in all individual cognitive domains except for memory, with effect sizes ranging from −0.17 to −0.22 SD. Poststroke declines in Mini-Mental State Examination scores (−0.36 SD) were also noted.

In terms of cognitive trajectory, the rate of decline before stroke in survivors was similar to that seen in peers who didn’t have a stroke (−0.048 and −0.049 SD per year in global cognition, respectively).

The researchers did not identify any vascular risk factors moderating cognitive decline following a stroke, consistent with prior research. However, cognitive decline was significantly more rapid in individuals without stroke, regardless of any future stroke, who had a history of diabetes, hypertension, high cholesterol, cardiovascular disease, depression, smoking, or were APOE4 carriers.

“Targeting modifiable vascular risk factors at an early stage may reduce the risk of stroke but also subsequent risk of stroke-related cognitive decline and cognitive impairment,” the researchers noted.
 

A ‘Major Step’ in the Right Direction

As previously reported by this news organization, in 2023 the American Heart Association (AHA) issued a statement noting that screening for cognitive impairment should be part of multidisciplinary care for stroke survivors.

Commenting for this news organization, Mitchell Elkind, MD, MS, AHA chief clinical science officer, said these new data are consistent with current AHA guidelines and statements that “support screening for cognitive and functional decline in patients both acutely and over the long term after stroke.”

Elkind noted that the 2022 guideline for intracerebral hemorrhage states that cognitive screening should occur “across the continuum of inpatient care and at intervals in the outpatient setting” and provides recommendations for cognitive therapy.

“Our 2021 scientific statement on the primary care of patients after stroke also recommends screening for both depression and cognitive impairment over both the short- and long-term,” said Elkind, professor of neurology and epidemiology at Columbia University Irving Medical Center in New York City.

“These documents recognize the fact that function and cognition can continue to decline years after stroke and that patients’ rehabilitation and support needs may therefore change over time after stroke,” Elkind added.

The authors of an accompanying commentary called it a “major step” in the right direction for the future of long-term stroke outcome assessment.

“As we develop new devices, indications, and time windows for stroke treatment, it may perhaps be wise to ensure trials steer away from simpler outcomes to more complex, granular ones,” wrote Yasmin Sadigh, MSc, and Victor Volovici, MD, PhD, with Erasmus University Medical Center, Rotterdam, the Netherlands.

The study had no commercial funding. The authors and commentary writers and Elkind have declared no conflicts of interest.

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

A first stroke in older adults is associated with substantial immediate and accelerated long-term cognitive decline, suggested a new study that underscores the need for continuous cognitive monitoring in this patient population.

Results from the study, which included 14 international cohorts of older adults, showed that stroke was associated with a significant acute decline in global cognition and a small, but significant, acceleration in the rate of cognitive decline over time.

Cognitive assessments in primary care are “crucial, especially since cognitive impairment is frequently missed or undiagnosed in hospitals,” lead author Jessica Lo, MSc, biostatistician and research associate with the Center for Healthy Brain Aging, University of New South Wales, Sydney, Australia, told this news organization.

She suggested clinicians incorporate long-term cognitive assessments into care plans, using more sensitive neuropsychological tests in primary care to detect early signs of cognitive impairment. “Early detection would enable timely interventions to improve outcomes,” Lo said.

She also noted that poststroke care typically includes physical rehabilitation but not cognitive rehabilitation, which many rehabilitation centers aren’t equipped to provide.

The study was published online in JAMA Network Open.
 

Mapping Cognitive Decline Trajectory

Cognitive impairment after stroke is common, but the trajectory of cognitive decline following a first stroke, relative to prestroke cognitive function, remains unclear.

The investigators leveraged data from 14 population-based cohort studies of 20,860 adults (mean age, 73 years; 59% women) to map the trajectory of cognitive function before and after a first stroke.

The primary outcome was global cognition, defined as the standardized average of four cognitive domains (language, memory, processing speed, and executive function).

During a mean follow-up of 7.5 years, 1041 (5%) adults (mean age, 79 years) experienced a first stroke, a mean of 4.5 years after study entry.

In adjusted analyses, stroke was associated with a significant acute decline of 0.25 SD in global cognition and a “small but significant” acceleration in the rate of decline of −0.038 SD per year, the authors reported.

Stroke was also associated with acute decline in all individual cognitive domains except for memory, with effect sizes ranging from −0.17 to −0.22 SD. Poststroke declines in Mini-Mental State Examination scores (−0.36 SD) were also noted.

In terms of cognitive trajectory, the rate of decline before stroke in survivors was similar to that seen in peers who didn’t have a stroke (−0.048 and −0.049 SD per year in global cognition, respectively).

The researchers did not identify any vascular risk factors moderating cognitive decline following a stroke, consistent with prior research. However, cognitive decline was significantly more rapid in individuals without stroke, regardless of any future stroke, who had a history of diabetes, hypertension, high cholesterol, cardiovascular disease, depression, smoking, or were APOE4 carriers.

“Targeting modifiable vascular risk factors at an early stage may reduce the risk of stroke but also subsequent risk of stroke-related cognitive decline and cognitive impairment,” the researchers noted.
 

A ‘Major Step’ in the Right Direction

As previously reported by this news organization, in 2023 the American Heart Association (AHA) issued a statement noting that screening for cognitive impairment should be part of multidisciplinary care for stroke survivors.

Commenting for this news organization, Mitchell Elkind, MD, MS, AHA chief clinical science officer, said these new data are consistent with current AHA guidelines and statements that “support screening for cognitive and functional decline in patients both acutely and over the long term after stroke.”

Elkind noted that the 2022 guideline for intracerebral hemorrhage states that cognitive screening should occur “across the continuum of inpatient care and at intervals in the outpatient setting” and provides recommendations for cognitive therapy.

“Our 2021 scientific statement on the primary care of patients after stroke also recommends screening for both depression and cognitive impairment over both the short- and long-term,” said Elkind, professor of neurology and epidemiology at Columbia University Irving Medical Center in New York City.

“These documents recognize the fact that function and cognition can continue to decline years after stroke and that patients’ rehabilitation and support needs may therefore change over time after stroke,” Elkind added.

The authors of an accompanying commentary called it a “major step” in the right direction for the future of long-term stroke outcome assessment.

“As we develop new devices, indications, and time windows for stroke treatment, it may perhaps be wise to ensure trials steer away from simpler outcomes to more complex, granular ones,” wrote Yasmin Sadigh, MSc, and Victor Volovici, MD, PhD, with Erasmus University Medical Center, Rotterdam, the Netherlands.

The study had no commercial funding. The authors and commentary writers and Elkind have declared no conflicts of interest.

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

A first stroke in older adults is associated with substantial immediate and accelerated long-term cognitive decline, suggested a new study that underscores the need for continuous cognitive monitoring in this patient population.

Results from the study, which included 14 international cohorts of older adults, showed that stroke was associated with a significant acute decline in global cognition and a small, but significant, acceleration in the rate of cognitive decline over time.

Cognitive assessments in primary care are “crucial, especially since cognitive impairment is frequently missed or undiagnosed in hospitals,” lead author Jessica Lo, MSc, biostatistician and research associate with the Center for Healthy Brain Aging, University of New South Wales, Sydney, Australia, told this news organization.

She suggested clinicians incorporate long-term cognitive assessments into care plans, using more sensitive neuropsychological tests in primary care to detect early signs of cognitive impairment. “Early detection would enable timely interventions to improve outcomes,” Lo said.

She also noted that poststroke care typically includes physical rehabilitation but not cognitive rehabilitation, which many rehabilitation centers aren’t equipped to provide.

The study was published online in JAMA Network Open.
 

Mapping Cognitive Decline Trajectory

Cognitive impairment after stroke is common, but the trajectory of cognitive decline following a first stroke, relative to prestroke cognitive function, remains unclear.

The investigators leveraged data from 14 population-based cohort studies of 20,860 adults (mean age, 73 years; 59% women) to map the trajectory of cognitive function before and after a first stroke.

The primary outcome was global cognition, defined as the standardized average of four cognitive domains (language, memory, processing speed, and executive function).

During a mean follow-up of 7.5 years, 1041 (5%) adults (mean age, 79 years) experienced a first stroke, a mean of 4.5 years after study entry.

In adjusted analyses, stroke was associated with a significant acute decline of 0.25 SD in global cognition and a “small but significant” acceleration in the rate of decline of −0.038 SD per year, the authors reported.

Stroke was also associated with acute decline in all individual cognitive domains except for memory, with effect sizes ranging from −0.17 to −0.22 SD. Poststroke declines in Mini-Mental State Examination scores (−0.36 SD) were also noted.

In terms of cognitive trajectory, the rate of decline before stroke in survivors was similar to that seen in peers who didn’t have a stroke (−0.048 and −0.049 SD per year in global cognition, respectively).

The researchers did not identify any vascular risk factors moderating cognitive decline following a stroke, consistent with prior research. However, cognitive decline was significantly more rapid in individuals without stroke, regardless of any future stroke, who had a history of diabetes, hypertension, high cholesterol, cardiovascular disease, depression, smoking, or were APOE4 carriers.

“Targeting modifiable vascular risk factors at an early stage may reduce the risk of stroke but also subsequent risk of stroke-related cognitive decline and cognitive impairment,” the researchers noted.
 

A ‘Major Step’ in the Right Direction

As previously reported by this news organization, in 2023 the American Heart Association (AHA) issued a statement noting that screening for cognitive impairment should be part of multidisciplinary care for stroke survivors.

Commenting for this news organization, Mitchell Elkind, MD, MS, AHA chief clinical science officer, said these new data are consistent with current AHA guidelines and statements that “support screening for cognitive and functional decline in patients both acutely and over the long term after stroke.”

Elkind noted that the 2022 guideline for intracerebral hemorrhage states that cognitive screening should occur “across the continuum of inpatient care and at intervals in the outpatient setting” and provides recommendations for cognitive therapy.

“Our 2021 scientific statement on the primary care of patients after stroke also recommends screening for both depression and cognitive impairment over both the short- and long-term,” said Elkind, professor of neurology and epidemiology at Columbia University Irving Medical Center in New York City.

“These documents recognize the fact that function and cognition can continue to decline years after stroke and that patients’ rehabilitation and support needs may therefore change over time after stroke,” Elkind added.

The authors of an accompanying commentary called it a “major step” in the right direction for the future of long-term stroke outcome assessment.

“As we develop new devices, indications, and time windows for stroke treatment, it may perhaps be wise to ensure trials steer away from simpler outcomes to more complex, granular ones,” wrote Yasmin Sadigh, MSc, and Victor Volovici, MD, PhD, with Erasmus University Medical Center, Rotterdam, the Netherlands.

The study had no commercial funding. The authors and commentary writers and Elkind have declared no conflicts of interest.

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

Early recognition of neurodevelopmental concerns and timely access to services have been shown to result in better outcomes for young children. But not all instruments are of equal value, and new research has sought to identify the most useful among them.

For their research, published online in Developmental Medicine & Child Neurology, Andrea Burgess, PhD, of the University of Queensland in Brisbane, Australia, and her colleagues looked at two decades’ worth of systematic reviews of screening, assessment, and diagnostic tools used in children younger than 6 years.

Eighty-six clinical reviews and six practice guidelines, all published between 2000 and 2023, were included in the scoping review, which covered nearly 250 different multi-domain and domain- and disorder-specific tools.

The diagnostic instruments were those used to diagnose the most common early childhood disorders, including intellectual disability, global developmental delay, communication disorders, autism spectrum disorder, attention-deficit/hyperactivity disorder, cerebral palsy, movement disorders, and fetal alcohol spectrum disorder. Burgess and her colleagues sought to determine which tools had the strongest evidence behind them, noting that comparisons were inherently limited by differences in the tested populations, cutoff values, and other factors.

Burgess and her colleagues identified 67 instruments — about a third of those analyzed in the study — “with good discriminative or predictive validity for the screening and assessment of developmental concerns or disability.” Recommended tools were classified by tool type and by patient age groups.

The reason a tool might not be recommended, Burgess said in an email, was for lack of psychometric testing or published evidence, or because the tool was very narrow in scope (eg, covering only a single aspect of a domain), had a small time window for use, or was too new to have been captured in published systematic reviews.
 

Top Recommendations

Among multi-domain assessment tools, the Bayley Scales of Infant and Toddler Development, the Battelle Developmental Inventory, and the Mullen Scales of Early Learning all emerged as highly recommended. The top diagnostic screening tool for autism was the revised version of Social Attention and Communication Surveillance. For cerebral palsy, the top-rated diagnostic assessment tools were Prechtl’s Qualitative Assessment of General Movements and the Hammersmith Infant Neurological Examination.

Ratifying findings by other groups, the researchers determined the Ages & Stages Questionnaires, Third Edition (ASQ-3) to be the best overall multi-domain screening instrument for early childhood development, thanks to its simplicity and ease of use by a wide range of practitioner types. Burgess and her colleagues noted, however, that the ASQ-3 “will not identify all children with developmental concerns and may incorrectly identify others,” and that it may be more accurate in children 2 years or older.
 

Patient Care Setting and Cultural, Socioeconomic Factors Are Key

This news organization spoke to two clinicians working with these and similar tools in the United States. Both said that the care setting can also influence the utility of tools, with cultural and socioeconomic factors playing important roles.

Liz Schwandt, PsyD, an early intervention specialist in Los Angeles, said in an interview that children living in high-risk communities in the United States have a larger burden of developmental delays. But for many families in these communities, accessing care can be complex, which is why well-designed, efficient screening tools like ASQ-3 are especially valuable in practice.

“The reality is you have 10 minutes with a lot of families, and if it’s an emergency, you need to know,” she said. “The ASQ-3 has a very broad age range for this type of instrument and can be used by different practitioner types. The reason it’s successful lies in its parent-centric approach and inherent ease of use. It’s quick, and you can score it using pencil and paper while chatting with the parent, and you can use it for multiple siblings in the space of one appointment.”

With very young children, in whom neurodevelopmental concerns often overlap domains, Schwandt said it can be more important to flag a potential problem early and initiate a nonspecific developmental intervention than wait for results from more precise assessments using more specialized tools. These often require multiple, multi-hour appointments, which can be difficult to attain in lower-resource settings in the United States and can delay care, she said.

Liza Mackintosh, MD, a pediatrician at a federally funded healthcare center in Los Angeles that serves mostly publicly insured families, called validated first-line screening tools “incredibly important.” While rates of developmental screenings in pediatric clinics are increasing, there is still room for improvement, she said.

Mackintosh’s institution does not currently use the ASQ-3 but a different screening tool, called the Survey of Well-Being of Young Children (SWYC), that is embedded into the electronic health record. (The SWYC was not among the tools highlighted in Burgess and colleagues’ review.) Like the ASQ-3, it is short and efficient, she said, and it is used in all children in the recommended age ranges.

“Our visits are on average only 20 minutes,” Mackintosh said. “There’s not enough time for an in-depth developmental assessment. We will flag things such as a speech delay, gross motor delay, or fine motor delay” and refer to early intervention centers for more in-depth developmental assessments as needed, she said.

“The biggest job of pediatricians working in communities that are under-resourced is advocating for those early intervention services,” Mackintosh added. “We really see our job as doing the recommended screening, putting that together with what we’re seeing clinically and on history, and then advocating for the right next step or early intervention. Because sometimes the diagnosis is — I don’t want to say irrelevant, but your treatment plan is still going to be the same. So while I don’t have a formal diagnosis yet, the child definitely needs therapies and we’re still going to get those therapies.”

Burgess and her colleagues stressed in their paper the importance of selecting tools that are culturally appropriate for Indigenous communities in Australia, noting that “inappropriate tools may lead to over- or under-recognition of children with developmental concerns.”

Schwandt and Mackintosh said that the same applies in US settings.

“We’ve done a good job translating screening tools into Chinese, Spanish, Vietnamese, and Russian,” Schwandt said. “But some of them assume a way of taking care of children that is not always shared across cultures. The expectations of how children should play and interact with adults can be very different, and there needs to be an understanding of that. Just putting something in Vietnamese doesn’t mean that there are obvious analogues to understanding what the questionnaire is asking.”

Mackintosh concurred. “A lot of times our patients will not do well on screening, even though they’re fine, because they don’t have the exposure to that activity that’s being asked about. So — is the child scribbling with crayons? Is she climbing up a ladder at a playground? In order to be able to do that, you need to have an environment that you are doing it in. The screeners have to really be appropriate for what the child is exposed to. And sometimes our patients just don’t have that exposure.”

Burgess and colleagues’ study was funded by the Australian government and the Merchant Charitable Foundation. The authors disclosed no financial conflicts of interest. Schwandt and Mackintosh disclosed no conflicts of interest related to their comments.
 

A version of this article appeared on Medscape.com.

Early recognition of neurodevelopmental concerns and timely access to services have been shown to result in better outcomes for young children. But not all instruments are of equal value, and new research has sought to identify the most useful among them.

For their research, published online in Developmental Medicine & Child Neurology, Andrea Burgess, PhD, of the University of Queensland in Brisbane, Australia, and her colleagues looked at two decades’ worth of systematic reviews of screening, assessment, and diagnostic tools used in children younger than 6 years.

Eighty-six clinical reviews and six practice guidelines, all published between 2000 and 2023, were included in the scoping review, which covered nearly 250 different multi-domain and domain- and disorder-specific tools.

The diagnostic instruments were those used to diagnose the most common early childhood disorders, including intellectual disability, global developmental delay, communication disorders, autism spectrum disorder, attention-deficit/hyperactivity disorder, cerebral palsy, movement disorders, and fetal alcohol spectrum disorder. Burgess and her colleagues sought to determine which tools had the strongest evidence behind them, noting that comparisons were inherently limited by differences in the tested populations, cutoff values, and other factors.

Burgess and her colleagues identified 67 instruments — about a third of those analyzed in the study — “with good discriminative or predictive validity for the screening and assessment of developmental concerns or disability.” Recommended tools were classified by tool type and by patient age groups.

The reason a tool might not be recommended, Burgess said in an email, was for lack of psychometric testing or published evidence, or because the tool was very narrow in scope (eg, covering only a single aspect of a domain), had a small time window for use, or was too new to have been captured in published systematic reviews.
 

Top Recommendations

Among multi-domain assessment tools, the Bayley Scales of Infant and Toddler Development, the Battelle Developmental Inventory, and the Mullen Scales of Early Learning all emerged as highly recommended. The top diagnostic screening tool for autism was the revised version of Social Attention and Communication Surveillance. For cerebral palsy, the top-rated diagnostic assessment tools were Prechtl’s Qualitative Assessment of General Movements and the Hammersmith Infant Neurological Examination.

Ratifying findings by other groups, the researchers determined the Ages & Stages Questionnaires, Third Edition (ASQ-3) to be the best overall multi-domain screening instrument for early childhood development, thanks to its simplicity and ease of use by a wide range of practitioner types. Burgess and her colleagues noted, however, that the ASQ-3 “will not identify all children with developmental concerns and may incorrectly identify others,” and that it may be more accurate in children 2 years or older.
 

Patient Care Setting and Cultural, Socioeconomic Factors Are Key

This news organization spoke to two clinicians working with these and similar tools in the United States. Both said that the care setting can also influence the utility of tools, with cultural and socioeconomic factors playing important roles.

Liz Schwandt, PsyD, an early intervention specialist in Los Angeles, said in an interview that children living in high-risk communities in the United States have a larger burden of developmental delays. But for many families in these communities, accessing care can be complex, which is why well-designed, efficient screening tools like ASQ-3 are especially valuable in practice.

“The reality is you have 10 minutes with a lot of families, and if it’s an emergency, you need to know,” she said. “The ASQ-3 has a very broad age range for this type of instrument and can be used by different practitioner types. The reason it’s successful lies in its parent-centric approach and inherent ease of use. It’s quick, and you can score it using pencil and paper while chatting with the parent, and you can use it for multiple siblings in the space of one appointment.”

With very young children, in whom neurodevelopmental concerns often overlap domains, Schwandt said it can be more important to flag a potential problem early and initiate a nonspecific developmental intervention than wait for results from more precise assessments using more specialized tools. These often require multiple, multi-hour appointments, which can be difficult to attain in lower-resource settings in the United States and can delay care, she said.

Liza Mackintosh, MD, a pediatrician at a federally funded healthcare center in Los Angeles that serves mostly publicly insured families, called validated first-line screening tools “incredibly important.” While rates of developmental screenings in pediatric clinics are increasing, there is still room for improvement, she said.

Mackintosh’s institution does not currently use the ASQ-3 but a different screening tool, called the Survey of Well-Being of Young Children (SWYC), that is embedded into the electronic health record. (The SWYC was not among the tools highlighted in Burgess and colleagues’ review.) Like the ASQ-3, it is short and efficient, she said, and it is used in all children in the recommended age ranges.

“Our visits are on average only 20 minutes,” Mackintosh said. “There’s not enough time for an in-depth developmental assessment. We will flag things such as a speech delay, gross motor delay, or fine motor delay” and refer to early intervention centers for more in-depth developmental assessments as needed, she said.

“The biggest job of pediatricians working in communities that are under-resourced is advocating for those early intervention services,” Mackintosh added. “We really see our job as doing the recommended screening, putting that together with what we’re seeing clinically and on history, and then advocating for the right next step or early intervention. Because sometimes the diagnosis is — I don’t want to say irrelevant, but your treatment plan is still going to be the same. So while I don’t have a formal diagnosis yet, the child definitely needs therapies and we’re still going to get those therapies.”

Burgess and her colleagues stressed in their paper the importance of selecting tools that are culturally appropriate for Indigenous communities in Australia, noting that “inappropriate tools may lead to over- or under-recognition of children with developmental concerns.”

Schwandt and Mackintosh said that the same applies in US settings.

“We’ve done a good job translating screening tools into Chinese, Spanish, Vietnamese, and Russian,” Schwandt said. “But some of them assume a way of taking care of children that is not always shared across cultures. The expectations of how children should play and interact with adults can be very different, and there needs to be an understanding of that. Just putting something in Vietnamese doesn’t mean that there are obvious analogues to understanding what the questionnaire is asking.”

Mackintosh concurred. “A lot of times our patients will not do well on screening, even though they’re fine, because they don’t have the exposure to that activity that’s being asked about. So — is the child scribbling with crayons? Is she climbing up a ladder at a playground? In order to be able to do that, you need to have an environment that you are doing it in. The screeners have to really be appropriate for what the child is exposed to. And sometimes our patients just don’t have that exposure.”

Burgess and colleagues’ study was funded by the Australian government and the Merchant Charitable Foundation. The authors disclosed no financial conflicts of interest. Schwandt and Mackintosh disclosed no conflicts of interest related to their comments.
 

A version of this article appeared on Medscape.com.

Early recognition of neurodevelopmental concerns and timely access to services have been shown to result in better outcomes for young children. But not all instruments are of equal value, and new research has sought to identify the most useful among them.

For their research, published online in Developmental Medicine & Child Neurology, Andrea Burgess, PhD, of the University of Queensland in Brisbane, Australia, and her colleagues looked at two decades’ worth of systematic reviews of screening, assessment, and diagnostic tools used in children younger than 6 years.

Eighty-six clinical reviews and six practice guidelines, all published between 2000 and 2023, were included in the scoping review, which covered nearly 250 different multi-domain and domain- and disorder-specific tools.

The diagnostic instruments were those used to diagnose the most common early childhood disorders, including intellectual disability, global developmental delay, communication disorders, autism spectrum disorder, attention-deficit/hyperactivity disorder, cerebral palsy, movement disorders, and fetal alcohol spectrum disorder. Burgess and her colleagues sought to determine which tools had the strongest evidence behind them, noting that comparisons were inherently limited by differences in the tested populations, cutoff values, and other factors.

Burgess and her colleagues identified 67 instruments — about a third of those analyzed in the study — “with good discriminative or predictive validity for the screening and assessment of developmental concerns or disability.” Recommended tools were classified by tool type and by patient age groups.

The reason a tool might not be recommended, Burgess said in an email, was for lack of psychometric testing or published evidence, or because the tool was very narrow in scope (eg, covering only a single aspect of a domain), had a small time window for use, or was too new to have been captured in published systematic reviews.
 

Top Recommendations

Among multi-domain assessment tools, the Bayley Scales of Infant and Toddler Development, the Battelle Developmental Inventory, and the Mullen Scales of Early Learning all emerged as highly recommended. The top diagnostic screening tool for autism was the revised version of Social Attention and Communication Surveillance. For cerebral palsy, the top-rated diagnostic assessment tools were Prechtl’s Qualitative Assessment of General Movements and the Hammersmith Infant Neurological Examination.

Ratifying findings by other groups, the researchers determined the Ages & Stages Questionnaires, Third Edition (ASQ-3) to be the best overall multi-domain screening instrument for early childhood development, thanks to its simplicity and ease of use by a wide range of practitioner types. Burgess and her colleagues noted, however, that the ASQ-3 “will not identify all children with developmental concerns and may incorrectly identify others,” and that it may be more accurate in children 2 years or older.
 

Patient Care Setting and Cultural, Socioeconomic Factors Are Key

This news organization spoke to two clinicians working with these and similar tools in the United States. Both said that the care setting can also influence the utility of tools, with cultural and socioeconomic factors playing important roles.

Liz Schwandt, PsyD, an early intervention specialist in Los Angeles, said in an interview that children living in high-risk communities in the United States have a larger burden of developmental delays. But for many families in these communities, accessing care can be complex, which is why well-designed, efficient screening tools like ASQ-3 are especially valuable in practice.

“The reality is you have 10 minutes with a lot of families, and if it’s an emergency, you need to know,” she said. “The ASQ-3 has a very broad age range for this type of instrument and can be used by different practitioner types. The reason it’s successful lies in its parent-centric approach and inherent ease of use. It’s quick, and you can score it using pencil and paper while chatting with the parent, and you can use it for multiple siblings in the space of one appointment.”

With very young children, in whom neurodevelopmental concerns often overlap domains, Schwandt said it can be more important to flag a potential problem early and initiate a nonspecific developmental intervention than wait for results from more precise assessments using more specialized tools. These often require multiple, multi-hour appointments, which can be difficult to attain in lower-resource settings in the United States and can delay care, she said.

Liza Mackintosh, MD, a pediatrician at a federally funded healthcare center in Los Angeles that serves mostly publicly insured families, called validated first-line screening tools “incredibly important.” While rates of developmental screenings in pediatric clinics are increasing, there is still room for improvement, she said.

Mackintosh’s institution does not currently use the ASQ-3 but a different screening tool, called the Survey of Well-Being of Young Children (SWYC), that is embedded into the electronic health record. (The SWYC was not among the tools highlighted in Burgess and colleagues’ review.) Like the ASQ-3, it is short and efficient, she said, and it is used in all children in the recommended age ranges.

“Our visits are on average only 20 minutes,” Mackintosh said. “There’s not enough time for an in-depth developmental assessment. We will flag things such as a speech delay, gross motor delay, or fine motor delay” and refer to early intervention centers for more in-depth developmental assessments as needed, she said.

“The biggest job of pediatricians working in communities that are under-resourced is advocating for those early intervention services,” Mackintosh added. “We really see our job as doing the recommended screening, putting that together with what we’re seeing clinically and on history, and then advocating for the right next step or early intervention. Because sometimes the diagnosis is — I don’t want to say irrelevant, but your treatment plan is still going to be the same. So while I don’t have a formal diagnosis yet, the child definitely needs therapies and we’re still going to get those therapies.”

Burgess and her colleagues stressed in their paper the importance of selecting tools that are culturally appropriate for Indigenous communities in Australia, noting that “inappropriate tools may lead to over- or under-recognition of children with developmental concerns.”

Schwandt and Mackintosh said that the same applies in US settings.

“We’ve done a good job translating screening tools into Chinese, Spanish, Vietnamese, and Russian,” Schwandt said. “But some of them assume a way of taking care of children that is not always shared across cultures. The expectations of how children should play and interact with adults can be very different, and there needs to be an understanding of that. Just putting something in Vietnamese doesn’t mean that there are obvious analogues to understanding what the questionnaire is asking.”

Mackintosh concurred. “A lot of times our patients will not do well on screening, even though they’re fine, because they don’t have the exposure to that activity that’s being asked about. So — is the child scribbling with crayons? Is she climbing up a ladder at a playground? In order to be able to do that, you need to have an environment that you are doing it in. The screeners have to really be appropriate for what the child is exposed to. And sometimes our patients just don’t have that exposure.”

Burgess and colleagues’ study was funded by the Australian government and the Merchant Charitable Foundation. The authors disclosed no financial conflicts of interest. Schwandt and Mackintosh disclosed no conflicts of interest related to their comments.
 

A version of this article appeared on Medscape.com.

Getting drugs to the brain is difficult. The very thing designed to protect the brain’s environment — the blood-brain barrier (BBB) — is one of the main reasons diseases like Alzheimer’s are so hard to treat.

And even if a drug can cross the BBB, it’s difficult to ensure it reaches specific areas of the brain like the hippocampus, which is located deep within the brain and notoriously difficult to target with conventional drugs.

However, new research shows that novel bioengineered proteins can target neurons in the hippocampus. Using a mouse model, the researchers found that these proteins could be delivered to the hippocampus intranasally — through the nose via a spray.

“This is an urgent topic because many potential therapeutic agents do not readily cross the blood-brain barrier or have limited effects even after intranasal delivery,” said Konrad Talbot, PhD, professor of neurosurgery and pathology at Loma Linda University, Loma Linda, California, who was not involved in the study.

This is the first time a protein drug, which is larger than many drug molecules, has been specifically delivered to the hippocampus, said Noriyasu Kamei, PhD, a professor of pharmaceutical science at Kobe Gakuin University in Kobe, Japan, and lead author of the study.
 

How Did They Do It?

“Smuggle” may be a flip term, but it’s not inaccurate.

Insulin has the ability to cross the BBB, so the team began with insulin as the vehicle. By attaching other molecules to an insulin fragment, researchers theorized they could create an insulin fusion protein that can be transported across the BBB and into the brain via a process called macropinocytosis.

They executed this technique in mice by fusing florescent proteins to insulin. To treat Alzheimer’s or other diseases, they would want to fuse therapeutic molecules to the insulin for brain delivery — a future step for their research.

Other groups are studying a similar approach using transferrin receptor instead of insulin to shuttle molecules across the BBB. However, the transferrin receptor doesn’t make it to the hippocampus, Kamei said.

A benefit of their system, Kamei pointed out, is that because the method just requires a small piece of insulin to work, it’s straightforward to produce in bacteria. Importantly, he said, the insulin fusion protein should not affect blood glucose levels.
 

Why Insulin?

Aside from its ability to cross the BBB, the team thought to use insulin as the basis of a fusion protein because of their previous work.

“I found that insulin has the unique characteristics to be accumulated specifically in the hippocampal neuronal layers,” Kamei explained. That potential for accumulation is key, as they can deliver more of a drug that way.

In their past work, Kamei and colleagues also found that it could be delivered from the nose to the brain, indicating that it may be possible to use a simple nasal spray.

“The potential for noninvasive delivery of proteins by intranasal administration to the hippocampal neurons is novel,” said John Varghese, PhD, professor of neurology at University of California Los Angeles (he was not involved in the study). He noted that it’s also possible that this method could be harnessed to treat other brain diseases.

There are other drugs that treat central nervous system diseases, such as desmopressin and buserelin, which are available as nasal sprays. However, these drugs are synthetic hormones, and though relatively small molecules, they do not cross the BBB.

There are also antibody treatments for Alzheimer’s, such as aducanumab (which will soon be discontinued), lecanemab, and donanemab; however, they aren’t always effective and they require an intravenous infusion, and while they cross the BBB to a degree, to bolster delivery to the brain, studies have proposed additional methods like focused ultrasound.

“Neuronal uptake of drugs potentially therapeutic for Alzheimer’s may be significantly enhanced by fusion of those drugs with insulin. This should be a research priority,” said Talbot.

While this is exciting and has potential, such drugs won’t be available anytime soon. Kamei would like to complete the research at a basic level in 5 years, including testing insulin fused with larger proteins such as therapeutic antibodies. If all goes well, they’ll move on to testing insulin fusion drugs in people.
 

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

Getting drugs to the brain is difficult. The very thing designed to protect the brain’s environment — the blood-brain barrier (BBB) — is one of the main reasons diseases like Alzheimer’s are so hard to treat.

And even if a drug can cross the BBB, it’s difficult to ensure it reaches specific areas of the brain like the hippocampus, which is located deep within the brain and notoriously difficult to target with conventional drugs.

However, new research shows that novel bioengineered proteins can target neurons in the hippocampus. Using a mouse model, the researchers found that these proteins could be delivered to the hippocampus intranasally — through the nose via a spray.

“This is an urgent topic because many potential therapeutic agents do not readily cross the blood-brain barrier or have limited effects even after intranasal delivery,” said Konrad Talbot, PhD, professor of neurosurgery and pathology at Loma Linda University, Loma Linda, California, who was not involved in the study.

This is the first time a protein drug, which is larger than many drug molecules, has been specifically delivered to the hippocampus, said Noriyasu Kamei, PhD, a professor of pharmaceutical science at Kobe Gakuin University in Kobe, Japan, and lead author of the study.
 

How Did They Do It?

“Smuggle” may be a flip term, but it’s not inaccurate.

Insulin has the ability to cross the BBB, so the team began with insulin as the vehicle. By attaching other molecules to an insulin fragment, researchers theorized they could create an insulin fusion protein that can be transported across the BBB and into the brain via a process called macropinocytosis.

They executed this technique in mice by fusing florescent proteins to insulin. To treat Alzheimer’s or other diseases, they would want to fuse therapeutic molecules to the insulin for brain delivery — a future step for their research.

Other groups are studying a similar approach using transferrin receptor instead of insulin to shuttle molecules across the BBB. However, the transferrin receptor doesn’t make it to the hippocampus, Kamei said.

A benefit of their system, Kamei pointed out, is that because the method just requires a small piece of insulin to work, it’s straightforward to produce in bacteria. Importantly, he said, the insulin fusion protein should not affect blood glucose levels.
 

Why Insulin?

Aside from its ability to cross the BBB, the team thought to use insulin as the basis of a fusion protein because of their previous work.

“I found that insulin has the unique characteristics to be accumulated specifically in the hippocampal neuronal layers,” Kamei explained. That potential for accumulation is key, as they can deliver more of a drug that way.

In their past work, Kamei and colleagues also found that it could be delivered from the nose to the brain, indicating that it may be possible to use a simple nasal spray.

“The potential for noninvasive delivery of proteins by intranasal administration to the hippocampal neurons is novel,” said John Varghese, PhD, professor of neurology at University of California Los Angeles (he was not involved in the study). He noted that it’s also possible that this method could be harnessed to treat other brain diseases.

There are other drugs that treat central nervous system diseases, such as desmopressin and buserelin, which are available as nasal sprays. However, these drugs are synthetic hormones, and though relatively small molecules, they do not cross the BBB.

There are also antibody treatments for Alzheimer’s, such as aducanumab (which will soon be discontinued), lecanemab, and donanemab; however, they aren’t always effective and they require an intravenous infusion, and while they cross the BBB to a degree, to bolster delivery to the brain, studies have proposed additional methods like focused ultrasound.

“Neuronal uptake of drugs potentially therapeutic for Alzheimer’s may be significantly enhanced by fusion of those drugs with insulin. This should be a research priority,” said Talbot.

While this is exciting and has potential, such drugs won’t be available anytime soon. Kamei would like to complete the research at a basic level in 5 years, including testing insulin fused with larger proteins such as therapeutic antibodies. If all goes well, they’ll move on to testing insulin fusion drugs in people.
 

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

Getting drugs to the brain is difficult. The very thing designed to protect the brain’s environment — the blood-brain barrier (BBB) — is one of the main reasons diseases like Alzheimer’s are so hard to treat.

And even if a drug can cross the BBB, it’s difficult to ensure it reaches specific areas of the brain like the hippocampus, which is located deep within the brain and notoriously difficult to target with conventional drugs.

However, new research shows that novel bioengineered proteins can target neurons in the hippocampus. Using a mouse model, the researchers found that these proteins could be delivered to the hippocampus intranasally — through the nose via a spray.

“This is an urgent topic because many potential therapeutic agents do not readily cross the blood-brain barrier or have limited effects even after intranasal delivery,” said Konrad Talbot, PhD, professor of neurosurgery and pathology at Loma Linda University, Loma Linda, California, who was not involved in the study.

This is the first time a protein drug, which is larger than many drug molecules, has been specifically delivered to the hippocampus, said Noriyasu Kamei, PhD, a professor of pharmaceutical science at Kobe Gakuin University in Kobe, Japan, and lead author of the study.
 

How Did They Do It?

“Smuggle” may be a flip term, but it’s not inaccurate.

Insulin has the ability to cross the BBB, so the team began with insulin as the vehicle. By attaching other molecules to an insulin fragment, researchers theorized they could create an insulin fusion protein that can be transported across the BBB and into the brain via a process called macropinocytosis.

They executed this technique in mice by fusing florescent proteins to insulin. To treat Alzheimer’s or other diseases, they would want to fuse therapeutic molecules to the insulin for brain delivery — a future step for their research.

Other groups are studying a similar approach using transferrin receptor instead of insulin to shuttle molecules across the BBB. However, the transferrin receptor doesn’t make it to the hippocampus, Kamei said.

A benefit of their system, Kamei pointed out, is that because the method just requires a small piece of insulin to work, it’s straightforward to produce in bacteria. Importantly, he said, the insulin fusion protein should not affect blood glucose levels.
 

Why Insulin?

Aside from its ability to cross the BBB, the team thought to use insulin as the basis of a fusion protein because of their previous work.

“I found that insulin has the unique characteristics to be accumulated specifically in the hippocampal neuronal layers,” Kamei explained. That potential for accumulation is key, as they can deliver more of a drug that way.

In their past work, Kamei and colleagues also found that it could be delivered from the nose to the brain, indicating that it may be possible to use a simple nasal spray.

“The potential for noninvasive delivery of proteins by intranasal administration to the hippocampal neurons is novel,” said John Varghese, PhD, professor of neurology at University of California Los Angeles (he was not involved in the study). He noted that it’s also possible that this method could be harnessed to treat other brain diseases.

There are other drugs that treat central nervous system diseases, such as desmopressin and buserelin, which are available as nasal sprays. However, these drugs are synthetic hormones, and though relatively small molecules, they do not cross the BBB.

There are also antibody treatments for Alzheimer’s, such as aducanumab (which will soon be discontinued), lecanemab, and donanemab; however, they aren’t always effective and they require an intravenous infusion, and while they cross the BBB to a degree, to bolster delivery to the brain, studies have proposed additional methods like focused ultrasound.

“Neuronal uptake of drugs potentially therapeutic for Alzheimer’s may be significantly enhanced by fusion of those drugs with insulin. This should be a research priority,” said Talbot.

While this is exciting and has potential, such drugs won’t be available anytime soon. Kamei would like to complete the research at a basic level in 5 years, including testing insulin fused with larger proteins such as therapeutic antibodies. If all goes well, they’ll move on to testing insulin fusion drugs in people.
 

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

PHILADELPHIA — Pimavanserin (Nuplazid, Acadia) is noninferior to quetiapine in patients with Parkinson’s disease psychosis at 56 days, results from a phase 3 trial showed.

In the first prospective comparison of the two antipsychotics in this patient population, pimavanserin yielded significant improvement across all parameters of efficacy without worsening motor symptoms and was very well tolerated, said study investigator Amey Mane, MD, Sun Pharma Laboratories, Mumbai, India.

Psychosis occurs in about 50% patients with Parkinson’s disease and is a major risk factor for hospitalization, nursing home placement, and mortality.

Antipsychotics are used to treat Parkinson’s disease psychosis, but evidence for the efficacy of quetiapine is inconsistent and clozapine requires regular monitoring for agranulocytosis, said Dr. Mane. Cholinergic blockade by these drugs can also increase non-motor symptoms such as constipation, drooling, and cognitive impairment.

Pimavanserin is an oral 5-HT2A inverse agonist and antagonist and the only Food and Drug Administration–approved medication for Parkinson’s disease psychosis, he said. The drug was approved in 2016, and its label was updated in 2023 to clarify that it can be used to treat patients with Parkinson’s disease psychosis, who also have dementia.

“To the best of our understanding, this is the first completed prospective study of pimavanserin with an active comparator, quetiapine,” in Parkinson’s disease psychosis, he said.

The findings were presented in a late-breaking abstract session at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024.
 

Primary Outcome at 56 Days

The assessor-blinded study enrolled 247 patients with Parkinson’s disease for at least 1 year, who were Hoehn and Yahr stage 3 or higher, with hallucinations and/or delusions on a stable dose of Parkinson’s disease medication for at least 4 weeks. The average duration of psychosis was 1.2 years.

Patients were randomly assigned to receive daily pimavanserin 34 mg or quetiapine 25-200 mg for 56 days and evaluated at baseline and days 14, 28, 42, and 56.

The mean change in Scale for the Assessment of Positive Symptoms–Parkinson’s disease (SAPS-PD) nine-item total scores improved from baseline in both groups at all visits (P < .0001) and was significantly greater at 42 days with pimavanserin than with quetiapine (−7.15 vs −6.33; P = .029).

The primary outcome of mean change in SAPS-PD total score at day 56 was −9.64 in the pimavanserin group and −8.37 in the quetiapine group (P = .008). The between-group difference was −1.27, and the upper bound of the 95% CI (−2.77 to 0.24) was lower than the prespecified margin of 0.9, demonstrating noninferiority, Dr. Mane said.
 

Secondary Endpoints and Safety

Pimavanserin was associated with significantly greater improvement than quetiapine for the following secondary outcomes:

• SAPS-Hallucinations and Delusions at day 42 (mean, −12.70 vs −11.40; P = .009) and day 56 (mean, −17.00 vs −15.60; P = .007)
• SAPS-Hallucinations at day 42 (mean, −5.61 vs −4.75; P = .01) and day 56 (mean, −7.33 vs −6.52; P = .02)
• Clinical Global Impression-Improvement score at day 56 (−1.90 vs −1.59; P = .01)
• Scales for Outcomes in Parkinson’s disease (SCOPA) scores for nighttime sleep at day 14 (−1.12 vs −0.85; P = .03) and SCOPA daytime wakefulness at day 28 (−2.42 vs −1.70; P = .01)

Treatment-emergent adverse events (TEAEs) were reported in 7.5% and 13.5% of the pimavanserin and quetiapine groups, respectively.

Five TEAEs, all of mild intensity, were reported as related to study drugs: Pyrexia (1), headache (1), and nasopharyngitis (2) with pimavanserin and headache (1) with quetiapine, Dr. Mane said. There was one unrelated fatal stroke in the quetiapine group. No drug discontinuations occurred because of TEAEs.
 

Delayed Onset of Action?

During a discussion of the results, Hubert Fernandez, MD, director, Center for Neurological Restoration, Cleveland Clinic in Ohio, asked whether the investigators observed a difference in onset between the two drugs.

“Our general impression in the United States is that pimavanserin has a slower uptake in efficacy as compared with quetiapine. If it [quetiapine] works, it works the next day or the day after, whereas with pimavanserin you have to wait for a week or 2. I was just wondering if that’s validated or just anecdotal experience,” he said.

Dr. Mane said the study showed no difference in efficacy at 14 days and greater improvement in efficacy between days 14 and 56.

Another attendee pointed out that quetiapine is particularly good at inducing sleep and asked whether some of the observed differences, especially early on, were due to the need to rapidly titrate quetiapine to induce sleep and get the sleep-wake cycle back on track.

“We did discuss this with most of our investigators, and they gave the same reason. It’s the titration with the quetiapine, and that’s why it’s seen in the early parts,” said Dr. Mane.

Reached for comment, Regina Katzenschlager, MD, Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Klinik Donaustadt, Vienna, Austria, said the majority of drugs commonly used for other types of psychosis cannot be used in PD because of motor worsening.

“Quetiapine is one of the very, very few options we have to treat people with Parkinson’s psychosis because it leads to little, if any, worsening and is the best tolerated,” she said. “Everything else is almost absolutely contraindicated. So that’s why an additional drug — this one has a slightly different mechanism — is incredibly helpful in the clinic because not everyone responds to quetiapine.”

Dr. Katzenschlager pointed out that pimavanserin is not approved in Europe and that the present study was conducted for regulatory purposes in India.

Dr. Mane is an employee of Sun Pharma Laboratories. Dr. Katzenschlager reported having no relevant financial relationships.

A version of this article appeared on Medscape.com.

PHILADELPHIA — Pimavanserin (Nuplazid, Acadia) is noninferior to quetiapine in patients with Parkinson’s disease psychosis at 56 days, results from a phase 3 trial showed.

In the first prospective comparison of the two antipsychotics in this patient population, pimavanserin yielded significant improvement across all parameters of efficacy without worsening motor symptoms and was very well tolerated, said study investigator Amey Mane, MD, Sun Pharma Laboratories, Mumbai, India.

Psychosis occurs in about 50% patients with Parkinson’s disease and is a major risk factor for hospitalization, nursing home placement, and mortality.

Antipsychotics are used to treat Parkinson’s disease psychosis, but evidence for the efficacy of quetiapine is inconsistent and clozapine requires regular monitoring for agranulocytosis, said Dr. Mane. Cholinergic blockade by these drugs can also increase non-motor symptoms such as constipation, drooling, and cognitive impairment.

Pimavanserin is an oral 5-HT2A inverse agonist and antagonist and the only Food and Drug Administration–approved medication for Parkinson’s disease psychosis, he said. The drug was approved in 2016, and its label was updated in 2023 to clarify that it can be used to treat patients with Parkinson’s disease psychosis, who also have dementia.

“To the best of our understanding, this is the first completed prospective study of pimavanserin with an active comparator, quetiapine,” in Parkinson’s disease psychosis, he said.

The findings were presented in a late-breaking abstract session at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024.
 

Primary Outcome at 56 Days

The assessor-blinded study enrolled 247 patients with Parkinson’s disease for at least 1 year, who were Hoehn and Yahr stage 3 or higher, with hallucinations and/or delusions on a stable dose of Parkinson’s disease medication for at least 4 weeks. The average duration of psychosis was 1.2 years.

Patients were randomly assigned to receive daily pimavanserin 34 mg or quetiapine 25-200 mg for 56 days and evaluated at baseline and days 14, 28, 42, and 56.

The mean change in Scale for the Assessment of Positive Symptoms–Parkinson’s disease (SAPS-PD) nine-item total scores improved from baseline in both groups at all visits (P < .0001) and was significantly greater at 42 days with pimavanserin than with quetiapine (−7.15 vs −6.33; P = .029).

The primary outcome of mean change in SAPS-PD total score at day 56 was −9.64 in the pimavanserin group and −8.37 in the quetiapine group (P = .008). The between-group difference was −1.27, and the upper bound of the 95% CI (−2.77 to 0.24) was lower than the prespecified margin of 0.9, demonstrating noninferiority, Dr. Mane said.
 

Secondary Endpoints and Safety

Pimavanserin was associated with significantly greater improvement than quetiapine for the following secondary outcomes:

• SAPS-Hallucinations and Delusions at day 42 (mean, −12.70 vs −11.40; P = .009) and day 56 (mean, −17.00 vs −15.60; P = .007)
• SAPS-Hallucinations at day 42 (mean, −5.61 vs −4.75; P = .01) and day 56 (mean, −7.33 vs −6.52; P = .02)
• Clinical Global Impression-Improvement score at day 56 (−1.90 vs −1.59; P = .01)
• Scales for Outcomes in Parkinson’s disease (SCOPA) scores for nighttime sleep at day 14 (−1.12 vs −0.85; P = .03) and SCOPA daytime wakefulness at day 28 (−2.42 vs −1.70; P = .01)

Treatment-emergent adverse events (TEAEs) were reported in 7.5% and 13.5% of the pimavanserin and quetiapine groups, respectively.

Five TEAEs, all of mild intensity, were reported as related to study drugs: Pyrexia (1), headache (1), and nasopharyngitis (2) with pimavanserin and headache (1) with quetiapine, Dr. Mane said. There was one unrelated fatal stroke in the quetiapine group. No drug discontinuations occurred because of TEAEs.
 

Delayed Onset of Action?

During a discussion of the results, Hubert Fernandez, MD, director, Center for Neurological Restoration, Cleveland Clinic in Ohio, asked whether the investigators observed a difference in onset between the two drugs.

“Our general impression in the United States is that pimavanserin has a slower uptake in efficacy as compared with quetiapine. If it [quetiapine] works, it works the next day or the day after, whereas with pimavanserin you have to wait for a week or 2. I was just wondering if that’s validated or just anecdotal experience,” he said.

Dr. Mane said the study showed no difference in efficacy at 14 days and greater improvement in efficacy between days 14 and 56.

Another attendee pointed out that quetiapine is particularly good at inducing sleep and asked whether some of the observed differences, especially early on, were due to the need to rapidly titrate quetiapine to induce sleep and get the sleep-wake cycle back on track.

“We did discuss this with most of our investigators, and they gave the same reason. It’s the titration with the quetiapine, and that’s why it’s seen in the early parts,” said Dr. Mane.

Reached for comment, Regina Katzenschlager, MD, Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Klinik Donaustadt, Vienna, Austria, said the majority of drugs commonly used for other types of psychosis cannot be used in PD because of motor worsening.

“Quetiapine is one of the very, very few options we have to treat people with Parkinson’s psychosis because it leads to little, if any, worsening and is the best tolerated,” she said. “Everything else is almost absolutely contraindicated. So that’s why an additional drug — this one has a slightly different mechanism — is incredibly helpful in the clinic because not everyone responds to quetiapine.”

Dr. Katzenschlager pointed out that pimavanserin is not approved in Europe and that the present study was conducted for regulatory purposes in India.

Dr. Mane is an employee of Sun Pharma Laboratories. Dr. Katzenschlager reported having no relevant financial relationships.

A version of this article appeared on Medscape.com.

PHILADELPHIA — Pimavanserin (Nuplazid, Acadia) is noninferior to quetiapine in patients with Parkinson’s disease psychosis at 56 days, results from a phase 3 trial showed.

In the first prospective comparison of the two antipsychotics in this patient population, pimavanserin yielded significant improvement across all parameters of efficacy without worsening motor symptoms and was very well tolerated, said study investigator Amey Mane, MD, Sun Pharma Laboratories, Mumbai, India.

Psychosis occurs in about 50% patients with Parkinson’s disease and is a major risk factor for hospitalization, nursing home placement, and mortality.

Antipsychotics are used to treat Parkinson’s disease psychosis, but evidence for the efficacy of quetiapine is inconsistent and clozapine requires regular monitoring for agranulocytosis, said Dr. Mane. Cholinergic blockade by these drugs can also increase non-motor symptoms such as constipation, drooling, and cognitive impairment.

Pimavanserin is an oral 5-HT2A inverse agonist and antagonist and the only Food and Drug Administration–approved medication for Parkinson’s disease psychosis, he said. The drug was approved in 2016, and its label was updated in 2023 to clarify that it can be used to treat patients with Parkinson’s disease psychosis, who also have dementia.

“To the best of our understanding, this is the first completed prospective study of pimavanserin with an active comparator, quetiapine,” in Parkinson’s disease psychosis, he said.

The findings were presented in a late-breaking abstract session at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024.
 

Primary Outcome at 56 Days

The assessor-blinded study enrolled 247 patients with Parkinson’s disease for at least 1 year, who were Hoehn and Yahr stage 3 or higher, with hallucinations and/or delusions on a stable dose of Parkinson’s disease medication for at least 4 weeks. The average duration of psychosis was 1.2 years.

Patients were randomly assigned to receive daily pimavanserin 34 mg or quetiapine 25-200 mg for 56 days and evaluated at baseline and days 14, 28, 42, and 56.

The mean change in Scale for the Assessment of Positive Symptoms–Parkinson’s disease (SAPS-PD) nine-item total scores improved from baseline in both groups at all visits (P < .0001) and was significantly greater at 42 days with pimavanserin than with quetiapine (−7.15 vs −6.33; P = .029).

The primary outcome of mean change in SAPS-PD total score at day 56 was −9.64 in the pimavanserin group and −8.37 in the quetiapine group (P = .008). The between-group difference was −1.27, and the upper bound of the 95% CI (−2.77 to 0.24) was lower than the prespecified margin of 0.9, demonstrating noninferiority, Dr. Mane said.
 

Secondary Endpoints and Safety

Pimavanserin was associated with significantly greater improvement than quetiapine for the following secondary outcomes:

• SAPS-Hallucinations and Delusions at day 42 (mean, −12.70 vs −11.40; P = .009) and day 56 (mean, −17.00 vs −15.60; P = .007)
• SAPS-Hallucinations at day 42 (mean, −5.61 vs −4.75; P = .01) and day 56 (mean, −7.33 vs −6.52; P = .02)
• Clinical Global Impression-Improvement score at day 56 (−1.90 vs −1.59; P = .01)
• Scales for Outcomes in Parkinson’s disease (SCOPA) scores for nighttime sleep at day 14 (−1.12 vs −0.85; P = .03) and SCOPA daytime wakefulness at day 28 (−2.42 vs −1.70; P = .01)

Treatment-emergent adverse events (TEAEs) were reported in 7.5% and 13.5% of the pimavanserin and quetiapine groups, respectively.

Five TEAEs, all of mild intensity, were reported as related to study drugs: Pyrexia (1), headache (1), and nasopharyngitis (2) with pimavanserin and headache (1) with quetiapine, Dr. Mane said. There was one unrelated fatal stroke in the quetiapine group. No drug discontinuations occurred because of TEAEs.
 

Delayed Onset of Action?

During a discussion of the results, Hubert Fernandez, MD, director, Center for Neurological Restoration, Cleveland Clinic in Ohio, asked whether the investigators observed a difference in onset between the two drugs.

“Our general impression in the United States is that pimavanserin has a slower uptake in efficacy as compared with quetiapine. If it [quetiapine] works, it works the next day or the day after, whereas with pimavanserin you have to wait for a week or 2. I was just wondering if that’s validated or just anecdotal experience,” he said.

Dr. Mane said the study showed no difference in efficacy at 14 days and greater improvement in efficacy between days 14 and 56.

Another attendee pointed out that quetiapine is particularly good at inducing sleep and asked whether some of the observed differences, especially early on, were due to the need to rapidly titrate quetiapine to induce sleep and get the sleep-wake cycle back on track.

“We did discuss this with most of our investigators, and they gave the same reason. It’s the titration with the quetiapine, and that’s why it’s seen in the early parts,” said Dr. Mane.

Reached for comment, Regina Katzenschlager, MD, Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Klinik Donaustadt, Vienna, Austria, said the majority of drugs commonly used for other types of psychosis cannot be used in PD because of motor worsening.

“Quetiapine is one of the very, very few options we have to treat people with Parkinson’s psychosis because it leads to little, if any, worsening and is the best tolerated,” she said. “Everything else is almost absolutely contraindicated. So that’s why an additional drug — this one has a slightly different mechanism — is incredibly helpful in the clinic because not everyone responds to quetiapine.”

Dr. Katzenschlager pointed out that pimavanserin is not approved in Europe and that the present study was conducted for regulatory purposes in India.

Dr. Mane is an employee of Sun Pharma Laboratories. Dr. Katzenschlager reported having no relevant financial relationships.

A version of this article appeared on Medscape.com.

We pediatricians consider ourselves as compassionate professionals, optimistic about the potential of all children. This is reflected in the American Academy of Pediatrics’ equity statement of “its mission to ensure the health and well-being of all children. This includes promoting nurturing, inclusive environments and actively opposing intolerance, bigotry, bias, and discrimination.”

A committee of the Developmental Behavioral Pediatric Network developed and published a consensus statement specifically about problems in the care of individuals with neurodevelopmental disabilities (NDD) called the Supporting Access for Everyone (SAFE) initiative. All of us care for children with NDD as one in six are affected with these conditions that impact cognition, communication, motor, social, and/or behavior skills such as autism, ADHD, intellectual disabilities (ID), learning disorders, hearing or vision impairment, and motor disabilities such as cerebral palsy. Children with NDD are overrepresented in our daily practice schedule due to their multiple medical, behavioral, and social needs. NDD are also more common among marginalized children with racial, ethnic, sexual, or gender identity minority status compounding their difficulties in accessing quality care.

NDD present similar challenges to care as other chronic conditions that also require longer visits, more documentation, long-term monitoring, team-based care, care coordination, and often referrals. But most chronic medical conditions we care for such as asthma, diabetes, cancer, hypertension, and renal disease have clear national guidelines and appropriate billing codes and are not stigmatizing. Most also do not intrinsically affect the nervous system or cause disability as for NDD that alter the behavioral presentation of the individual in a way that changes their care.

Discrimination against individuals with NDD and other disabilities, called “ableism,” can take many forms: assuming a child with communication difficulty or ID is unable to understand explanations about their care; the presence of one NDD condition ending the clinician’s search for other issues; complicated problems or difficult behaviors in the medical setting truncating care, etc. To be equitable in the care of individuals with NDD we need to be aware of discrimination and also go beyond guidelines to personalize the accommodations we advise and make.
 

Adjustments Needed for Special Needs

As pediatricians we already adjust our interactions, starting instinctively, to the development level of the child we perceive before us. We approach infants slowly and softly, we speak in shorter sentences to toddlers, we joke around with school-aged children, and we take extra care about privacy with teens. This serves the relationships well for neurotypical children. But our (and our staff’s) perceptions of children with autism, ID, genetic syndromes that include NDD, or motor disabilities based on their behavioral presentation may not accurately recognize or accommodate their abilities or needs. Communication and environmental adjustments may need to be much more individualized to provide respectful care, comfort and even safety.

As an example, at this time 1 in 36 children have autism with or without ID. Defining features of autism include differences in social communication, repetitive or restrictive interests or behaviors, and hypersensitivity to the environment plus any coexisting conditions such as anxiety and hyperactivity. But most children with autism have completely age appropriate and typical physical appearance and their underlying condition may not even be known. The office setting, without special attention to the needs of a child with autism, may be frightening, loud, too bright, too crowded, fast paced, and confusing. The result of their sensitivities and difficulty communicating may lead to increased agitation, repetitive behaviors (sometimes called “stimming”), shrieking, attempts to escape the room, refusal to allow for vital signs or undressing, even aggression. Strategies for calming a neurotypical child such as talking or touching may make matters worse instead of better. We need help from the child and family and a plan to optimize their medical encounters.

If not adequately accommodated, children with many varieties of NDD end up not getting all the routine healthcare they need (eg vaccinations, blood tests, vital signs, even complete physical exams including dental) as well as having more adverse events during health care, including traumatizing seclusion, not allowing a support person to be present, restraint, injuries, and accidents. When more complex procedures are needed, eg x-ray, MRI, EEG, lab studies, or surgery, successful outcomes may be lower. Children with NDD have higher rates of often avoidable morbidity and mortality than those without, in part due to these barriers to complete care. While environmental accommodations to wheelchair users for accessibility has greatly improved in recent years, access to other kinds of individualized accommodations have lagged behind.
 

Accommodation Planning

There are a variety of factors that need to be taken into consideration in accommodating an individual with NDD. The family becomes the expert, along with the child, in knowing the child’s triggers, preferences, abilities, and level of understanding to accept and consent for care. An accommodation plan should be created using shared and supported decision making with the family and child and allowing for child preferences, regardless of their ability level, whenever possible. Development of an accommodation plan may benefit from multidisciplinary input, eg psychology, physical therapy, speech pathology, depending on the child’s needs and the practice’s ability to adapt.

The SAFE initiative is in the process of creating a checklist aiming to facilitate a description being created for each individual to help plan for a successful medical encounter while optimizing the child’s comfort, participation, and safety. While the checklist is not yet ready, we can start now by asking families and children in preparation for or at the start of a visit about their needs and writing a shared document that can also be placed in the electronic health record for the entire care team for informing care going forward.

It is especially important for the family to keep a copy of the care plan and for it to be sent as part of referrals for procedures or specialty visits so that the professionals can prepare and adapt the encounter. An excellent example is a how some hospitals schedule a practice visit for the child to experience the sights and sounds and people the child will encounter, for example, before an EEG, when nothing is required of the child. Scheduling the actual procedure at times of day when clinics are less crowded and wait times are shorter can improve the chances of success.

Some categories and details that might be included in an accommodation plan are listed below:

You might start the plan with the child’s preferred name/nickname, family member or support person names, and diagnoses along with a brief overview of the child’s level of functioning. Then list categories of needs and preferences along with suggestions or requests.

• Motor: Does the child have or need assistance entering the building, visit room, bathroom, or transferring to the exam table? What kind of assistance, if any, and by whom?
• Sensory: Is the child disturbed by noise, lights, or being touched? Does the child want to use equipment to be comfortable such as headphones, earplugs, or sunglasses or need a quiet room, care without perfumes, or dimmed lighting? Does the child typically refuse aspects of the physical examination?
• Behavioral regulation: What helps the child to stay calm? Are there certain triggers to becoming upset? Are there early cues that an upset is coming? What and who can help in the case of an upset?
• Habits/preferences: Are there certain comfort objects or habits your child needs? Are there habits your child needs to do, such as a certain order of events, or use of social stories or pictures, to cooperate or feel comfortable?
• Communication: How does the child make his/her needs known? Does the child/family speak English or another language? Does he/she use sign language or an augmentative communication device? What level of understanding does your child have; for example, similar to what age for a typical child? Is there a care plan with accommodations already available that needs review or needs revision with the child’s development or is a new one needed? Was the care plan developed including the child’s participation and assent or is more collaboration needed?
• History: Has your child had any very upsetting experiences in healthcare settings? What happened? Has the trauma been addressed? Are there reminders of the trauma that should be avoided?
• Other: Are there other things we should know about your child as an individual to provide the best care?

There are many actions needed to do better at ensuring equitable care for individuals with NDD. We should educate our office and medical staff about NDD in children and the importance of accommodating their needs, and ways to do it. The morning huddle can be used to remind staff of upcoming visits of children who may need accommodations. We then need to use quality improvement methods to check in periodically on how the changes are working for the children, families, and practice in order to continually improve.

The overall healthcare system also needs to change. Billing codes should reflect the time, complexity of accommodations, and documentation that were required for care. Episodes of the visit may need to be broken up within the day or over several days to allow the child to practice, calm down, and cooperate and this should be accounted for in billing. Given that NDD are generally lifelong conditions, payment systems that require measures of progress such as value-based payment based on improved outcomes will need to be adjusted to measure quality of care rather than significant progress.

We need to advocate for both individual children and for system changes to work toward equity of care for those with disabilities to make their lives more comfortable as well as ours.

Dr. Howard is assistant professor of pediatrics at The Johns Hopkins University School of Medicine, 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 [email protected].

We pediatricians consider ourselves as compassionate professionals, optimistic about the potential of all children. This is reflected in the American Academy of Pediatrics’ equity statement of “its mission to ensure the health and well-being of all children. This includes promoting nurturing, inclusive environments and actively opposing intolerance, bigotry, bias, and discrimination.”

A committee of the Developmental Behavioral Pediatric Network developed and published a consensus statement specifically about problems in the care of individuals with neurodevelopmental disabilities (NDD) called the Supporting Access for Everyone (SAFE) initiative. All of us care for children with NDD as one in six are affected with these conditions that impact cognition, communication, motor, social, and/or behavior skills such as autism, ADHD, intellectual disabilities (ID), learning disorders, hearing or vision impairment, and motor disabilities such as cerebral palsy. Children with NDD are overrepresented in our daily practice schedule due to their multiple medical, behavioral, and social needs. NDD are also more common among marginalized children with racial, ethnic, sexual, or gender identity minority status compounding their difficulties in accessing quality care.

NDD present similar challenges to care as other chronic conditions that also require longer visits, more documentation, long-term monitoring, team-based care, care coordination, and often referrals. But most chronic medical conditions we care for such as asthma, diabetes, cancer, hypertension, and renal disease have clear national guidelines and appropriate billing codes and are not stigmatizing. Most also do not intrinsically affect the nervous system or cause disability as for NDD that alter the behavioral presentation of the individual in a way that changes their care.

Discrimination against individuals with NDD and other disabilities, called “ableism,” can take many forms: assuming a child with communication difficulty or ID is unable to understand explanations about their care; the presence of one NDD condition ending the clinician’s search for other issues; complicated problems or difficult behaviors in the medical setting truncating care, etc. To be equitable in the care of individuals with NDD we need to be aware of discrimination and also go beyond guidelines to personalize the accommodations we advise and make.
 

Adjustments Needed for Special Needs

As pediatricians we already adjust our interactions, starting instinctively, to the development level of the child we perceive before us. We approach infants slowly and softly, we speak in shorter sentences to toddlers, we joke around with school-aged children, and we take extra care about privacy with teens. This serves the relationships well for neurotypical children. But our (and our staff’s) perceptions of children with autism, ID, genetic syndromes that include NDD, or motor disabilities based on their behavioral presentation may not accurately recognize or accommodate their abilities or needs. Communication and environmental adjustments may need to be much more individualized to provide respectful care, comfort and even safety.

As an example, at this time 1 in 36 children have autism with or without ID. Defining features of autism include differences in social communication, repetitive or restrictive interests or behaviors, and hypersensitivity to the environment plus any coexisting conditions such as anxiety and hyperactivity. But most children with autism have completely age appropriate and typical physical appearance and their underlying condition may not even be known. The office setting, without special attention to the needs of a child with autism, may be frightening, loud, too bright, too crowded, fast paced, and confusing. The result of their sensitivities and difficulty communicating may lead to increased agitation, repetitive behaviors (sometimes called “stimming”), shrieking, attempts to escape the room, refusal to allow for vital signs or undressing, even aggression. Strategies for calming a neurotypical child such as talking or touching may make matters worse instead of better. We need help from the child and family and a plan to optimize their medical encounters.

If not adequately accommodated, children with many varieties of NDD end up not getting all the routine healthcare they need (eg vaccinations, blood tests, vital signs, even complete physical exams including dental) as well as having more adverse events during health care, including traumatizing seclusion, not allowing a support person to be present, restraint, injuries, and accidents. When more complex procedures are needed, eg x-ray, MRI, EEG, lab studies, or surgery, successful outcomes may be lower. Children with NDD have higher rates of often avoidable morbidity and mortality than those without, in part due to these barriers to complete care. While environmental accommodations to wheelchair users for accessibility has greatly improved in recent years, access to other kinds of individualized accommodations have lagged behind.
 

Accommodation Planning

There are a variety of factors that need to be taken into consideration in accommodating an individual with NDD. The family becomes the expert, along with the child, in knowing the child’s triggers, preferences, abilities, and level of understanding to accept and consent for care. An accommodation plan should be created using shared and supported decision making with the family and child and allowing for child preferences, regardless of their ability level, whenever possible. Development of an accommodation plan may benefit from multidisciplinary input, eg psychology, physical therapy, speech pathology, depending on the child’s needs and the practice’s ability to adapt.

The SAFE initiative is in the process of creating a checklist aiming to facilitate a description being created for each individual to help plan for a successful medical encounter while optimizing the child’s comfort, participation, and safety. While the checklist is not yet ready, we can start now by asking families and children in preparation for or at the start of a visit about their needs and writing a shared document that can also be placed in the electronic health record for the entire care team for informing care going forward.

It is especially important for the family to keep a copy of the care plan and for it to be sent as part of referrals for procedures or specialty visits so that the professionals can prepare and adapt the encounter. An excellent example is a how some hospitals schedule a practice visit for the child to experience the sights and sounds and people the child will encounter, for example, before an EEG, when nothing is required of the child. Scheduling the actual procedure at times of day when clinics are less crowded and wait times are shorter can improve the chances of success.

Some categories and details that might be included in an accommodation plan are listed below:

You might start the plan with the child’s preferred name/nickname, family member or support person names, and diagnoses along with a brief overview of the child’s level of functioning. Then list categories of needs and preferences along with suggestions or requests.

• Motor: Does the child have or need assistance entering the building, visit room, bathroom, or transferring to the exam table? What kind of assistance, if any, and by whom?
• Sensory: Is the child disturbed by noise, lights, or being touched? Does the child want to use equipment to be comfortable such as headphones, earplugs, or sunglasses or need a quiet room, care without perfumes, or dimmed lighting? Does the child typically refuse aspects of the physical examination?
• Behavioral regulation: What helps the child to stay calm? Are there certain triggers to becoming upset? Are there early cues that an upset is coming? What and who can help in the case of an upset?
• Habits/preferences: Are there certain comfort objects or habits your child needs? Are there habits your child needs to do, such as a certain order of events, or use of social stories or pictures, to cooperate or feel comfortable?
• Communication: How does the child make his/her needs known? Does the child/family speak English or another language? Does he/she use sign language or an augmentative communication device? What level of understanding does your child have; for example, similar to what age for a typical child? Is there a care plan with accommodations already available that needs review or needs revision with the child’s development or is a new one needed? Was the care plan developed including the child’s participation and assent or is more collaboration needed?
• History: Has your child had any very upsetting experiences in healthcare settings? What happened? Has the trauma been addressed? Are there reminders of the trauma that should be avoided?
• Other: Are there other things we should know about your child as an individual to provide the best care?

There are many actions needed to do better at ensuring equitable care for individuals with NDD. We should educate our office and medical staff about NDD in children and the importance of accommodating their needs, and ways to do it. The morning huddle can be used to remind staff of upcoming visits of children who may need accommodations. We then need to use quality improvement methods to check in periodically on how the changes are working for the children, families, and practice in order to continually improve.

The overall healthcare system also needs to change. Billing codes should reflect the time, complexity of accommodations, and documentation that were required for care. Episodes of the visit may need to be broken up within the day or over several days to allow the child to practice, calm down, and cooperate and this should be accounted for in billing. Given that NDD are generally lifelong conditions, payment systems that require measures of progress such as value-based payment based on improved outcomes will need to be adjusted to measure quality of care rather than significant progress.

We need to advocate for both individual children and for system changes to work toward equity of care for those with disabilities to make their lives more comfortable as well as ours.

Dr. Howard is assistant professor of pediatrics at The Johns Hopkins University School of Medicine, 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 [email protected].

We pediatricians consider ourselves as compassionate professionals, optimistic about the potential of all children. This is reflected in the American Academy of Pediatrics’ equity statement of “its mission to ensure the health and well-being of all children. This includes promoting nurturing, inclusive environments and actively opposing intolerance, bigotry, bias, and discrimination.”

A committee of the Developmental Behavioral Pediatric Network developed and published a consensus statement specifically about problems in the care of individuals with neurodevelopmental disabilities (NDD) called the Supporting Access for Everyone (SAFE) initiative. All of us care for children with NDD as one in six are affected with these conditions that impact cognition, communication, motor, social, and/or behavior skills such as autism, ADHD, intellectual disabilities (ID), learning disorders, hearing or vision impairment, and motor disabilities such as cerebral palsy. Children with NDD are overrepresented in our daily practice schedule due to their multiple medical, behavioral, and social needs. NDD are also more common among marginalized children with racial, ethnic, sexual, or gender identity minority status compounding their difficulties in accessing quality care.

NDD present similar challenges to care as other chronic conditions that also require longer visits, more documentation, long-term monitoring, team-based care, care coordination, and often referrals. But most chronic medical conditions we care for such as asthma, diabetes, cancer, hypertension, and renal disease have clear national guidelines and appropriate billing codes and are not stigmatizing. Most also do not intrinsically affect the nervous system or cause disability as for NDD that alter the behavioral presentation of the individual in a way that changes their care.

Discrimination against individuals with NDD and other disabilities, called “ableism,” can take many forms: assuming a child with communication difficulty or ID is unable to understand explanations about their care; the presence of one NDD condition ending the clinician’s search for other issues; complicated problems or difficult behaviors in the medical setting truncating care, etc. To be equitable in the care of individuals with NDD we need to be aware of discrimination and also go beyond guidelines to personalize the accommodations we advise and make.
 

Adjustments Needed for Special Needs

As pediatricians we already adjust our interactions, starting instinctively, to the development level of the child we perceive before us. We approach infants slowly and softly, we speak in shorter sentences to toddlers, we joke around with school-aged children, and we take extra care about privacy with teens. This serves the relationships well for neurotypical children. But our (and our staff’s) perceptions of children with autism, ID, genetic syndromes that include NDD, or motor disabilities based on their behavioral presentation may not accurately recognize or accommodate their abilities or needs. Communication and environmental adjustments may need to be much more individualized to provide respectful care, comfort and even safety.

As an example, at this time 1 in 36 children have autism with or without ID. Defining features of autism include differences in social communication, repetitive or restrictive interests or behaviors, and hypersensitivity to the environment plus any coexisting conditions such as anxiety and hyperactivity. But most children with autism have completely age appropriate and typical physical appearance and their underlying condition may not even be known. The office setting, without special attention to the needs of a child with autism, may be frightening, loud, too bright, too crowded, fast paced, and confusing. The result of their sensitivities and difficulty communicating may lead to increased agitation, repetitive behaviors (sometimes called “stimming”), shrieking, attempts to escape the room, refusal to allow for vital signs or undressing, even aggression. Strategies for calming a neurotypical child such as talking or touching may make matters worse instead of better. We need help from the child and family and a plan to optimize their medical encounters.

If not adequately accommodated, children with many varieties of NDD end up not getting all the routine healthcare they need (eg vaccinations, blood tests, vital signs, even complete physical exams including dental) as well as having more adverse events during health care, including traumatizing seclusion, not allowing a support person to be present, restraint, injuries, and accidents. When more complex procedures are needed, eg x-ray, MRI, EEG, lab studies, or surgery, successful outcomes may be lower. Children with NDD have higher rates of often avoidable morbidity and mortality than those without, in part due to these barriers to complete care. While environmental accommodations to wheelchair users for accessibility has greatly improved in recent years, access to other kinds of individualized accommodations have lagged behind.
 

Accommodation Planning

There are a variety of factors that need to be taken into consideration in accommodating an individual with NDD. The family becomes the expert, along with the child, in knowing the child’s triggers, preferences, abilities, and level of understanding to accept and consent for care. An accommodation plan should be created using shared and supported decision making with the family and child and allowing for child preferences, regardless of their ability level, whenever possible. Development of an accommodation plan may benefit from multidisciplinary input, eg psychology, physical therapy, speech pathology, depending on the child’s needs and the practice’s ability to adapt.

The SAFE initiative is in the process of creating a checklist aiming to facilitate a description being created for each individual to help plan for a successful medical encounter while optimizing the child’s comfort, participation, and safety. While the checklist is not yet ready, we can start now by asking families and children in preparation for or at the start of a visit about their needs and writing a shared document that can also be placed in the electronic health record for the entire care team for informing care going forward.

It is especially important for the family to keep a copy of the care plan and for it to be sent as part of referrals for procedures or specialty visits so that the professionals can prepare and adapt the encounter. An excellent example is a how some hospitals schedule a practice visit for the child to experience the sights and sounds and people the child will encounter, for example, before an EEG, when nothing is required of the child. Scheduling the actual procedure at times of day when clinics are less crowded and wait times are shorter can improve the chances of success.

Some categories and details that might be included in an accommodation plan are listed below:

You might start the plan with the child’s preferred name/nickname, family member or support person names, and diagnoses along with a brief overview of the child’s level of functioning. Then list categories of needs and preferences along with suggestions or requests.

• Motor: Does the child have or need assistance entering the building, visit room, bathroom, or transferring to the exam table? What kind of assistance, if any, and by whom?
• Sensory: Is the child disturbed by noise, lights, or being touched? Does the child want to use equipment to be comfortable such as headphones, earplugs, or sunglasses or need a quiet room, care without perfumes, or dimmed lighting? Does the child typically refuse aspects of the physical examination?
• Behavioral regulation: What helps the child to stay calm? Are there certain triggers to becoming upset? Are there early cues that an upset is coming? What and who can help in the case of an upset?
• Habits/preferences: Are there certain comfort objects or habits your child needs? Are there habits your child needs to do, such as a certain order of events, or use of social stories or pictures, to cooperate or feel comfortable?
• Communication: How does the child make his/her needs known? Does the child/family speak English or another language? Does he/she use sign language or an augmentative communication device? What level of understanding does your child have; for example, similar to what age for a typical child? Is there a care plan with accommodations already available that needs review or needs revision with the child’s development or is a new one needed? Was the care plan developed including the child’s participation and assent or is more collaboration needed?
• History: Has your child had any very upsetting experiences in healthcare settings? What happened? Has the trauma been addressed? Are there reminders of the trauma that should be avoided?
• Other: Are there other things we should know about your child as an individual to provide the best care?

There are many actions needed to do better at ensuring equitable care for individuals with NDD. We should educate our office and medical staff about NDD in children and the importance of accommodating their needs, and ways to do it. The morning huddle can be used to remind staff of upcoming visits of children who may need accommodations. We then need to use quality improvement methods to check in periodically on how the changes are working for the children, families, and practice in order to continually improve.

The overall healthcare system also needs to change. Billing codes should reflect the time, complexity of accommodations, and documentation that were required for care. Episodes of the visit may need to be broken up within the day or over several days to allow the child to practice, calm down, and cooperate and this should be accounted for in billing. Given that NDD are generally lifelong conditions, payment systems that require measures of progress such as value-based payment based on improved outcomes will need to be adjusted to measure quality of care rather than significant progress.

We need to advocate for both individual children and for system changes to work toward equity of care for those with disabilities to make their lives more comfortable as well as ours.

Dr. Howard is assistant professor of pediatrics at The Johns Hopkins University School of Medicine, 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 [email protected].

In a recent study of 6 monthly injections of 140 mg erenumab (Aimovig, Amgen), most patients with chronic migraine and nonopioid medication overuse headache (MOH) achieved remission. Published online in JAMA Neurology, the study is the first prospective, double-blind, randomized, placebo-controlled attempt to investigate patients with chronic migraine and MOH related to nonopioid medications, according to lead author Stewart J. Tepper, MD, and his coauthors.

Prior Studies Did Not Focus on MOH

Several prior phase 2 and 3 trials of calcitonin gene-related peptide (CGRP) ligand or receptor inhibitors that have been FDA-approved for migraine prevention have been performed. These drugs include erenumab, fremanezumab (Ajovy, Teva), galcanezumab (Emgality, Lilly), and eptinezumab (Vyepti, Lundbeck), for patients with and without medication overuse, said Alan M. Rapoport, MD, who was not involved with the new study. Dr. Rapoport is a clinical professor of neurology at the David Geffen School of Medicine of the University of California, in Los Angeles; past president of the International Headache Society; and founder and director emeritus of The New England Center for Headache in Stamford, Connecticut.

“But we could not call them patients with MOH because they weren’t studied prospectively, so that they had medication overuse according to International Classification of Headache Disorders (ICHD-3) criteria,” said Dr. Rapoport.

Phase 4, Randomized, Placebo-Controlled Trial

In the present clinical trial, investigators enrolled 584 patients with nonopioid MOH and history of failing at least one preventive treatment. After a 4-week baseline phase, researchers randomized patients 1:1:1 to 6 months’ treatment with erenumab 70 mg, erenumab 140 mg, or placebo.

Investigators defined remission as either of the following through months 4-6:

• < 10 mean monthly acute headache medication days per month (AHMD)
• < 14 mean monthly headache days (MHD)

In the primary analysis, 69.1% of patients in the 140 mg cohort achieved remission (P < .001) versus placebo. Remission rates in the 70 mg and the placebo cohorts were 60.3% (P < .13) and 52.6%, respectively. AHMD for the 140-mg, 70-mg, and placebo groups fell by 9.4, 7.8, and 6.6 days per month, respectively. Migraine Physical Function Impact Diary (non-EU sites) and Headache Impact Test-6 (EU sites) scores also showed greater improvement for patients treated with erenumab.

No new safety signals emerged, although erenumab-treated participants experienced 2-2.5 times as much COVID-19 disease.

Regarding the primary endpoint, said Dr. Rapoport, the 70-mg dose might also have yielded statistically significant improvement over placebo with a larger sample size. “I have seen that the higher dose of erenumab can be superior for efficacy than the lower in some of the double-blind trials,” he said. The 52.6% placebo response rate was rather high, he added, but not necessarily higher than in other migraine prevention trials.

“Placebo is a type of treatment,” Dr. Rapoport said. “It’s not as strong as the actual medication, which is specific for prevention, but it does work on the brain to some extent.”

He was more concerned, however, that authors did not counsel study patients about reducing or discontinuing their overused medications in a unified manner. Rather, it was left to individual investigators’ discretion, in different countries, as to whether to educate patients about the harms of medication overuse. “The fascinating aspect of this paper was that no patient was asked to detoxify from the overused medication,” said Dr. Rapoport, “and yet so many patients no longer had MOH at 6 months.”
 

Detox Versus No Detox

In a pioneering study of migraine medication overuse headache (then called rebound headache) published by Lee Kudrow, MD, in Advances in Neurology in 1982, patients who discontinued the overused medication fared much better than those who did not. Adding amitriptyline for migraine prevention further improved results, mostly in those who discontinued their overused medication.

Anticipating possible concerns, the authors wrote that their approach “may also be seen as a strength, as it represents a scenario closer to real life and avoids undue interference with the physician-patient relationship.” Indeed, said Dr. Rapoport, study results are perhaps more impressive because they were achieved through treatment with erenumab alone, without detoxification.
 

Managing Chronic Migraine and MOH

Until erenumab’s 2018 approval, migraine prevention options were limited to tricyclic antidepressants, beta blockers, and antiseizure medicines – though these medicines never seemed to work very well without detoxification, said Dr. Rapoport. Neurologists still use these categories for migraine prevention, he added, “because insurance companies insist that before we give the more expensive, newer medications like those that block CGRP, patients must fail 2 of those 3 categories of older medications which are not approved for chronic migraine.” Only onabotulinumtoxinA (Botox) is FDA-approved for chronic migraine. “There has been no head-to-head comparison of it and any of the monoclonal antibodies against CGRP,” he said.

In a March 2024 publication in Headache, the American Headache Society stated that requiring patients to fail older drugs is inappropriate, and that CGRP inhibitors, though costly, should be first-line for headache prevention. The key advantage of any drug that blocks CGRP in treating MOH is that unlike older drugs, CGRP inhibitors appear to work well even without detoxification, said Dr. Rapoport.

Additional study limitations included the possibility that the 24-week treatment period might not have allowed complete evaluation of long-term efficacy, the authors wrote. “These are usually pretty sick patients,” said Dr. Rapoport, who acknowledged the difficulty of keeping placebo patients off preventive medication altogether for 6 months. The study was extended to 12 months, and the results of an opiate overusers cohort also will be published.

Authors noted that according to a study published in Headache in 2022, most Americans with chronic migraine commonly go without preventive medications. Moreover, such medications do not always work. Accordingly, Dr. Rapoport said, the study duration was reasonable provided patients understood that they had a 33% chance of receiving no effective preventive medication over 6 months.

Extending the study’s month-long baseline period to 3 months before starting erenumab might have been helpful, he added, as that is the timeframe required to confirm MOH diagnosis according to ICHD-3. “However,” said Dr. Rapoport, “3 months with only usual medications, and then 1/3 of patients going 6-12 months with only placebo, would be tough for some patients.”

Dr. Rapoport reports no relevant financial conflicts.

In a recent study of 6 monthly injections of 140 mg erenumab (Aimovig, Amgen), most patients with chronic migraine and nonopioid medication overuse headache (MOH) achieved remission. Published online in JAMA Neurology, the study is the first prospective, double-blind, randomized, placebo-controlled attempt to investigate patients with chronic migraine and MOH related to nonopioid medications, according to lead author Stewart J. Tepper, MD, and his coauthors.

Prior Studies Did Not Focus on MOH

Several prior phase 2 and 3 trials of calcitonin gene-related peptide (CGRP) ligand or receptor inhibitors that have been FDA-approved for migraine prevention have been performed. These drugs include erenumab, fremanezumab (Ajovy, Teva), galcanezumab (Emgality, Lilly), and eptinezumab (Vyepti, Lundbeck), for patients with and without medication overuse, said Alan M. Rapoport, MD, who was not involved with the new study. Dr. Rapoport is a clinical professor of neurology at the David Geffen School of Medicine of the University of California, in Los Angeles; past president of the International Headache Society; and founder and director emeritus of The New England Center for Headache in Stamford, Connecticut.

“But we could not call them patients with MOH because they weren’t studied prospectively, so that they had medication overuse according to International Classification of Headache Disorders (ICHD-3) criteria,” said Dr. Rapoport.

Phase 4, Randomized, Placebo-Controlled Trial

In the present clinical trial, investigators enrolled 584 patients with nonopioid MOH and history of failing at least one preventive treatment. After a 4-week baseline phase, researchers randomized patients 1:1:1 to 6 months’ treatment with erenumab 70 mg, erenumab 140 mg, or placebo.

Investigators defined remission as either of the following through months 4-6:

• < 10 mean monthly acute headache medication days per month (AHMD)
• < 14 mean monthly headache days (MHD)

In the primary analysis, 69.1% of patients in the 140 mg cohort achieved remission (P < .001) versus placebo. Remission rates in the 70 mg and the placebo cohorts were 60.3% (P < .13) and 52.6%, respectively. AHMD for the 140-mg, 70-mg, and placebo groups fell by 9.4, 7.8, and 6.6 days per month, respectively. Migraine Physical Function Impact Diary (non-EU sites) and Headache Impact Test-6 (EU sites) scores also showed greater improvement for patients treated with erenumab.

No new safety signals emerged, although erenumab-treated participants experienced 2-2.5 times as much COVID-19 disease.

Regarding the primary endpoint, said Dr. Rapoport, the 70-mg dose might also have yielded statistically significant improvement over placebo with a larger sample size. “I have seen that the higher dose of erenumab can be superior for efficacy than the lower in some of the double-blind trials,” he said. The 52.6% placebo response rate was rather high, he added, but not necessarily higher than in other migraine prevention trials.

“Placebo is a type of treatment,” Dr. Rapoport said. “It’s not as strong as the actual medication, which is specific for prevention, but it does work on the brain to some extent.”

He was more concerned, however, that authors did not counsel study patients about reducing or discontinuing their overused medications in a unified manner. Rather, it was left to individual investigators’ discretion, in different countries, as to whether to educate patients about the harms of medication overuse. “The fascinating aspect of this paper was that no patient was asked to detoxify from the overused medication,” said Dr. Rapoport, “and yet so many patients no longer had MOH at 6 months.”
 

Detox Versus No Detox

In a pioneering study of migraine medication overuse headache (then called rebound headache) published by Lee Kudrow, MD, in Advances in Neurology in 1982, patients who discontinued the overused medication fared much better than those who did not. Adding amitriptyline for migraine prevention further improved results, mostly in those who discontinued their overused medication.

Anticipating possible concerns, the authors wrote that their approach “may also be seen as a strength, as it represents a scenario closer to real life and avoids undue interference with the physician-patient relationship.” Indeed, said Dr. Rapoport, study results are perhaps more impressive because they were achieved through treatment with erenumab alone, without detoxification.
 

Managing Chronic Migraine and MOH

Until erenumab’s 2018 approval, migraine prevention options were limited to tricyclic antidepressants, beta blockers, and antiseizure medicines – though these medicines never seemed to work very well without detoxification, said Dr. Rapoport. Neurologists still use these categories for migraine prevention, he added, “because insurance companies insist that before we give the more expensive, newer medications like those that block CGRP, patients must fail 2 of those 3 categories of older medications which are not approved for chronic migraine.” Only onabotulinumtoxinA (Botox) is FDA-approved for chronic migraine. “There has been no head-to-head comparison of it and any of the monoclonal antibodies against CGRP,” he said.

In a March 2024 publication in Headache, the American Headache Society stated that requiring patients to fail older drugs is inappropriate, and that CGRP inhibitors, though costly, should be first-line for headache prevention. The key advantage of any drug that blocks CGRP in treating MOH is that unlike older drugs, CGRP inhibitors appear to work well even without detoxification, said Dr. Rapoport.

Additional study limitations included the possibility that the 24-week treatment period might not have allowed complete evaluation of long-term efficacy, the authors wrote. “These are usually pretty sick patients,” said Dr. Rapoport, who acknowledged the difficulty of keeping placebo patients off preventive medication altogether for 6 months. The study was extended to 12 months, and the results of an opiate overusers cohort also will be published.

Authors noted that according to a study published in Headache in 2022, most Americans with chronic migraine commonly go without preventive medications. Moreover, such medications do not always work. Accordingly, Dr. Rapoport said, the study duration was reasonable provided patients understood that they had a 33% chance of receiving no effective preventive medication over 6 months.

Extending the study’s month-long baseline period to 3 months before starting erenumab might have been helpful, he added, as that is the timeframe required to confirm MOH diagnosis according to ICHD-3. “However,” said Dr. Rapoport, “3 months with only usual medications, and then 1/3 of patients going 6-12 months with only placebo, would be tough for some patients.”

Dr. Rapoport reports no relevant financial conflicts.

In a recent study of 6 monthly injections of 140 mg erenumab (Aimovig, Amgen), most patients with chronic migraine and nonopioid medication overuse headache (MOH) achieved remission. Published online in JAMA Neurology, the study is the first prospective, double-blind, randomized, placebo-controlled attempt to investigate patients with chronic migraine and MOH related to nonopioid medications, according to lead author Stewart J. Tepper, MD, and his coauthors.

Prior Studies Did Not Focus on MOH

Several prior phase 2 and 3 trials of calcitonin gene-related peptide (CGRP) ligand or receptor inhibitors that have been FDA-approved for migraine prevention have been performed. These drugs include erenumab, fremanezumab (Ajovy, Teva), galcanezumab (Emgality, Lilly), and eptinezumab (Vyepti, Lundbeck), for patients with and without medication overuse, said Alan M. Rapoport, MD, who was not involved with the new study. Dr. Rapoport is a clinical professor of neurology at the David Geffen School of Medicine of the University of California, in Los Angeles; past president of the International Headache Society; and founder and director emeritus of The New England Center for Headache in Stamford, Connecticut.

“But we could not call them patients with MOH because they weren’t studied prospectively, so that they had medication overuse according to International Classification of Headache Disorders (ICHD-3) criteria,” said Dr. Rapoport.

Phase 4, Randomized, Placebo-Controlled Trial

In the present clinical trial, investigators enrolled 584 patients with nonopioid MOH and history of failing at least one preventive treatment. After a 4-week baseline phase, researchers randomized patients 1:1:1 to 6 months’ treatment with erenumab 70 mg, erenumab 140 mg, or placebo.

Investigators defined remission as either of the following through months 4-6:

• < 10 mean monthly acute headache medication days per month (AHMD)
• < 14 mean monthly headache days (MHD)

In the primary analysis, 69.1% of patients in the 140 mg cohort achieved remission (P < .001) versus placebo. Remission rates in the 70 mg and the placebo cohorts were 60.3% (P < .13) and 52.6%, respectively. AHMD for the 140-mg, 70-mg, and placebo groups fell by 9.4, 7.8, and 6.6 days per month, respectively. Migraine Physical Function Impact Diary (non-EU sites) and Headache Impact Test-6 (EU sites) scores also showed greater improvement for patients treated with erenumab.

No new safety signals emerged, although erenumab-treated participants experienced 2-2.5 times as much COVID-19 disease.

Regarding the primary endpoint, said Dr. Rapoport, the 70-mg dose might also have yielded statistically significant improvement over placebo with a larger sample size. “I have seen that the higher dose of erenumab can be superior for efficacy than the lower in some of the double-blind trials,” he said. The 52.6% placebo response rate was rather high, he added, but not necessarily higher than in other migraine prevention trials.

“Placebo is a type of treatment,” Dr. Rapoport said. “It’s not as strong as the actual medication, which is specific for prevention, but it does work on the brain to some extent.”

He was more concerned, however, that authors did not counsel study patients about reducing or discontinuing their overused medications in a unified manner. Rather, it was left to individual investigators’ discretion, in different countries, as to whether to educate patients about the harms of medication overuse. “The fascinating aspect of this paper was that no patient was asked to detoxify from the overused medication,” said Dr. Rapoport, “and yet so many patients no longer had MOH at 6 months.”
 

Detox Versus No Detox

In a pioneering study of migraine medication overuse headache (then called rebound headache) published by Lee Kudrow, MD, in Advances in Neurology in 1982, patients who discontinued the overused medication fared much better than those who did not. Adding amitriptyline for migraine prevention further improved results, mostly in those who discontinued their overused medication.

Anticipating possible concerns, the authors wrote that their approach “may also be seen as a strength, as it represents a scenario closer to real life and avoids undue interference with the physician-patient relationship.” Indeed, said Dr. Rapoport, study results are perhaps more impressive because they were achieved through treatment with erenumab alone, without detoxification.
 

Managing Chronic Migraine and MOH

Until erenumab’s 2018 approval, migraine prevention options were limited to tricyclic antidepressants, beta blockers, and antiseizure medicines – though these medicines never seemed to work very well without detoxification, said Dr. Rapoport. Neurologists still use these categories for migraine prevention, he added, “because insurance companies insist that before we give the more expensive, newer medications like those that block CGRP, patients must fail 2 of those 3 categories of older medications which are not approved for chronic migraine.” Only onabotulinumtoxinA (Botox) is FDA-approved for chronic migraine. “There has been no head-to-head comparison of it and any of the monoclonal antibodies against CGRP,” he said.

In a March 2024 publication in Headache, the American Headache Society stated that requiring patients to fail older drugs is inappropriate, and that CGRP inhibitors, though costly, should be first-line for headache prevention. The key advantage of any drug that blocks CGRP in treating MOH is that unlike older drugs, CGRP inhibitors appear to work well even without detoxification, said Dr. Rapoport.

Additional study limitations included the possibility that the 24-week treatment period might not have allowed complete evaluation of long-term efficacy, the authors wrote. “These are usually pretty sick patients,” said Dr. Rapoport, who acknowledged the difficulty of keeping placebo patients off preventive medication altogether for 6 months. The study was extended to 12 months, and the results of an opiate overusers cohort also will be published.

Authors noted that according to a study published in Headache in 2022, most Americans with chronic migraine commonly go without preventive medications. Moreover, such medications do not always work. Accordingly, Dr. Rapoport said, the study duration was reasonable provided patients understood that they had a 33% chance of receiving no effective preventive medication over 6 months.

Extending the study’s month-long baseline period to 3 months before starting erenumab might have been helpful, he added, as that is the timeframe required to confirm MOH diagnosis according to ICHD-3. “However,” said Dr. Rapoport, “3 months with only usual medications, and then 1/3 of patients going 6-12 months with only placebo, would be tough for some patients.”

Dr. Rapoport reports no relevant financial conflicts.

TOPLINE:

High levels of urinary cadmium are associated with double the risk for global cognitive impairment in White adults, a new study shows. There was no such association between the heavy metal and cognitive function in Black adults.

METHODOLOGY:

• Investigators reviewed data on 2172 adults (mean age, 64 years; 61% White; 39% Black; 55% women) from the ongoing REGARDS population-based prospective cohort study in the United States who were free of cognitive impairment or stroke at baseline.
• Global cognitive impairment was assessed annually using the Six-Item Screener, and domain-based cognitive impairment was assessed every 2 years using the Enhanced Cognitive Battery.
• Blood and urine samples were collected from the participants at baseline, and levels of urinary cadmium were assessed using a urinary creatinine-correction method.
• Covariates included participants’ age, sex, smoking pack-years, alcohol consumption, and education level.
• Mean follow-up was 10 years.

TAKEAWAY:

• Global cognitive impairment was observed in 195 cases and domain-based cognitive impairment in 53 cases.
• High levels of urinary cadmium were associated with double the risk of developing global cognitive impairment in White adults (odds ratio [OR], 2.07; 95% CI, 1.18-3.64).
• No association was observed between urinary cadmium and global cognitive impairment in the overall cohort or in Black adults.
• Median smoking pack-years — a significant source of cadmium exposure for the US population — was significantly higher in White participants than Black participants (P = .001 for the highest tertile of urinary cadmium concentration).

IN PRACTICE:

“These results need to be confirmed with studies that measure cadmium levels over time, include more people and follow people over a longer time, but there are many reasons to reduce exposure to cadmium, whether it’s through implementing policies and regulations for air pollution and drinking water or people changing their behaviors by stopping smoking or being around cigarette smoke,” lead author Liping Lu, MD, PhD, MS, Columbia University, New York City, said in a press release.

SOURCE:

The study was published online in Neurology.

LIMITATIONS:

Urinary cadmium levels were tested only at baseline, which may not have captured changes in exposure over time. A limited number of patients with cognitive impairment used the Enhanced Cognitive Battery. The study did not include occupational information, and the potential for residual confounding from smoking could not be completely excluded. The follow-up time may have been insufficient for observing a significant effect on cognition, and competing risks for mortality associated with cadmium exposure could also have affected the findings.

DISCLOSURES:

The study was co-funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging of the National Institutes of Health (NIH). Several authors were partially supported by the NIH. Detailed disclosures are provided in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

High levels of urinary cadmium are associated with double the risk for global cognitive impairment in White adults, a new study shows. There was no such association between the heavy metal and cognitive function in Black adults.

METHODOLOGY:

• Investigators reviewed data on 2172 adults (mean age, 64 years; 61% White; 39% Black; 55% women) from the ongoing REGARDS population-based prospective cohort study in the United States who were free of cognitive impairment or stroke at baseline.
• Global cognitive impairment was assessed annually using the Six-Item Screener, and domain-based cognitive impairment was assessed every 2 years using the Enhanced Cognitive Battery.
• Blood and urine samples were collected from the participants at baseline, and levels of urinary cadmium were assessed using a urinary creatinine-correction method.
• Covariates included participants’ age, sex, smoking pack-years, alcohol consumption, and education level.
• Mean follow-up was 10 years.

TAKEAWAY:

• Global cognitive impairment was observed in 195 cases and domain-based cognitive impairment in 53 cases.
• High levels of urinary cadmium were associated with double the risk of developing global cognitive impairment in White adults (odds ratio [OR], 2.07; 95% CI, 1.18-3.64).
• No association was observed between urinary cadmium and global cognitive impairment in the overall cohort or in Black adults.
• Median smoking pack-years — a significant source of cadmium exposure for the US population — was significantly higher in White participants than Black participants (P = .001 for the highest tertile of urinary cadmium concentration).

IN PRACTICE:

“These results need to be confirmed with studies that measure cadmium levels over time, include more people and follow people over a longer time, but there are many reasons to reduce exposure to cadmium, whether it’s through implementing policies and regulations for air pollution and drinking water or people changing their behaviors by stopping smoking or being around cigarette smoke,” lead author Liping Lu, MD, PhD, MS, Columbia University, New York City, said in a press release.

SOURCE:

The study was published online in Neurology.

LIMITATIONS:

Urinary cadmium levels were tested only at baseline, which may not have captured changes in exposure over time. A limited number of patients with cognitive impairment used the Enhanced Cognitive Battery. The study did not include occupational information, and the potential for residual confounding from smoking could not be completely excluded. The follow-up time may have been insufficient for observing a significant effect on cognition, and competing risks for mortality associated with cadmium exposure could also have affected the findings.

DISCLOSURES:

The study was co-funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging of the National Institutes of Health (NIH). Several authors were partially supported by the NIH. Detailed disclosures are provided in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

High levels of urinary cadmium are associated with double the risk for global cognitive impairment in White adults, a new study shows. There was no such association between the heavy metal and cognitive function in Black adults.

METHODOLOGY:

• Investigators reviewed data on 2172 adults (mean age, 64 years; 61% White; 39% Black; 55% women) from the ongoing REGARDS population-based prospective cohort study in the United States who were free of cognitive impairment or stroke at baseline.
• Global cognitive impairment was assessed annually using the Six-Item Screener, and domain-based cognitive impairment was assessed every 2 years using the Enhanced Cognitive Battery.
• Blood and urine samples were collected from the participants at baseline, and levels of urinary cadmium were assessed using a urinary creatinine-correction method.
• Covariates included participants’ age, sex, smoking pack-years, alcohol consumption, and education level.
• Mean follow-up was 10 years.

TAKEAWAY:

• Global cognitive impairment was observed in 195 cases and domain-based cognitive impairment in 53 cases.
• High levels of urinary cadmium were associated with double the risk of developing global cognitive impairment in White adults (odds ratio [OR], 2.07; 95% CI, 1.18-3.64).
• No association was observed between urinary cadmium and global cognitive impairment in the overall cohort or in Black adults.
• Median smoking pack-years — a significant source of cadmium exposure for the US population — was significantly higher in White participants than Black participants (P = .001 for the highest tertile of urinary cadmium concentration).

IN PRACTICE:

“These results need to be confirmed with studies that measure cadmium levels over time, include more people and follow people over a longer time, but there are many reasons to reduce exposure to cadmium, whether it’s through implementing policies and regulations for air pollution and drinking water or people changing their behaviors by stopping smoking or being around cigarette smoke,” lead author Liping Lu, MD, PhD, MS, Columbia University, New York City, said in a press release.

SOURCE:

The study was published online in Neurology.

LIMITATIONS:

Urinary cadmium levels were tested only at baseline, which may not have captured changes in exposure over time. A limited number of patients with cognitive impairment used the Enhanced Cognitive Battery. The study did not include occupational information, and the potential for residual confounding from smoking could not be completely excluded. The follow-up time may have been insufficient for observing a significant effect on cognition, and competing risks for mortality associated with cadmium exposure could also have affected the findings.

DISCLOSURES:

The study was co-funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging of the National Institutes of Health (NIH). Several authors were partially supported by the NIH. Detailed disclosures are provided in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

DUBLIN – As healthcare systems across Europe deal with an increasing prevalence of cognitive impairment, family doctors are emerging as key players in assessing and supporting patients’ decision-making capacities. 

This was a central theme at the 29th WONCA Europe Conference, where the European Young Family Doctors Movement (EYFDM) presented insights from a project conducted across Europe, involving young general practitioners who participated in workshops held in multiple countries.

“Family doctors are the linchpin in these decisions,” said Alina Zidaru, MD, from the Irish College of Physicians, Dublin. “They understand the patient’s history, build long-term relationships, and are best positioned to ensure that decisions reflect the patient’s values, not just what the law or the family might say.”

Dr. Zidaru and her colleague, Nick Mamo, MD, member of EYFDM in Glasgow, Scotland, emphasized the central role family doctors play in ensuring that patient rights and preferences are respected, regardless of their cognitive state. They are often the first to identify cognitive impairments and must carefully navigate the legal and ethical landscape of decision-making support.

“Often, we focus too much on avoiding harm and overlook the principle of autonomy,” said Dr. Mamo. “But it’s essential to give patients the right to make their own decisions, even when those decisions might seem unwise to us.”
 

The Case of Jay

Dr. Zidaru said: “We’ve conducted workshops in Brussels, Vienna, and Sydney, focusing on how to build habits that support patients. We presented real-life cases, like Jay, a 43-year-old man with trisomy and a moderate intellectual disability who must decide whether to undergo surgery for a hernia. The most significant challenge was ensuring continuity of care and respecting his autonomy, despite cognitive limitations.”

Jay’s case illustrates the complex ethical dilemmas faced by family doctors when balancing autonomy with patient safety. In many cases, cognitive impairments raise concerns about whether a patient can make decisions independently. 

During the session, the audience was asked to share their thoughts on the case and to indicate whether they would allow Jay to make his own decision, and if they felt confident in assessing his cognitive capacity. The responses revealed a range of mixed feelings. 
 

Legal and Cultural Variations Across Europe

The session also explored how different European countries approach decision-making for cognitively impaired individuals. A clear divide exists between nations that give family members automatic decision-making rights and those that require legal appointments. 

In the United Kingdom, the Mental Capacity Act 2005 presumes capacity unless proven otherwise. Family doctors can assess patients’ decision-making abilities using any validated tool they find suitable. They should also aim to ensure that decisions are made in the patient’s best interests if they lack capacity. Family members only have legal authority if appointed through formal means, such as a lasting power of attorney.

In Spain and Italy, functional assessments are performed when patients retain decision-making authority in areas where they demonstrate competence. Legal guardianship can be appointed by the courts, sometimes limited to specific areas, but it is intended to support rather than replace the patient’s autonomy. 

In France and Portugal, guardianship may be implemented in specific domains, but the patient’s ability to participate in decisions is always prioritized. 

In Turkey, according to Turkish general practitioners in the audience, the courts and close family members often share the decision-making responsibility.

Dr. Zidaru added that Ireland’s Assisted Decision-Making (Capacity) Act 2015 introduced significant changes to how cognitive impairment is managed there. “Ireland adopted a standardized functional test of capacity, used by any doctor. A person can still make decisions as long as they understand, retain, and weigh the information needed to make that choice. If their capacity diminishes, a decision-making assistant, co–decision-maker, or representative can be appointed, but the patient’s will and preferences always come first.”
 

Family Doctors, a Growing Responsibility

“It’s not just about the legal framework: it’s about cultural awareness and early communication,” added Dr. Mamo. “We have to ask ourselves: Do patients have the right to make bad decisions? And how do we, as family doctors, respect that while still ensuring their safety?”

The session concluded with a discussion on how the role of family doctors in decision-making for cognitively impaired patients will evolve as populations age and the incidence of conditions like dementia increases. The workload is rising, and the need for clear, consistent guidelines is critical.

“Family doctors will continue to play a central role in managing these challenges,” Dr. Zidaru emphasized. “But we need more resources, more education, and more support to ensure we can respect patient autonomy without compromising their well-being.”

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

DUBLIN – As healthcare systems across Europe deal with an increasing prevalence of cognitive impairment, family doctors are emerging as key players in assessing and supporting patients’ decision-making capacities. 

This was a central theme at the 29th WONCA Europe Conference, where the European Young Family Doctors Movement (EYFDM) presented insights from a project conducted across Europe, involving young general practitioners who participated in workshops held in multiple countries.

“Family doctors are the linchpin in these decisions,” said Alina Zidaru, MD, from the Irish College of Physicians, Dublin. “They understand the patient’s history, build long-term relationships, and are best positioned to ensure that decisions reflect the patient’s values, not just what the law or the family might say.”

Dr. Zidaru and her colleague, Nick Mamo, MD, member of EYFDM in Glasgow, Scotland, emphasized the central role family doctors play in ensuring that patient rights and preferences are respected, regardless of their cognitive state. They are often the first to identify cognitive impairments and must carefully navigate the legal and ethical landscape of decision-making support.

“Often, we focus too much on avoiding harm and overlook the principle of autonomy,” said Dr. Mamo. “But it’s essential to give patients the right to make their own decisions, even when those decisions might seem unwise to us.”
 

The Case of Jay

Dr. Zidaru said: “We’ve conducted workshops in Brussels, Vienna, and Sydney, focusing on how to build habits that support patients. We presented real-life cases, like Jay, a 43-year-old man with trisomy and a moderate intellectual disability who must decide whether to undergo surgery for a hernia. The most significant challenge was ensuring continuity of care and respecting his autonomy, despite cognitive limitations.”

Jay’s case illustrates the complex ethical dilemmas faced by family doctors when balancing autonomy with patient safety. In many cases, cognitive impairments raise concerns about whether a patient can make decisions independently. 

During the session, the audience was asked to share their thoughts on the case and to indicate whether they would allow Jay to make his own decision, and if they felt confident in assessing his cognitive capacity. The responses revealed a range of mixed feelings. 
 

Legal and Cultural Variations Across Europe

The session also explored how different European countries approach decision-making for cognitively impaired individuals. A clear divide exists between nations that give family members automatic decision-making rights and those that require legal appointments. 

In the United Kingdom, the Mental Capacity Act 2005 presumes capacity unless proven otherwise. Family doctors can assess patients’ decision-making abilities using any validated tool they find suitable. They should also aim to ensure that decisions are made in the patient’s best interests if they lack capacity. Family members only have legal authority if appointed through formal means, such as a lasting power of attorney.

In Spain and Italy, functional assessments are performed when patients retain decision-making authority in areas where they demonstrate competence. Legal guardianship can be appointed by the courts, sometimes limited to specific areas, but it is intended to support rather than replace the patient’s autonomy. 

In France and Portugal, guardianship may be implemented in specific domains, but the patient’s ability to participate in decisions is always prioritized. 

In Turkey, according to Turkish general practitioners in the audience, the courts and close family members often share the decision-making responsibility.

Dr. Zidaru added that Ireland’s Assisted Decision-Making (Capacity) Act 2015 introduced significant changes to how cognitive impairment is managed there. “Ireland adopted a standardized functional test of capacity, used by any doctor. A person can still make decisions as long as they understand, retain, and weigh the information needed to make that choice. If their capacity diminishes, a decision-making assistant, co–decision-maker, or representative can be appointed, but the patient’s will and preferences always come first.”
 

Family Doctors, a Growing Responsibility

“It’s not just about the legal framework: it’s about cultural awareness and early communication,” added Dr. Mamo. “We have to ask ourselves: Do patients have the right to make bad decisions? And how do we, as family doctors, respect that while still ensuring their safety?”

The session concluded with a discussion on how the role of family doctors in decision-making for cognitively impaired patients will evolve as populations age and the incidence of conditions like dementia increases. The workload is rising, and the need for clear, consistent guidelines is critical.

“Family doctors will continue to play a central role in managing these challenges,” Dr. Zidaru emphasized. “But we need more resources, more education, and more support to ensure we can respect patient autonomy without compromising their well-being.”

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

DUBLIN – As healthcare systems across Europe deal with an increasing prevalence of cognitive impairment, family doctors are emerging as key players in assessing and supporting patients’ decision-making capacities. 

This was a central theme at the 29th WONCA Europe Conference, where the European Young Family Doctors Movement (EYFDM) presented insights from a project conducted across Europe, involving young general practitioners who participated in workshops held in multiple countries.

“Family doctors are the linchpin in these decisions,” said Alina Zidaru, MD, from the Irish College of Physicians, Dublin. “They understand the patient’s history, build long-term relationships, and are best positioned to ensure that decisions reflect the patient’s values, not just what the law or the family might say.”

Dr. Zidaru and her colleague, Nick Mamo, MD, member of EYFDM in Glasgow, Scotland, emphasized the central role family doctors play in ensuring that patient rights and preferences are respected, regardless of their cognitive state. They are often the first to identify cognitive impairments and must carefully navigate the legal and ethical landscape of decision-making support.

“Often, we focus too much on avoiding harm and overlook the principle of autonomy,” said Dr. Mamo. “But it’s essential to give patients the right to make their own decisions, even when those decisions might seem unwise to us.”
 

The Case of Jay

Dr. Zidaru said: “We’ve conducted workshops in Brussels, Vienna, and Sydney, focusing on how to build habits that support patients. We presented real-life cases, like Jay, a 43-year-old man with trisomy and a moderate intellectual disability who must decide whether to undergo surgery for a hernia. The most significant challenge was ensuring continuity of care and respecting his autonomy, despite cognitive limitations.”

Jay’s case illustrates the complex ethical dilemmas faced by family doctors when balancing autonomy with patient safety. In many cases, cognitive impairments raise concerns about whether a patient can make decisions independently. 

During the session, the audience was asked to share their thoughts on the case and to indicate whether they would allow Jay to make his own decision, and if they felt confident in assessing his cognitive capacity. The responses revealed a range of mixed feelings. 
 

Legal and Cultural Variations Across Europe

The session also explored how different European countries approach decision-making for cognitively impaired individuals. A clear divide exists between nations that give family members automatic decision-making rights and those that require legal appointments. 

In the United Kingdom, the Mental Capacity Act 2005 presumes capacity unless proven otherwise. Family doctors can assess patients’ decision-making abilities using any validated tool they find suitable. They should also aim to ensure that decisions are made in the patient’s best interests if they lack capacity. Family members only have legal authority if appointed through formal means, such as a lasting power of attorney.

In Spain and Italy, functional assessments are performed when patients retain decision-making authority in areas where they demonstrate competence. Legal guardianship can be appointed by the courts, sometimes limited to specific areas, but it is intended to support rather than replace the patient’s autonomy. 

In France and Portugal, guardianship may be implemented in specific domains, but the patient’s ability to participate in decisions is always prioritized. 

In Turkey, according to Turkish general practitioners in the audience, the courts and close family members often share the decision-making responsibility.

Dr. Zidaru added that Ireland’s Assisted Decision-Making (Capacity) Act 2015 introduced significant changes to how cognitive impairment is managed there. “Ireland adopted a standardized functional test of capacity, used by any doctor. A person can still make decisions as long as they understand, retain, and weigh the information needed to make that choice. If their capacity diminishes, a decision-making assistant, co–decision-maker, or representative can be appointed, but the patient’s will and preferences always come first.”
 

Family Doctors, a Growing Responsibility

“It’s not just about the legal framework: it’s about cultural awareness and early communication,” added Dr. Mamo. “We have to ask ourselves: Do patients have the right to make bad decisions? And how do we, as family doctors, respect that while still ensuring their safety?”

The session concluded with a discussion on how the role of family doctors in decision-making for cognitively impaired patients will evolve as populations age and the incidence of conditions like dementia increases. The workload is rising, and the need for clear, consistent guidelines is critical.

“Family doctors will continue to play a central role in managing these challenges,” Dr. Zidaru emphasized. “But we need more resources, more education, and more support to ensure we can respect patient autonomy without compromising their well-being.”

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

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

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

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

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

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

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