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Strong two-way link between epilepsy and depression
, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.
“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.
The study was published online in Neurology.
Epilepsy then depression
The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.
In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).
The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).
The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.
The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.
The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
Depression then epilepsy
The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).
As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.
The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.
The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.
For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.
Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.
“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.
“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
Clinical implications
Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”
“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.
“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.
The findings do have implications for care, he said.
“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.
“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.
“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.
The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.
“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.
The study was published online in Neurology.
Epilepsy then depression
The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.
In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).
The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).
The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.
The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.
The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
Depression then epilepsy
The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).
As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.
The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.
The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.
For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.
Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.
“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.
“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
Clinical implications
Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”
“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.
“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.
The findings do have implications for care, he said.
“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.
“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.
“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.
The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.
“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.
The study was published online in Neurology.
Epilepsy then depression
The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.
In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).
The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).
The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.
The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.
The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
Depression then epilepsy
The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).
As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.
The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.
The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.
For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.
Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.
“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.
“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
Clinical implications
Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”
“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.
“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.
The findings do have implications for care, he said.
“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.
“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.
“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.
The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Pediatric emergencies associated with unnecessary testing: AAP
Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.
“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”
The five recommendations are as follows:
- Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
- Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
- Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
- Abdominal radiographs should not be obtained for suspected constipation.
- Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.
The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.
“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.
A version of this article first appeared on Medscape.com.
Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.
“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”
The five recommendations are as follows:
- Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
- Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
- Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
- Abdominal radiographs should not be obtained for suspected constipation.
- Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.
The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.
“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.
A version of this article first appeared on Medscape.com.
Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.
“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”
The five recommendations are as follows:
- Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
- Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
- Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
- Abdominal radiographs should not be obtained for suspected constipation.
- Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.
The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.
“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.
A version of this article first appeared on Medscape.com.
Injury in pregnant women ups cerebral palsy risk in offspring
The offspring of mothers who sustain unintentional injuries during pregnancy appear to have a modest 33% increased risk of developing cerebral palsy (CP) – higher when injuries are more severe, multiple, or lead to delivery soon afterward, a Canadian birth cohort study found.
Such children may benefit from long-term monitoring for neurodevelpmental issues, wrote a group led by Asma Ahmed, MD, PhD, MPH, a pediatric epidemiologist at the Hospital for Sick Children Research Institute in Toronto in JAMA Pediatrics.
“We need to provide better support for babies whose mothers have been injured in pregnancy, especially after severe injuries,” Dr. Ahmed said in a press release. “As well, these findings suggest the need for early monitoring of babies’ development, regular check-ups, and longer-term neurodevelopmental assessments.” Future studies should directly measure injury severity and its possible link to CP.
Current guidelines, however, focus on monitoring fetal condition immediately after injury with little attention to its long-term effects.
In their findings from the population-based linkage study of 2,110,177 children born in Ontario’s public health system during 2002-2017 and followed to 2018 with a median follow-up of 8 years:
- A total of 81,281 fetuses were exposed in utero to unintentional maternal injury.
- Overall, 0.3% children were diagnosed with CP, and the mean CP incidence rates were 4.36 per 10,000 child-years for the exposed versus 2.93 for the unexposed.
- In those exposed, the hazard ratio was 1.33 (95% confidence interval, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics.
- Injuries resulting in hospitalization or delivery within 1 week were linked to higher adjusted hazard ratios of 2.18 (95% CI, 1.29-3.68) and 3.40 (95% CI, 1.93-6.00), respectively.
- Injuries most frequently resulted from transportation mishaps, falls, and being struck by a person or object. They were most commonly associated with age younger than 20 years, substance use disorder, residence in rural and under-resourced areas, and lower socioeconomic status.
The authors noted that complications after maternal injuries – which affect 6%-8% of pregnant women – include uterine rupture, preterm delivery, and placental abruption and are linked to fetal complications such as asphyxia. The association with an offspring’s neurodevelopment has been rarely investigated. One U.K. population study, however, suggested a link between vehicular crashes and higher CP risk in preterm infants.
A related editorial on the study noted that while CP affects about two to four children per 1,000 live births each year in high-income countries, the etiological causes of most cases remain unknown. “This large population-based cohort study ... should inspire more research into preventing and mitigating factors for maternal injuries and offspring CP development,” wrote Zeyan Liew, PhD, MPH, and Haoran Zhuo, MPH, of Yale University School of Public Health in New Haven, Conn.
This study was supported by Santé-Québec and ICES, a research institute funded by the Ontario Ministry of Health and the Ministry of Long-Term Care.
Dr. Ahmed and coauthor Seungmi Yang, PhD, reported research funding from Santé-Québec during the conduct of the study.
The offspring of mothers who sustain unintentional injuries during pregnancy appear to have a modest 33% increased risk of developing cerebral palsy (CP) – higher when injuries are more severe, multiple, or lead to delivery soon afterward, a Canadian birth cohort study found.
Such children may benefit from long-term monitoring for neurodevelpmental issues, wrote a group led by Asma Ahmed, MD, PhD, MPH, a pediatric epidemiologist at the Hospital for Sick Children Research Institute in Toronto in JAMA Pediatrics.
“We need to provide better support for babies whose mothers have been injured in pregnancy, especially after severe injuries,” Dr. Ahmed said in a press release. “As well, these findings suggest the need for early monitoring of babies’ development, regular check-ups, and longer-term neurodevelopmental assessments.” Future studies should directly measure injury severity and its possible link to CP.
Current guidelines, however, focus on monitoring fetal condition immediately after injury with little attention to its long-term effects.
In their findings from the population-based linkage study of 2,110,177 children born in Ontario’s public health system during 2002-2017 and followed to 2018 with a median follow-up of 8 years:
- A total of 81,281 fetuses were exposed in utero to unintentional maternal injury.
- Overall, 0.3% children were diagnosed with CP, and the mean CP incidence rates were 4.36 per 10,000 child-years for the exposed versus 2.93 for the unexposed.
- In those exposed, the hazard ratio was 1.33 (95% confidence interval, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics.
- Injuries resulting in hospitalization or delivery within 1 week were linked to higher adjusted hazard ratios of 2.18 (95% CI, 1.29-3.68) and 3.40 (95% CI, 1.93-6.00), respectively.
- Injuries most frequently resulted from transportation mishaps, falls, and being struck by a person or object. They were most commonly associated with age younger than 20 years, substance use disorder, residence in rural and under-resourced areas, and lower socioeconomic status.
The authors noted that complications after maternal injuries – which affect 6%-8% of pregnant women – include uterine rupture, preterm delivery, and placental abruption and are linked to fetal complications such as asphyxia. The association with an offspring’s neurodevelopment has been rarely investigated. One U.K. population study, however, suggested a link between vehicular crashes and higher CP risk in preterm infants.
A related editorial on the study noted that while CP affects about two to four children per 1,000 live births each year in high-income countries, the etiological causes of most cases remain unknown. “This large population-based cohort study ... should inspire more research into preventing and mitigating factors for maternal injuries and offspring CP development,” wrote Zeyan Liew, PhD, MPH, and Haoran Zhuo, MPH, of Yale University School of Public Health in New Haven, Conn.
This study was supported by Santé-Québec and ICES, a research institute funded by the Ontario Ministry of Health and the Ministry of Long-Term Care.
Dr. Ahmed and coauthor Seungmi Yang, PhD, reported research funding from Santé-Québec during the conduct of the study.
The offspring of mothers who sustain unintentional injuries during pregnancy appear to have a modest 33% increased risk of developing cerebral palsy (CP) – higher when injuries are more severe, multiple, or lead to delivery soon afterward, a Canadian birth cohort study found.
Such children may benefit from long-term monitoring for neurodevelpmental issues, wrote a group led by Asma Ahmed, MD, PhD, MPH, a pediatric epidemiologist at the Hospital for Sick Children Research Institute in Toronto in JAMA Pediatrics.
“We need to provide better support for babies whose mothers have been injured in pregnancy, especially after severe injuries,” Dr. Ahmed said in a press release. “As well, these findings suggest the need for early monitoring of babies’ development, regular check-ups, and longer-term neurodevelopmental assessments.” Future studies should directly measure injury severity and its possible link to CP.
Current guidelines, however, focus on monitoring fetal condition immediately after injury with little attention to its long-term effects.
In their findings from the population-based linkage study of 2,110,177 children born in Ontario’s public health system during 2002-2017 and followed to 2018 with a median follow-up of 8 years:
- A total of 81,281 fetuses were exposed in utero to unintentional maternal injury.
- Overall, 0.3% children were diagnosed with CP, and the mean CP incidence rates were 4.36 per 10,000 child-years for the exposed versus 2.93 for the unexposed.
- In those exposed, the hazard ratio was 1.33 (95% confidence interval, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics.
- Injuries resulting in hospitalization or delivery within 1 week were linked to higher adjusted hazard ratios of 2.18 (95% CI, 1.29-3.68) and 3.40 (95% CI, 1.93-6.00), respectively.
- Injuries most frequently resulted from transportation mishaps, falls, and being struck by a person or object. They were most commonly associated with age younger than 20 years, substance use disorder, residence in rural and under-resourced areas, and lower socioeconomic status.
The authors noted that complications after maternal injuries – which affect 6%-8% of pregnant women – include uterine rupture, preterm delivery, and placental abruption and are linked to fetal complications such as asphyxia. The association with an offspring’s neurodevelopment has been rarely investigated. One U.K. population study, however, suggested a link between vehicular crashes and higher CP risk in preterm infants.
A related editorial on the study noted that while CP affects about two to four children per 1,000 live births each year in high-income countries, the etiological causes of most cases remain unknown. “This large population-based cohort study ... should inspire more research into preventing and mitigating factors for maternal injuries and offspring CP development,” wrote Zeyan Liew, PhD, MPH, and Haoran Zhuo, MPH, of Yale University School of Public Health in New Haven, Conn.
This study was supported by Santé-Québec and ICES, a research institute funded by the Ontario Ministry of Health and the Ministry of Long-Term Care.
Dr. Ahmed and coauthor Seungmi Yang, PhD, reported research funding from Santé-Québec during the conduct of the study.
FROM JAMA PEDIATRICS
Confirmed: Amyloid, tau levels rise years before Alzheimer’s onset
“Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations,” the investigators note.
“These data may suggest that there is a short therapeutic window for slowing AD pathogenesis prior to the emergence of clinical symptoms – and that this window may occur after amyloid accumulation begins but before amyloid has substantial impacts on tau accumulation,” study investigator Corinne Pettigrew, PhD, department of neurology, Johns Hopkins University School of Medicine, Baltimore, told this news organization.
The study was published online in Alzheimer’s and Dementia.
Novel long-term CSF data
The study builds on previous research by examining changes in cerebrospinal fluid (CSF) biomarkers over longer periods than had been done previously, particularly among largely middle-aged and cognitively normal at baseline individuals.
The researchers examined changes in amyloid beta (Aβ) 42/Aβ40, phosphorylated tau181 (p-tau181), and total tau (t-tau) in CSF over an average of 10.7 years (and up to 23 years) among 278 individuals who were largely middle-aged persons who were cognitively normal at baseline.
“To our knowledge, no prior study among initially cognitively normal, primarily middle-aged individuals has described CSF AD biomarker changes over this duration of follow-up,” the researchers write.
During follow-up, 94 individuals who initially had normal cognition developed mild cognitive impairment (MCI).
Lower baseline levels of amyloid were associated with greater increases in tau (more strongly in men than women), while accelerations in tau were more closely linked to onset of MCI, the researchers report.
Among individuals who developed MCI, biomarker levels were more abnormal and tau increased to a greater extent prior to the onset of MCI symptoms, they found.
Clear impact of APOE4
The findings also suggest that among APOE4 carriers, amyloid onset occurs at an earlier age and rates of amyloid positivity are higher, but there are no differences in rates of change in amyloid over time.
“APOE4 genetic status was not related to changes in CSF beta-amyloid after accounting for the fact that APOE4 carriers have higher rates of amyloid positivity,” said Dr. Pettigrew.
“These findings suggest that APOE4 genetic status shifts the age of onset of amyloid accumulation (with APOE4 carriers having an earlier age of onset compared to non-carriers), but that APOE4 is not related to rates of change in CSF beta-amyloid over time,” she added.
“Thus, cognitively normal APOE4 carriers may be in more advanced preclinical AD stages at younger ages than individuals who are not APOE4 carriers, which is likely relevant for optimizing clinical trial recruitment strategies,” she said.
Funding for the study was provided by the National Institutes of Health. Dr. Pettigrew has disclosed no relevant financial relationships. The original article contains a complete list of author disclosures.
A version of this article first appeared on Medscape.com.
“Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations,” the investigators note.
“These data may suggest that there is a short therapeutic window for slowing AD pathogenesis prior to the emergence of clinical symptoms – and that this window may occur after amyloid accumulation begins but before amyloid has substantial impacts on tau accumulation,” study investigator Corinne Pettigrew, PhD, department of neurology, Johns Hopkins University School of Medicine, Baltimore, told this news organization.
The study was published online in Alzheimer’s and Dementia.
Novel long-term CSF data
The study builds on previous research by examining changes in cerebrospinal fluid (CSF) biomarkers over longer periods than had been done previously, particularly among largely middle-aged and cognitively normal at baseline individuals.
The researchers examined changes in amyloid beta (Aβ) 42/Aβ40, phosphorylated tau181 (p-tau181), and total tau (t-tau) in CSF over an average of 10.7 years (and up to 23 years) among 278 individuals who were largely middle-aged persons who were cognitively normal at baseline.
“To our knowledge, no prior study among initially cognitively normal, primarily middle-aged individuals has described CSF AD biomarker changes over this duration of follow-up,” the researchers write.
During follow-up, 94 individuals who initially had normal cognition developed mild cognitive impairment (MCI).
Lower baseline levels of amyloid were associated with greater increases in tau (more strongly in men than women), while accelerations in tau were more closely linked to onset of MCI, the researchers report.
Among individuals who developed MCI, biomarker levels were more abnormal and tau increased to a greater extent prior to the onset of MCI symptoms, they found.
Clear impact of APOE4
The findings also suggest that among APOE4 carriers, amyloid onset occurs at an earlier age and rates of amyloid positivity are higher, but there are no differences in rates of change in amyloid over time.
“APOE4 genetic status was not related to changes in CSF beta-amyloid after accounting for the fact that APOE4 carriers have higher rates of amyloid positivity,” said Dr. Pettigrew.
“These findings suggest that APOE4 genetic status shifts the age of onset of amyloid accumulation (with APOE4 carriers having an earlier age of onset compared to non-carriers), but that APOE4 is not related to rates of change in CSF beta-amyloid over time,” she added.
“Thus, cognitively normal APOE4 carriers may be in more advanced preclinical AD stages at younger ages than individuals who are not APOE4 carriers, which is likely relevant for optimizing clinical trial recruitment strategies,” she said.
Funding for the study was provided by the National Institutes of Health. Dr. Pettigrew has disclosed no relevant financial relationships. The original article contains a complete list of author disclosures.
A version of this article first appeared on Medscape.com.
“Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations,” the investigators note.
“These data may suggest that there is a short therapeutic window for slowing AD pathogenesis prior to the emergence of clinical symptoms – and that this window may occur after amyloid accumulation begins but before amyloid has substantial impacts on tau accumulation,” study investigator Corinne Pettigrew, PhD, department of neurology, Johns Hopkins University School of Medicine, Baltimore, told this news organization.
The study was published online in Alzheimer’s and Dementia.
Novel long-term CSF data
The study builds on previous research by examining changes in cerebrospinal fluid (CSF) biomarkers over longer periods than had been done previously, particularly among largely middle-aged and cognitively normal at baseline individuals.
The researchers examined changes in amyloid beta (Aβ) 42/Aβ40, phosphorylated tau181 (p-tau181), and total tau (t-tau) in CSF over an average of 10.7 years (and up to 23 years) among 278 individuals who were largely middle-aged persons who were cognitively normal at baseline.
“To our knowledge, no prior study among initially cognitively normal, primarily middle-aged individuals has described CSF AD biomarker changes over this duration of follow-up,” the researchers write.
During follow-up, 94 individuals who initially had normal cognition developed mild cognitive impairment (MCI).
Lower baseline levels of amyloid were associated with greater increases in tau (more strongly in men than women), while accelerations in tau were more closely linked to onset of MCI, the researchers report.
Among individuals who developed MCI, biomarker levels were more abnormal and tau increased to a greater extent prior to the onset of MCI symptoms, they found.
Clear impact of APOE4
The findings also suggest that among APOE4 carriers, amyloid onset occurs at an earlier age and rates of amyloid positivity are higher, but there are no differences in rates of change in amyloid over time.
“APOE4 genetic status was not related to changes in CSF beta-amyloid after accounting for the fact that APOE4 carriers have higher rates of amyloid positivity,” said Dr. Pettigrew.
“These findings suggest that APOE4 genetic status shifts the age of onset of amyloid accumulation (with APOE4 carriers having an earlier age of onset compared to non-carriers), but that APOE4 is not related to rates of change in CSF beta-amyloid over time,” she added.
“Thus, cognitively normal APOE4 carriers may be in more advanced preclinical AD stages at younger ages than individuals who are not APOE4 carriers, which is likely relevant for optimizing clinical trial recruitment strategies,” she said.
Funding for the study was provided by the National Institutes of Health. Dr. Pettigrew has disclosed no relevant financial relationships. The original article contains a complete list of author disclosures.
A version of this article first appeared on Medscape.com.
FROM ALZHEIMER’S AND DEMENTIA
Single chest x-ray could predict 10-year CVD risk
who presented the results of their deep-learning model at the annual meeting of the Radiological Society of North America.
Current American College of Cardiologists and American Heart Association guidelines recommend estimating 10-year risk of major adverse cardiovascular events (MACE) to determine whether a patient should receive statins to help prevent atherosclerotic cardiovascular disease (ASCVD). Statins are recommended for patients with a 10-year risk of 7.5% or higher, the authors noted.
The current ASCVD risk score is determined with nine factors: age, sex, race, systolic blood pressure, hypertension treatment, smoking, type 2 diabetes, and a lipid panel.
Not all data points available in EHR
But not all of those data points may be available through the electronic health record, “which makes novel and easier approaches for population-wide screening desirable,” said lead researcher Jakob Weiss, MD, a radiologist affiliated with the Cardiovascular Imaging Research Center at Massachusetts General Hospital and the AI in medicine program at the Brigham and Women’s Hospital in Boston.
Chest x-ray images, on the other hand, are commonly available. The images carry rich information beyond diagnostic data but have not been used in this type of prediction model because AI models have been lacking, Dr. Weiss said.
The researchers trained a deep-learning model with single chest x-rays only.
They used 147,497 chest x-rays from 40,643 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial, a multicenter, randomized controlled trial designed and sponsored by the National Cancer Institute.
Dr. Weiss acknowledged that the population used to train the model was heavily White and that should be a consideration in validating the model.
They compared their model’s ability to predict 10-year ASCVD risk with the standard ACC/AHA model.
“Based on a single chest radiograph image, deep learning can predict the risk of future cardiovascular events independent of cardiovascular risk factors and with similar performance to the established and guideline-recommended ASCVD risk score,” Dr. Weiss said.
Tested against independent group
They tested the model against an independent group of 11,430 outpatients (average age, 60 years; 42.9% male) who underwent a routine outpatient chest x-ray at Mass General Brigham and were potentially eligible to receive statins.
Of those 11,430 patients, 1,096 (9.6%) had a major adverse cardiac event over the median follow-up of 10.3 years.
There was a significant association of CXR-CVD risk and MACE among patients eligible to receive statins, the researchers found (hazard ratio, 2.03; 95% confidence interval, 1.81-2.30; P < .001), which remained significant after adjusting for cardiovascular risk factors (adjusted HR, 1.63; 95% CI, 1.43-1.86; P < .001).
Some of the variables were missing in the standard model, but in a subgroup of 2,401 patients, all the variables were available.
They calculated ASCVD risk in that subgroup using the standard model and the CXR model and found that the performance was similar (c-statistic, 0.64 vs. 0.65; P = .48) to the ASCVD risk score (aHR, 1.58; 95% CI, 1.20-2.09; P = .001).
Ritu R. Gill MD, MPH, associate professor of radiology at Harvard Medical School in Boston, who was not part of the study, said in an interview that “the predictive algorithm is promising and potentially translatable and could enhance the annual medical checkup in a select population.
“The algorithm was developed using the PLCO cohort with radiographs, which are likely subjects in the lung cancer screening arm,” she said. “This cohort would be at high risk of cardiovascular diseases, as smoking is a known risk factor for atherosclerotic disease, and therefore the results are expected.
“The algorithm needs to be validated in an independent database with inclusion of subjects with younger age groups and adjusted for gender and racial diversity,” Gill said.
David Cho, MD, a cardiologist at the University of California, Los Angeles, who also was not part of the study, said in an interview that “this work is a great example of AI being able to detect clinically relevant outcomes with a widely used and low-cost screening test.
“The volume of data needed to train these models is already out there,” Dr. Cho said. “It just needs to be mined.”
He noted that this tool, if validated in randomized trials, could help determine risk among patients living in places where access to specialized cardiac care is limited.
Dr. Weiss and Dr. Cho disclosed no relevant financial relationships. Dr. Gill has received research support from Cannon Inc and consultant fees from Imbio and WorldCare.
A version of this article first appeared on Medscape.com.
who presented the results of their deep-learning model at the annual meeting of the Radiological Society of North America.
Current American College of Cardiologists and American Heart Association guidelines recommend estimating 10-year risk of major adverse cardiovascular events (MACE) to determine whether a patient should receive statins to help prevent atherosclerotic cardiovascular disease (ASCVD). Statins are recommended for patients with a 10-year risk of 7.5% or higher, the authors noted.
The current ASCVD risk score is determined with nine factors: age, sex, race, systolic blood pressure, hypertension treatment, smoking, type 2 diabetes, and a lipid panel.
Not all data points available in EHR
But not all of those data points may be available through the electronic health record, “which makes novel and easier approaches for population-wide screening desirable,” said lead researcher Jakob Weiss, MD, a radiologist affiliated with the Cardiovascular Imaging Research Center at Massachusetts General Hospital and the AI in medicine program at the Brigham and Women’s Hospital in Boston.
Chest x-ray images, on the other hand, are commonly available. The images carry rich information beyond diagnostic data but have not been used in this type of prediction model because AI models have been lacking, Dr. Weiss said.
The researchers trained a deep-learning model with single chest x-rays only.
They used 147,497 chest x-rays from 40,643 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial, a multicenter, randomized controlled trial designed and sponsored by the National Cancer Institute.
Dr. Weiss acknowledged that the population used to train the model was heavily White and that should be a consideration in validating the model.
They compared their model’s ability to predict 10-year ASCVD risk with the standard ACC/AHA model.
“Based on a single chest radiograph image, deep learning can predict the risk of future cardiovascular events independent of cardiovascular risk factors and with similar performance to the established and guideline-recommended ASCVD risk score,” Dr. Weiss said.
Tested against independent group
They tested the model against an independent group of 11,430 outpatients (average age, 60 years; 42.9% male) who underwent a routine outpatient chest x-ray at Mass General Brigham and were potentially eligible to receive statins.
Of those 11,430 patients, 1,096 (9.6%) had a major adverse cardiac event over the median follow-up of 10.3 years.
There was a significant association of CXR-CVD risk and MACE among patients eligible to receive statins, the researchers found (hazard ratio, 2.03; 95% confidence interval, 1.81-2.30; P < .001), which remained significant after adjusting for cardiovascular risk factors (adjusted HR, 1.63; 95% CI, 1.43-1.86; P < .001).
Some of the variables were missing in the standard model, but in a subgroup of 2,401 patients, all the variables were available.
They calculated ASCVD risk in that subgroup using the standard model and the CXR model and found that the performance was similar (c-statistic, 0.64 vs. 0.65; P = .48) to the ASCVD risk score (aHR, 1.58; 95% CI, 1.20-2.09; P = .001).
Ritu R. Gill MD, MPH, associate professor of radiology at Harvard Medical School in Boston, who was not part of the study, said in an interview that “the predictive algorithm is promising and potentially translatable and could enhance the annual medical checkup in a select population.
“The algorithm was developed using the PLCO cohort with radiographs, which are likely subjects in the lung cancer screening arm,” she said. “This cohort would be at high risk of cardiovascular diseases, as smoking is a known risk factor for atherosclerotic disease, and therefore the results are expected.
“The algorithm needs to be validated in an independent database with inclusion of subjects with younger age groups and adjusted for gender and racial diversity,” Gill said.
David Cho, MD, a cardiologist at the University of California, Los Angeles, who also was not part of the study, said in an interview that “this work is a great example of AI being able to detect clinically relevant outcomes with a widely used and low-cost screening test.
“The volume of data needed to train these models is already out there,” Dr. Cho said. “It just needs to be mined.”
He noted that this tool, if validated in randomized trials, could help determine risk among patients living in places where access to specialized cardiac care is limited.
Dr. Weiss and Dr. Cho disclosed no relevant financial relationships. Dr. Gill has received research support from Cannon Inc and consultant fees from Imbio and WorldCare.
A version of this article first appeared on Medscape.com.
who presented the results of their deep-learning model at the annual meeting of the Radiological Society of North America.
Current American College of Cardiologists and American Heart Association guidelines recommend estimating 10-year risk of major adverse cardiovascular events (MACE) to determine whether a patient should receive statins to help prevent atherosclerotic cardiovascular disease (ASCVD). Statins are recommended for patients with a 10-year risk of 7.5% or higher, the authors noted.
The current ASCVD risk score is determined with nine factors: age, sex, race, systolic blood pressure, hypertension treatment, smoking, type 2 diabetes, and a lipid panel.
Not all data points available in EHR
But not all of those data points may be available through the electronic health record, “which makes novel and easier approaches for population-wide screening desirable,” said lead researcher Jakob Weiss, MD, a radiologist affiliated with the Cardiovascular Imaging Research Center at Massachusetts General Hospital and the AI in medicine program at the Brigham and Women’s Hospital in Boston.
Chest x-ray images, on the other hand, are commonly available. The images carry rich information beyond diagnostic data but have not been used in this type of prediction model because AI models have been lacking, Dr. Weiss said.
The researchers trained a deep-learning model with single chest x-rays only.
They used 147,497 chest x-rays from 40,643 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial, a multicenter, randomized controlled trial designed and sponsored by the National Cancer Institute.
Dr. Weiss acknowledged that the population used to train the model was heavily White and that should be a consideration in validating the model.
They compared their model’s ability to predict 10-year ASCVD risk with the standard ACC/AHA model.
“Based on a single chest radiograph image, deep learning can predict the risk of future cardiovascular events independent of cardiovascular risk factors and with similar performance to the established and guideline-recommended ASCVD risk score,” Dr. Weiss said.
Tested against independent group
They tested the model against an independent group of 11,430 outpatients (average age, 60 years; 42.9% male) who underwent a routine outpatient chest x-ray at Mass General Brigham and were potentially eligible to receive statins.
Of those 11,430 patients, 1,096 (9.6%) had a major adverse cardiac event over the median follow-up of 10.3 years.
There was a significant association of CXR-CVD risk and MACE among patients eligible to receive statins, the researchers found (hazard ratio, 2.03; 95% confidence interval, 1.81-2.30; P < .001), which remained significant after adjusting for cardiovascular risk factors (adjusted HR, 1.63; 95% CI, 1.43-1.86; P < .001).
Some of the variables were missing in the standard model, but in a subgroup of 2,401 patients, all the variables were available.
They calculated ASCVD risk in that subgroup using the standard model and the CXR model and found that the performance was similar (c-statistic, 0.64 vs. 0.65; P = .48) to the ASCVD risk score (aHR, 1.58; 95% CI, 1.20-2.09; P = .001).
Ritu R. Gill MD, MPH, associate professor of radiology at Harvard Medical School in Boston, who was not part of the study, said in an interview that “the predictive algorithm is promising and potentially translatable and could enhance the annual medical checkup in a select population.
“The algorithm was developed using the PLCO cohort with radiographs, which are likely subjects in the lung cancer screening arm,” she said. “This cohort would be at high risk of cardiovascular diseases, as smoking is a known risk factor for atherosclerotic disease, and therefore the results are expected.
“The algorithm needs to be validated in an independent database with inclusion of subjects with younger age groups and adjusted for gender and racial diversity,” Gill said.
David Cho, MD, a cardiologist at the University of California, Los Angeles, who also was not part of the study, said in an interview that “this work is a great example of AI being able to detect clinically relevant outcomes with a widely used and low-cost screening test.
“The volume of data needed to train these models is already out there,” Dr. Cho said. “It just needs to be mined.”
He noted that this tool, if validated in randomized trials, could help determine risk among patients living in places where access to specialized cardiac care is limited.
Dr. Weiss and Dr. Cho disclosed no relevant financial relationships. Dr. Gill has received research support from Cannon Inc and consultant fees from Imbio and WorldCare.
A version of this article first appeared on Medscape.com.
AT RSNA 2022
Migraine in children and teens: managing the pain
By the time Mira Halker started high school, hardly a day passed that she wasn’t either getting a migraine attack or recovering from one. She missed volleyball team practice. She missed classes. She missed social events. And few people understood. After all, she looked healthy.
“A lot of times, people think I’m faking it,” said Mira, now 16, who lives in Phoenix. Friends called her flaky; her volleyball coaches questioned her dedication to the team. “I’m like, ‘I’m not trying to get out of this. This is not what this is about,’ ” she said.
Her mother, Rashmi B. Halker Singh, MD, is a neurologist at Mayo Clinic who happens to specialize in migraine. Even so, finding a solution was not easy. Neither ibuprofen nor triptans, nor various preventive measures such as a daily prescription for topiramate controlled the pain and associated symptoms. Mira was barely making it through her school day and had to quit volleyball. Then, in the spring of 10th grade, Mira told her mother that she couldn’t go to prom because the loud noises and lights could give her a migraine attack.
Mother and daughter decided it was time to get even more aggressive. “There are these key moments in life that you can’t get back,” Dr. Singh said. “Migraine steals so much from you.”
Diagnosis
One of the challenges Mira’s physicians faced was deciding which medications and other therapies to prescribe to a teenager. Drug companies have been releasing a steady stream of new treatments for migraine headaches, and researchers promise more are on the way soon. Here’s what works for children, what hasn’t yet been approved for use with minors, and how to diagnose migraines in the first place, from experts at some of the nation’s leading pediatric headache centers.
Migraine affects about 10% of children, according to the American Migraine Foundation. The headaches can strike children as early as age 3 or 4 years, said Robert Little, MD, a pediatric neurologist at Phoenix Children’s Hospital.
Before puberty, boys report more migraine attacks than girls, according to the American Academy of Pediatrics. But that reverses in adolescence: By age 17, as many as 8% of boys and 23% of girls have had migraine. To diagnose migraine, Juliana H. VanderPluym, MD, associate professor of neurology at Mayo Clinic in Phoenix, said she uses the criteria published in the latest edition of the International Classification of Headache Disorders (ICHD): A patient must have had at least five attacks in their life; and in children and adolescents, the attacks must last no less than 2 hours.
In addition, the headaches should exhibit at least two out of four features:
1. Occur more on one side of the head than the other (although Dr. VanderPluym said in children and adolescents headaches often are bilateral).
2. Be of moderate to severe intensity.
3. Have a pounding or throbbing quality.
4. Grow worse with activity or cause an avoidance of activity.
If the attacks meet those criteria, clinicians should check to see if they meet at least one out of the two following:
1. Are sensitive to light and sounds.
2. Are associated with nausea and/or vomiting.
A clinician should consider whether the headaches are not better accounted for by another diagnosis, according to the ICHD criteria. But, Dr. VanderPluym warned that does not necessarily mean running a slew of tests.
“In the absence of red flag features, it is more than likely going to be migraine headache,” she said. That’s especially true if a child has a family history of migraine, as the condition is often passed down from parent to child.
Ultimately, the diagnosis is fairly simple and can be made in a minute or less, said Jack Gladstein, MD, a pediatrician at the University of Maryland whose research focuses on the clinical care of children and adolescents with headache.
“Migraine is acute,” Dr. Gladstein said. “It’s really bad. And it’s recurrent.”
First line of treatment
Whatever a patient takes to treat a migraine, they should hit it early and hard, Dr. Gladstein said.
“The first thing you say, as a primary care physician, is treat your migraine at first twinge, whatever you use. Don’t wait, don’t wish it away,” he said. “The longer you wait, the less chance anything will work.”
The second piece of advice, Dr. Gladstein said, is that whatever drug a patient is taking, they should be on the highest feasible dose. “Work as fast as you can to treat them. You want the brain to reset as quickly as you can,” he said.
Patients should begin with over-the-counter pain relievers, Dr. Little said. If those prove insufficient, they can try a triptan. Rizatriptan is the only such agent that the Food and Drug Administration has approved for children aged 6-17 years. Other drugs in the class – sumatriptan/naproxen, almotriptan, and zolmitriptan – are approved for children 12 and older.
Another migraine therapy recently approved for children aged 12 and older is the use of neurostimulators. “It’s helpful to be aware of them,” Dr. VanderPluym said.
However, if neurostimulators and acute medications prove insufficient, clinicians should warn patients not to up their doses of triptans. Rebound headaches can occur if patients take triptans more than twice a week, or a maximum 10 days per month.
Another possibility is to add a preventive therapy. One mild, first option is nutraceuticals, like riboflavin (vitamin B2) or magnesium, said Anisa F. Kelley, MD, a neurologist and associate director of the headache program at the Ann and Robert H. Lurie Children’s Hospital of Chicago.
“We don’t have definitive evidence, but they’re probably doing more benefit than they are harm,” Dr. Kelley said of these therapies. “In patients who have anywhere from 4 to 8 migraine days a month, where you’re in that in-between period where you don’t necessarily need a [prescription] prophylactic, I will often start with a nutraceutical,” Dr. Kelley said.
For those patients who don’t respond to nutraceuticals, or who need more support, clinicians can prescribe amitriptyline or topiramate. Dr. VanderPluym said.
A 2017 study found such prophylactics to be no more effective than placebo in pediatric migraine patients, but experts caution the results should not be considered definitive.
For one thing, the study enrolled a highly selective group of participants, with milder forms of migraine who may have improved anyway, Dr. VanderPluym said. All participants also received lifestyle counseling.
Every time participants came in for a follow-up, they were asked questions such as how much water were they drinking and how much sleep were they getting, Dr. Kelley noted. The takeaway, she said: “Pediatric and adolescent migraine [management] is very, very much reliant on lifestyle factors.”
Lifestyle triggers
Clinicians should counsel their migraine patients about lifestyle changes, experts said. Getting adequate sleep, staying hydrated, and managing stress can help reduce the intensity and frequency of attacks.
Migraine patients should also be mindful of their screen time, Dr. Kelley added.
“I’ve had lots and lots of patients who find excessive screen time will trigger or worsen migraine,” she said.
As for other potential triggers of attacks, the evidence is mixed.
“There’s clearly an association with disrupted sleep and migraine, and that has been very well established,” Dr. Little said. “And there is some modest amount of evidence that regular exercise can be helpful.” But for reported food triggers, he said, there have been very inconclusive results.
Commonly reported triggers include MSG, red wine, chocolate, and aged cheese. When Dr. Little’s patients keep headache diaries, tracking their meals alongside when they got migraine attacks, they often discover individualized triggers – strawberries, for instance, in one case, he said.
Scientists believe migraines result from the inappropriate activation of the trigeminal ganglion. “The question is, what causes it to get triggered? And how does it get triggered?” Dr. Gladstein said. “And that’s where there’s a lot of difference of opinion and no conclusive evidence.” Clinicians also should make sure that something else – usually depression, anxiety, insomnia, and dizziness – is not hindering effective migraine management. “If someone has terrible insomnia, until you treat the insomnia, the headaches aren’t going to get better,” he said.
As for Mira, her migraine attacks did not significantly improve, despite trying triptans, prophylactics, lifestyle changes, and shots to block nerve pain. When the headaches threatened Mira’s chance to go to her prom, her neurologist suggested trying something different. The physician persuaded the family’s insurance to cover a calcitonin gene-related peptide antagonist, an injectable monoclonal antibody treatment for migraine that the FDA has currently approved only for use in adults.
The difference for Mira has been extraordinary.
“I can do so much more than I was able to do,” said Mira, who attended the dance migraine free. “I feel liberated.”
It’s only migraine
One of the greatest challenges in diagnosing migraine can be reassuring the patient, the parents, even clinicians themselves that migraine really is the cause of all this pain and discomfort, experts said.
“A lot of migraine treatment actually comes down to migraine education,” Dr. VanderPluym said.
Patients and their parents often wonder how they can be sure that this pain is not resulting from something more dangerous than migraine, Dr. Little said. In these cases, he cites practice guidelines published by the American Academy of Neurology.
“The gist of those guidelines is that most pediatric patients do not need further workup,” he said. “But I think that there’s always a fear that you’re missing something because we don’t have a test that we can do” for migraine.
Some warning signs that further tests might be warranted, Dr. Kelley said, include:
- Headaches that wake a patient up in the middle of the night.
- Headaches that start first thing in the morning, especially those that include vomiting.
- A headache pattern that suddenly gets much worse.
- Certain symptoms that accompany the headache, such as tingling, numbness or double vision.
Although all of these signs can still stem from migraines – tingling or numbness, for instance, can be signs of migraine aura – running additional tests can rule out more serious concerns, she said.
By the time Mira Halker started high school, hardly a day passed that she wasn’t either getting a migraine attack or recovering from one. She missed volleyball team practice. She missed classes. She missed social events. And few people understood. After all, she looked healthy.
“A lot of times, people think I’m faking it,” said Mira, now 16, who lives in Phoenix. Friends called her flaky; her volleyball coaches questioned her dedication to the team. “I’m like, ‘I’m not trying to get out of this. This is not what this is about,’ ” she said.
Her mother, Rashmi B. Halker Singh, MD, is a neurologist at Mayo Clinic who happens to specialize in migraine. Even so, finding a solution was not easy. Neither ibuprofen nor triptans, nor various preventive measures such as a daily prescription for topiramate controlled the pain and associated symptoms. Mira was barely making it through her school day and had to quit volleyball. Then, in the spring of 10th grade, Mira told her mother that she couldn’t go to prom because the loud noises and lights could give her a migraine attack.
Mother and daughter decided it was time to get even more aggressive. “There are these key moments in life that you can’t get back,” Dr. Singh said. “Migraine steals so much from you.”
Diagnosis
One of the challenges Mira’s physicians faced was deciding which medications and other therapies to prescribe to a teenager. Drug companies have been releasing a steady stream of new treatments for migraine headaches, and researchers promise more are on the way soon. Here’s what works for children, what hasn’t yet been approved for use with minors, and how to diagnose migraines in the first place, from experts at some of the nation’s leading pediatric headache centers.
Migraine affects about 10% of children, according to the American Migraine Foundation. The headaches can strike children as early as age 3 or 4 years, said Robert Little, MD, a pediatric neurologist at Phoenix Children’s Hospital.
Before puberty, boys report more migraine attacks than girls, according to the American Academy of Pediatrics. But that reverses in adolescence: By age 17, as many as 8% of boys and 23% of girls have had migraine. To diagnose migraine, Juliana H. VanderPluym, MD, associate professor of neurology at Mayo Clinic in Phoenix, said she uses the criteria published in the latest edition of the International Classification of Headache Disorders (ICHD): A patient must have had at least five attacks in their life; and in children and adolescents, the attacks must last no less than 2 hours.
In addition, the headaches should exhibit at least two out of four features:
1. Occur more on one side of the head than the other (although Dr. VanderPluym said in children and adolescents headaches often are bilateral).
2. Be of moderate to severe intensity.
3. Have a pounding or throbbing quality.
4. Grow worse with activity or cause an avoidance of activity.
If the attacks meet those criteria, clinicians should check to see if they meet at least one out of the two following:
1. Are sensitive to light and sounds.
2. Are associated with nausea and/or vomiting.
A clinician should consider whether the headaches are not better accounted for by another diagnosis, according to the ICHD criteria. But, Dr. VanderPluym warned that does not necessarily mean running a slew of tests.
“In the absence of red flag features, it is more than likely going to be migraine headache,” she said. That’s especially true if a child has a family history of migraine, as the condition is often passed down from parent to child.
Ultimately, the diagnosis is fairly simple and can be made in a minute or less, said Jack Gladstein, MD, a pediatrician at the University of Maryland whose research focuses on the clinical care of children and adolescents with headache.
“Migraine is acute,” Dr. Gladstein said. “It’s really bad. And it’s recurrent.”
First line of treatment
Whatever a patient takes to treat a migraine, they should hit it early and hard, Dr. Gladstein said.
“The first thing you say, as a primary care physician, is treat your migraine at first twinge, whatever you use. Don’t wait, don’t wish it away,” he said. “The longer you wait, the less chance anything will work.”
The second piece of advice, Dr. Gladstein said, is that whatever drug a patient is taking, they should be on the highest feasible dose. “Work as fast as you can to treat them. You want the brain to reset as quickly as you can,” he said.
Patients should begin with over-the-counter pain relievers, Dr. Little said. If those prove insufficient, they can try a triptan. Rizatriptan is the only such agent that the Food and Drug Administration has approved for children aged 6-17 years. Other drugs in the class – sumatriptan/naproxen, almotriptan, and zolmitriptan – are approved for children 12 and older.
Another migraine therapy recently approved for children aged 12 and older is the use of neurostimulators. “It’s helpful to be aware of them,” Dr. VanderPluym said.
However, if neurostimulators and acute medications prove insufficient, clinicians should warn patients not to up their doses of triptans. Rebound headaches can occur if patients take triptans more than twice a week, or a maximum 10 days per month.
Another possibility is to add a preventive therapy. One mild, first option is nutraceuticals, like riboflavin (vitamin B2) or magnesium, said Anisa F. Kelley, MD, a neurologist and associate director of the headache program at the Ann and Robert H. Lurie Children’s Hospital of Chicago.
“We don’t have definitive evidence, but they’re probably doing more benefit than they are harm,” Dr. Kelley said of these therapies. “In patients who have anywhere from 4 to 8 migraine days a month, where you’re in that in-between period where you don’t necessarily need a [prescription] prophylactic, I will often start with a nutraceutical,” Dr. Kelley said.
For those patients who don’t respond to nutraceuticals, or who need more support, clinicians can prescribe amitriptyline or topiramate. Dr. VanderPluym said.
A 2017 study found such prophylactics to be no more effective than placebo in pediatric migraine patients, but experts caution the results should not be considered definitive.
For one thing, the study enrolled a highly selective group of participants, with milder forms of migraine who may have improved anyway, Dr. VanderPluym said. All participants also received lifestyle counseling.
Every time participants came in for a follow-up, they were asked questions such as how much water were they drinking and how much sleep were they getting, Dr. Kelley noted. The takeaway, she said: “Pediatric and adolescent migraine [management] is very, very much reliant on lifestyle factors.”
Lifestyle triggers
Clinicians should counsel their migraine patients about lifestyle changes, experts said. Getting adequate sleep, staying hydrated, and managing stress can help reduce the intensity and frequency of attacks.
Migraine patients should also be mindful of their screen time, Dr. Kelley added.
“I’ve had lots and lots of patients who find excessive screen time will trigger or worsen migraine,” she said.
As for other potential triggers of attacks, the evidence is mixed.
“There’s clearly an association with disrupted sleep and migraine, and that has been very well established,” Dr. Little said. “And there is some modest amount of evidence that regular exercise can be helpful.” But for reported food triggers, he said, there have been very inconclusive results.
Commonly reported triggers include MSG, red wine, chocolate, and aged cheese. When Dr. Little’s patients keep headache diaries, tracking their meals alongside when they got migraine attacks, they often discover individualized triggers – strawberries, for instance, in one case, he said.
Scientists believe migraines result from the inappropriate activation of the trigeminal ganglion. “The question is, what causes it to get triggered? And how does it get triggered?” Dr. Gladstein said. “And that’s where there’s a lot of difference of opinion and no conclusive evidence.” Clinicians also should make sure that something else – usually depression, anxiety, insomnia, and dizziness – is not hindering effective migraine management. “If someone has terrible insomnia, until you treat the insomnia, the headaches aren’t going to get better,” he said.
As for Mira, her migraine attacks did not significantly improve, despite trying triptans, prophylactics, lifestyle changes, and shots to block nerve pain. When the headaches threatened Mira’s chance to go to her prom, her neurologist suggested trying something different. The physician persuaded the family’s insurance to cover a calcitonin gene-related peptide antagonist, an injectable monoclonal antibody treatment for migraine that the FDA has currently approved only for use in adults.
The difference for Mira has been extraordinary.
“I can do so much more than I was able to do,” said Mira, who attended the dance migraine free. “I feel liberated.”
It’s only migraine
One of the greatest challenges in diagnosing migraine can be reassuring the patient, the parents, even clinicians themselves that migraine really is the cause of all this pain and discomfort, experts said.
“A lot of migraine treatment actually comes down to migraine education,” Dr. VanderPluym said.
Patients and their parents often wonder how they can be sure that this pain is not resulting from something more dangerous than migraine, Dr. Little said. In these cases, he cites practice guidelines published by the American Academy of Neurology.
“The gist of those guidelines is that most pediatric patients do not need further workup,” he said. “But I think that there’s always a fear that you’re missing something because we don’t have a test that we can do” for migraine.
Some warning signs that further tests might be warranted, Dr. Kelley said, include:
- Headaches that wake a patient up in the middle of the night.
- Headaches that start first thing in the morning, especially those that include vomiting.
- A headache pattern that suddenly gets much worse.
- Certain symptoms that accompany the headache, such as tingling, numbness or double vision.
Although all of these signs can still stem from migraines – tingling or numbness, for instance, can be signs of migraine aura – running additional tests can rule out more serious concerns, she said.
By the time Mira Halker started high school, hardly a day passed that she wasn’t either getting a migraine attack or recovering from one. She missed volleyball team practice. She missed classes. She missed social events. And few people understood. After all, she looked healthy.
“A lot of times, people think I’m faking it,” said Mira, now 16, who lives in Phoenix. Friends called her flaky; her volleyball coaches questioned her dedication to the team. “I’m like, ‘I’m not trying to get out of this. This is not what this is about,’ ” she said.
Her mother, Rashmi B. Halker Singh, MD, is a neurologist at Mayo Clinic who happens to specialize in migraine. Even so, finding a solution was not easy. Neither ibuprofen nor triptans, nor various preventive measures such as a daily prescription for topiramate controlled the pain and associated symptoms. Mira was barely making it through her school day and had to quit volleyball. Then, in the spring of 10th grade, Mira told her mother that she couldn’t go to prom because the loud noises and lights could give her a migraine attack.
Mother and daughter decided it was time to get even more aggressive. “There are these key moments in life that you can’t get back,” Dr. Singh said. “Migraine steals so much from you.”
Diagnosis
One of the challenges Mira’s physicians faced was deciding which medications and other therapies to prescribe to a teenager. Drug companies have been releasing a steady stream of new treatments for migraine headaches, and researchers promise more are on the way soon. Here’s what works for children, what hasn’t yet been approved for use with minors, and how to diagnose migraines in the first place, from experts at some of the nation’s leading pediatric headache centers.
Migraine affects about 10% of children, according to the American Migraine Foundation. The headaches can strike children as early as age 3 or 4 years, said Robert Little, MD, a pediatric neurologist at Phoenix Children’s Hospital.
Before puberty, boys report more migraine attacks than girls, according to the American Academy of Pediatrics. But that reverses in adolescence: By age 17, as many as 8% of boys and 23% of girls have had migraine. To diagnose migraine, Juliana H. VanderPluym, MD, associate professor of neurology at Mayo Clinic in Phoenix, said she uses the criteria published in the latest edition of the International Classification of Headache Disorders (ICHD): A patient must have had at least five attacks in their life; and in children and adolescents, the attacks must last no less than 2 hours.
In addition, the headaches should exhibit at least two out of four features:
1. Occur more on one side of the head than the other (although Dr. VanderPluym said in children and adolescents headaches often are bilateral).
2. Be of moderate to severe intensity.
3. Have a pounding or throbbing quality.
4. Grow worse with activity or cause an avoidance of activity.
If the attacks meet those criteria, clinicians should check to see if they meet at least one out of the two following:
1. Are sensitive to light and sounds.
2. Are associated with nausea and/or vomiting.
A clinician should consider whether the headaches are not better accounted for by another diagnosis, according to the ICHD criteria. But, Dr. VanderPluym warned that does not necessarily mean running a slew of tests.
“In the absence of red flag features, it is more than likely going to be migraine headache,” she said. That’s especially true if a child has a family history of migraine, as the condition is often passed down from parent to child.
Ultimately, the diagnosis is fairly simple and can be made in a minute or less, said Jack Gladstein, MD, a pediatrician at the University of Maryland whose research focuses on the clinical care of children and adolescents with headache.
“Migraine is acute,” Dr. Gladstein said. “It’s really bad. And it’s recurrent.”
First line of treatment
Whatever a patient takes to treat a migraine, they should hit it early and hard, Dr. Gladstein said.
“The first thing you say, as a primary care physician, is treat your migraine at first twinge, whatever you use. Don’t wait, don’t wish it away,” he said. “The longer you wait, the less chance anything will work.”
The second piece of advice, Dr. Gladstein said, is that whatever drug a patient is taking, they should be on the highest feasible dose. “Work as fast as you can to treat them. You want the brain to reset as quickly as you can,” he said.
Patients should begin with over-the-counter pain relievers, Dr. Little said. If those prove insufficient, they can try a triptan. Rizatriptan is the only such agent that the Food and Drug Administration has approved for children aged 6-17 years. Other drugs in the class – sumatriptan/naproxen, almotriptan, and zolmitriptan – are approved for children 12 and older.
Another migraine therapy recently approved for children aged 12 and older is the use of neurostimulators. “It’s helpful to be aware of them,” Dr. VanderPluym said.
However, if neurostimulators and acute medications prove insufficient, clinicians should warn patients not to up their doses of triptans. Rebound headaches can occur if patients take triptans more than twice a week, or a maximum 10 days per month.
Another possibility is to add a preventive therapy. One mild, first option is nutraceuticals, like riboflavin (vitamin B2) or magnesium, said Anisa F. Kelley, MD, a neurologist and associate director of the headache program at the Ann and Robert H. Lurie Children’s Hospital of Chicago.
“We don’t have definitive evidence, but they’re probably doing more benefit than they are harm,” Dr. Kelley said of these therapies. “In patients who have anywhere from 4 to 8 migraine days a month, where you’re in that in-between period where you don’t necessarily need a [prescription] prophylactic, I will often start with a nutraceutical,” Dr. Kelley said.
For those patients who don’t respond to nutraceuticals, or who need more support, clinicians can prescribe amitriptyline or topiramate. Dr. VanderPluym said.
A 2017 study found such prophylactics to be no more effective than placebo in pediatric migraine patients, but experts caution the results should not be considered definitive.
For one thing, the study enrolled a highly selective group of participants, with milder forms of migraine who may have improved anyway, Dr. VanderPluym said. All participants also received lifestyle counseling.
Every time participants came in for a follow-up, they were asked questions such as how much water were they drinking and how much sleep were they getting, Dr. Kelley noted. The takeaway, she said: “Pediatric and adolescent migraine [management] is very, very much reliant on lifestyle factors.”
Lifestyle triggers
Clinicians should counsel their migraine patients about lifestyle changes, experts said. Getting adequate sleep, staying hydrated, and managing stress can help reduce the intensity and frequency of attacks.
Migraine patients should also be mindful of their screen time, Dr. Kelley added.
“I’ve had lots and lots of patients who find excessive screen time will trigger or worsen migraine,” she said.
As for other potential triggers of attacks, the evidence is mixed.
“There’s clearly an association with disrupted sleep and migraine, and that has been very well established,” Dr. Little said. “And there is some modest amount of evidence that regular exercise can be helpful.” But for reported food triggers, he said, there have been very inconclusive results.
Commonly reported triggers include MSG, red wine, chocolate, and aged cheese. When Dr. Little’s patients keep headache diaries, tracking their meals alongside when they got migraine attacks, they often discover individualized triggers – strawberries, for instance, in one case, he said.
Scientists believe migraines result from the inappropriate activation of the trigeminal ganglion. “The question is, what causes it to get triggered? And how does it get triggered?” Dr. Gladstein said. “And that’s where there’s a lot of difference of opinion and no conclusive evidence.” Clinicians also should make sure that something else – usually depression, anxiety, insomnia, and dizziness – is not hindering effective migraine management. “If someone has terrible insomnia, until you treat the insomnia, the headaches aren’t going to get better,” he said.
As for Mira, her migraine attacks did not significantly improve, despite trying triptans, prophylactics, lifestyle changes, and shots to block nerve pain. When the headaches threatened Mira’s chance to go to her prom, her neurologist suggested trying something different. The physician persuaded the family’s insurance to cover a calcitonin gene-related peptide antagonist, an injectable monoclonal antibody treatment for migraine that the FDA has currently approved only for use in adults.
The difference for Mira has been extraordinary.
“I can do so much more than I was able to do,” said Mira, who attended the dance migraine free. “I feel liberated.”
It’s only migraine
One of the greatest challenges in diagnosing migraine can be reassuring the patient, the parents, even clinicians themselves that migraine really is the cause of all this pain and discomfort, experts said.
“A lot of migraine treatment actually comes down to migraine education,” Dr. VanderPluym said.
Patients and their parents often wonder how they can be sure that this pain is not resulting from something more dangerous than migraine, Dr. Little said. In these cases, he cites practice guidelines published by the American Academy of Neurology.
“The gist of those guidelines is that most pediatric patients do not need further workup,” he said. “But I think that there’s always a fear that you’re missing something because we don’t have a test that we can do” for migraine.
Some warning signs that further tests might be warranted, Dr. Kelley said, include:
- Headaches that wake a patient up in the middle of the night.
- Headaches that start first thing in the morning, especially those that include vomiting.
- A headache pattern that suddenly gets much worse.
- Certain symptoms that accompany the headache, such as tingling, numbness or double vision.
Although all of these signs can still stem from migraines – tingling or numbness, for instance, can be signs of migraine aura – running additional tests can rule out more serious concerns, she said.
‘Modest’ benefit for lecanemab in Alzheimer’s disease, but adverse events are common
SAN FRANCISCO –
In the CLARITY AD trial, adverse events (AEs) were common compared with placebo, including amyloid-related edema and effusions; and a recent news report linked a second death to the drug.
Moving forward, “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease,” wrote Christopher H. van Dyck, MD, Yale University, New Haven, Conn., and colleagues.
The full trial findings were presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, with simultaneous publication on Nov. 29 in the New England Journal of Medicine.
Complications in the field
The phase 3 trial of lecanemab has been closely watched in AD circles, especially considering positive early data released in September and reported by this news organization at that time.
The Food and Drug Administration is expected to make a decision about possible approval of the drug in January 2023. Only one other antiamyloid treatment, the highly controversial and expensive aducanumab (Aduhelm), is currently approved by the FDA.
For the new 18-month, randomized, double-blind CLARITY AD trial, researchers enrolled 1,795 patients aged 50-90 years (average age, 71 years) with early AD. All were randomly assigned to receive either a placebo (n = 898) or intravenous lecanemab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets amyloid beta (A-beta) protofibrils, at 10 mg/kg of body weight every 2 weeks (n = 897).
The study ran from 2019 to 2021. The participants (52% women, 20% non-White) were recruited in North America, Europe, and Asia. Safety data included all participants, and the modified intention-to-treat group included 1,734 participants, with 859 receiving lecanemab and 875 receiving placebo.
The primary endpoint was the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Scores from 0.5 to 6 are signs of early AD, according to the study. The mean baseline score for both groups was 3.2. The adjusted mean change at 18 months was 1.21 for lecanemab versus 1.66 for placebo (difference, –0.45; 95% confidence interval [CI], –0.67 to –0.23; P < .001).
As Dr. van Dyck noted in his presentation at the CTAD meting, this represents a 27% slowing of the decline in the lecanemab group.
The published findings do not speculate about how this difference would affect the day-to-day life of participants who took the drug, although it does refer to “modestly less decline” of cognition/function in the lecanemab group.
Other measurements that suggest cognitive improvements in the lecanemab group versus placebo include the Alzheimer’s Disease Assessment Scale–Cognitive Subscale score (mean difference, –1.44; 95% CI, –2.27 to –0.61), the Alzheimer’s Disease Composite Score (mean difference, –0.05; 95% CI, –.074 to –.027,), and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment score (mean difference, 2.0; 95% CI, 1.2-2.8; all, P < .001).
Overall, Dr. van Dyck said, “Lecanemab met the primary and secondary endpoints versus placebo at 18 months, with highly significant differences starting at 6 months.”
In a substudy of 698 participants, results showed that amyloid burden fell at a higher rate in the lecanemab group than in the placebo group (difference, –59.1 centiloids; 95% CI, –62.6 to –55.6).
“Lecanemab has high selectivity for soluble aggregated species of A-beta as compared with monomeric amyloid, with moderate selectivity for fibrillar amyloid; this profile is considered to target the most toxic pathologic amyloid species,” the researchers wrote.
Concerning AE data
With respect to AEs, deaths occurred in both groups (0.7% in those who took lecanemab and 0.8% in those who took the placebo). The researchers did not attribute any deaths to the drug. However, according to a report in the journal Science published Nov. 27, a 65-year-old woman who was taking the drug as part of a clinical trial “recently died from a massive brain hemorrhage that some researchers link to the drug.”
The woman, the second person “whose death was linked to lecanemab,” died after suffering a stroke. Researchers summarized a case report as saying that the drug “contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels.”
Eisai, which sponsored the new trial, told Science that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause.”
In a CTAD presentation, study coauthor Marwan Sabbagh, MD, Barrow Neurological Institute, Phoenix, said two hemorrhage-related deaths occurred in an open-label extension. One was in the context of a tissue plasminogen activator treatment for a stroke, which fits with the description of the case in the Science report. “Causality with lecanemab is a little difficult ...,” he said. “Patients on anticoagulation might need further consideration.”
In the CLARITY AD Trial, serious AEs occurred in 14% of the lecanemab group, leading to discontinuation 6.9% of the time, and in 11.3% of the placebo group, leading to discontinuation 2.9% of the time, the investigators reported.
They added that, in the lecanemab group, the most common AEs, defined as affecting more than 10% of participants, were infusion-related reactions (26.4% vs. 7.4% for placebo); amyloid-related imaging abnormalities with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (17.3% vs. 9%, respectively); amyloid-related imaging abnormalities with edema or effusions (12.6% vs. 1.7%); headache (11.1% vs. 8.1%); and falls (10.4% vs. 9.6%).
In addition, macrohemorrhage was reported in 0.6% of the lecanemab group and 0.1% of the placebo group.
Cautious optimism
In separate interviews, two Alzheimer’s specialists who weren’t involved in the study praised the trial and described the findings as “exciting.” But they also highlighted its limitations.
Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School and chief medical officer of Linus Health, said the study represents impressive progress after 60-plus trials examining anti-amyloid monoclonal antibodies. “This is the first trial that shows a clinical benefit that can be measured,” he said.
However, it’s unclear whether the changes “are really going to make a difference in people’s lives,” he said. The drug is likely to be expensive, owing to the large investment needed for research, he added, and patients will have to undergo costly testing, such as PET scans and spinal taps.
Still, “this could be a valuable adjunct to the armamentarium we have,” which includes interventions such as lifestyle changes, he said.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, noted that the trial reached its primary and secondary endpoints and that the drug had what he called a “modest” effect on cognition.
However, the drugmaker will need to explore the adverse effects, he said, especially among patients with atrial fibrillation who take anticoagulants. And, he said, medicine is still far from the ultimate goal – fully reversing cognitive decline.
Michael Weiner, MD, president of the CTAD22 Scientific Committee, noted in a press release that there is “growing evidence” that some antiamyloid therapies, “especially lecanemab and donanemab” have shown promising results.
“Unfortunately, these treatments are also associated with abnormal differences seen in imaging, including brain swelling and bleeding in the brain,” said Dr. Weiner, professor of radiology, medicine, and neurology at the University of California, San Francisco.
“There is considerable controversy concerning the significance and impact of these findings, including whether or not governments and medical insurance will provide financial coverage for such treatments,” he added.
Rave reviews from the Alzheimer’s Association
In a statement, the Alzheimer’s Association raved about lecanemab and declared that the FDA should approve lecanemab on an accelerated basis. The study “confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease ...” the association said, adding that “it could mean many months more of recognizing their spouse, children and grandchildren.”
The association, which is a staunch supporter of aducanumab, called on the Centers for Medicare & Medicaid Services to cover the drug if the FDA approves it. The association’s statement did not address the drug’s potential high cost, the adverse effects, or the two reported deaths.
The trial was supported by Eisai (regulatory sponsor) with partial funding from Biogen. Dr. van Dyck reports having received research grants from Biogen, Eisai, Biohaven, Cerevel Therapeutics, Eli Lilly, Genentech, Janssen, Novartis, and UCB. He has been a consultant to Cerevel, Eisai, Ono Pharmaceutical, and Roche. Relevant financial relationships for the other investigators are fully listed in the original article.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO –
In the CLARITY AD trial, adverse events (AEs) were common compared with placebo, including amyloid-related edema and effusions; and a recent news report linked a second death to the drug.
Moving forward, “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease,” wrote Christopher H. van Dyck, MD, Yale University, New Haven, Conn., and colleagues.
The full trial findings were presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, with simultaneous publication on Nov. 29 in the New England Journal of Medicine.
Complications in the field
The phase 3 trial of lecanemab has been closely watched in AD circles, especially considering positive early data released in September and reported by this news organization at that time.
The Food and Drug Administration is expected to make a decision about possible approval of the drug in January 2023. Only one other antiamyloid treatment, the highly controversial and expensive aducanumab (Aduhelm), is currently approved by the FDA.
For the new 18-month, randomized, double-blind CLARITY AD trial, researchers enrolled 1,795 patients aged 50-90 years (average age, 71 years) with early AD. All were randomly assigned to receive either a placebo (n = 898) or intravenous lecanemab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets amyloid beta (A-beta) protofibrils, at 10 mg/kg of body weight every 2 weeks (n = 897).
The study ran from 2019 to 2021. The participants (52% women, 20% non-White) were recruited in North America, Europe, and Asia. Safety data included all participants, and the modified intention-to-treat group included 1,734 participants, with 859 receiving lecanemab and 875 receiving placebo.
The primary endpoint was the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Scores from 0.5 to 6 are signs of early AD, according to the study. The mean baseline score for both groups was 3.2. The adjusted mean change at 18 months was 1.21 for lecanemab versus 1.66 for placebo (difference, –0.45; 95% confidence interval [CI], –0.67 to –0.23; P < .001).
As Dr. van Dyck noted in his presentation at the CTAD meting, this represents a 27% slowing of the decline in the lecanemab group.
The published findings do not speculate about how this difference would affect the day-to-day life of participants who took the drug, although it does refer to “modestly less decline” of cognition/function in the lecanemab group.
Other measurements that suggest cognitive improvements in the lecanemab group versus placebo include the Alzheimer’s Disease Assessment Scale–Cognitive Subscale score (mean difference, –1.44; 95% CI, –2.27 to –0.61), the Alzheimer’s Disease Composite Score (mean difference, –0.05; 95% CI, –.074 to –.027,), and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment score (mean difference, 2.0; 95% CI, 1.2-2.8; all, P < .001).
Overall, Dr. van Dyck said, “Lecanemab met the primary and secondary endpoints versus placebo at 18 months, with highly significant differences starting at 6 months.”
In a substudy of 698 participants, results showed that amyloid burden fell at a higher rate in the lecanemab group than in the placebo group (difference, –59.1 centiloids; 95% CI, –62.6 to –55.6).
“Lecanemab has high selectivity for soluble aggregated species of A-beta as compared with monomeric amyloid, with moderate selectivity for fibrillar amyloid; this profile is considered to target the most toxic pathologic amyloid species,” the researchers wrote.
Concerning AE data
With respect to AEs, deaths occurred in both groups (0.7% in those who took lecanemab and 0.8% in those who took the placebo). The researchers did not attribute any deaths to the drug. However, according to a report in the journal Science published Nov. 27, a 65-year-old woman who was taking the drug as part of a clinical trial “recently died from a massive brain hemorrhage that some researchers link to the drug.”
The woman, the second person “whose death was linked to lecanemab,” died after suffering a stroke. Researchers summarized a case report as saying that the drug “contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels.”
Eisai, which sponsored the new trial, told Science that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause.”
In a CTAD presentation, study coauthor Marwan Sabbagh, MD, Barrow Neurological Institute, Phoenix, said two hemorrhage-related deaths occurred in an open-label extension. One was in the context of a tissue plasminogen activator treatment for a stroke, which fits with the description of the case in the Science report. “Causality with lecanemab is a little difficult ...,” he said. “Patients on anticoagulation might need further consideration.”
In the CLARITY AD Trial, serious AEs occurred in 14% of the lecanemab group, leading to discontinuation 6.9% of the time, and in 11.3% of the placebo group, leading to discontinuation 2.9% of the time, the investigators reported.
They added that, in the lecanemab group, the most common AEs, defined as affecting more than 10% of participants, were infusion-related reactions (26.4% vs. 7.4% for placebo); amyloid-related imaging abnormalities with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (17.3% vs. 9%, respectively); amyloid-related imaging abnormalities with edema or effusions (12.6% vs. 1.7%); headache (11.1% vs. 8.1%); and falls (10.4% vs. 9.6%).
In addition, macrohemorrhage was reported in 0.6% of the lecanemab group and 0.1% of the placebo group.
Cautious optimism
In separate interviews, two Alzheimer’s specialists who weren’t involved in the study praised the trial and described the findings as “exciting.” But they also highlighted its limitations.
Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School and chief medical officer of Linus Health, said the study represents impressive progress after 60-plus trials examining anti-amyloid monoclonal antibodies. “This is the first trial that shows a clinical benefit that can be measured,” he said.
However, it’s unclear whether the changes “are really going to make a difference in people’s lives,” he said. The drug is likely to be expensive, owing to the large investment needed for research, he added, and patients will have to undergo costly testing, such as PET scans and spinal taps.
Still, “this could be a valuable adjunct to the armamentarium we have,” which includes interventions such as lifestyle changes, he said.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, noted that the trial reached its primary and secondary endpoints and that the drug had what he called a “modest” effect on cognition.
However, the drugmaker will need to explore the adverse effects, he said, especially among patients with atrial fibrillation who take anticoagulants. And, he said, medicine is still far from the ultimate goal – fully reversing cognitive decline.
Michael Weiner, MD, president of the CTAD22 Scientific Committee, noted in a press release that there is “growing evidence” that some antiamyloid therapies, “especially lecanemab and donanemab” have shown promising results.
“Unfortunately, these treatments are also associated with abnormal differences seen in imaging, including brain swelling and bleeding in the brain,” said Dr. Weiner, professor of radiology, medicine, and neurology at the University of California, San Francisco.
“There is considerable controversy concerning the significance and impact of these findings, including whether or not governments and medical insurance will provide financial coverage for such treatments,” he added.
Rave reviews from the Alzheimer’s Association
In a statement, the Alzheimer’s Association raved about lecanemab and declared that the FDA should approve lecanemab on an accelerated basis. The study “confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease ...” the association said, adding that “it could mean many months more of recognizing their spouse, children and grandchildren.”
The association, which is a staunch supporter of aducanumab, called on the Centers for Medicare & Medicaid Services to cover the drug if the FDA approves it. The association’s statement did not address the drug’s potential high cost, the adverse effects, or the two reported deaths.
The trial was supported by Eisai (regulatory sponsor) with partial funding from Biogen. Dr. van Dyck reports having received research grants from Biogen, Eisai, Biohaven, Cerevel Therapeutics, Eli Lilly, Genentech, Janssen, Novartis, and UCB. He has been a consultant to Cerevel, Eisai, Ono Pharmaceutical, and Roche. Relevant financial relationships for the other investigators are fully listed in the original article.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO –
In the CLARITY AD trial, adverse events (AEs) were common compared with placebo, including amyloid-related edema and effusions; and a recent news report linked a second death to the drug.
Moving forward, “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease,” wrote Christopher H. van Dyck, MD, Yale University, New Haven, Conn., and colleagues.
The full trial findings were presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, with simultaneous publication on Nov. 29 in the New England Journal of Medicine.
Complications in the field
The phase 3 trial of lecanemab has been closely watched in AD circles, especially considering positive early data released in September and reported by this news organization at that time.
The Food and Drug Administration is expected to make a decision about possible approval of the drug in January 2023. Only one other antiamyloid treatment, the highly controversial and expensive aducanumab (Aduhelm), is currently approved by the FDA.
For the new 18-month, randomized, double-blind CLARITY AD trial, researchers enrolled 1,795 patients aged 50-90 years (average age, 71 years) with early AD. All were randomly assigned to receive either a placebo (n = 898) or intravenous lecanemab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets amyloid beta (A-beta) protofibrils, at 10 mg/kg of body weight every 2 weeks (n = 897).
The study ran from 2019 to 2021. The participants (52% women, 20% non-White) were recruited in North America, Europe, and Asia. Safety data included all participants, and the modified intention-to-treat group included 1,734 participants, with 859 receiving lecanemab and 875 receiving placebo.
The primary endpoint was the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Scores from 0.5 to 6 are signs of early AD, according to the study. The mean baseline score for both groups was 3.2. The adjusted mean change at 18 months was 1.21 for lecanemab versus 1.66 for placebo (difference, –0.45; 95% confidence interval [CI], –0.67 to –0.23; P < .001).
As Dr. van Dyck noted in his presentation at the CTAD meting, this represents a 27% slowing of the decline in the lecanemab group.
The published findings do not speculate about how this difference would affect the day-to-day life of participants who took the drug, although it does refer to “modestly less decline” of cognition/function in the lecanemab group.
Other measurements that suggest cognitive improvements in the lecanemab group versus placebo include the Alzheimer’s Disease Assessment Scale–Cognitive Subscale score (mean difference, –1.44; 95% CI, –2.27 to –0.61), the Alzheimer’s Disease Composite Score (mean difference, –0.05; 95% CI, –.074 to –.027,), and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment score (mean difference, 2.0; 95% CI, 1.2-2.8; all, P < .001).
Overall, Dr. van Dyck said, “Lecanemab met the primary and secondary endpoints versus placebo at 18 months, with highly significant differences starting at 6 months.”
In a substudy of 698 participants, results showed that amyloid burden fell at a higher rate in the lecanemab group than in the placebo group (difference, –59.1 centiloids; 95% CI, –62.6 to –55.6).
“Lecanemab has high selectivity for soluble aggregated species of A-beta as compared with monomeric amyloid, with moderate selectivity for fibrillar amyloid; this profile is considered to target the most toxic pathologic amyloid species,” the researchers wrote.
Concerning AE data
With respect to AEs, deaths occurred in both groups (0.7% in those who took lecanemab and 0.8% in those who took the placebo). The researchers did not attribute any deaths to the drug. However, according to a report in the journal Science published Nov. 27, a 65-year-old woman who was taking the drug as part of a clinical trial “recently died from a massive brain hemorrhage that some researchers link to the drug.”
The woman, the second person “whose death was linked to lecanemab,” died after suffering a stroke. Researchers summarized a case report as saying that the drug “contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels.”
Eisai, which sponsored the new trial, told Science that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause.”
In a CTAD presentation, study coauthor Marwan Sabbagh, MD, Barrow Neurological Institute, Phoenix, said two hemorrhage-related deaths occurred in an open-label extension. One was in the context of a tissue plasminogen activator treatment for a stroke, which fits with the description of the case in the Science report. “Causality with lecanemab is a little difficult ...,” he said. “Patients on anticoagulation might need further consideration.”
In the CLARITY AD Trial, serious AEs occurred in 14% of the lecanemab group, leading to discontinuation 6.9% of the time, and in 11.3% of the placebo group, leading to discontinuation 2.9% of the time, the investigators reported.
They added that, in the lecanemab group, the most common AEs, defined as affecting more than 10% of participants, were infusion-related reactions (26.4% vs. 7.4% for placebo); amyloid-related imaging abnormalities with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (17.3% vs. 9%, respectively); amyloid-related imaging abnormalities with edema or effusions (12.6% vs. 1.7%); headache (11.1% vs. 8.1%); and falls (10.4% vs. 9.6%).
In addition, macrohemorrhage was reported in 0.6% of the lecanemab group and 0.1% of the placebo group.
Cautious optimism
In separate interviews, two Alzheimer’s specialists who weren’t involved in the study praised the trial and described the findings as “exciting.” But they also highlighted its limitations.
Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School and chief medical officer of Linus Health, said the study represents impressive progress after 60-plus trials examining anti-amyloid monoclonal antibodies. “This is the first trial that shows a clinical benefit that can be measured,” he said.
However, it’s unclear whether the changes “are really going to make a difference in people’s lives,” he said. The drug is likely to be expensive, owing to the large investment needed for research, he added, and patients will have to undergo costly testing, such as PET scans and spinal taps.
Still, “this could be a valuable adjunct to the armamentarium we have,” which includes interventions such as lifestyle changes, he said.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, noted that the trial reached its primary and secondary endpoints and that the drug had what he called a “modest” effect on cognition.
However, the drugmaker will need to explore the adverse effects, he said, especially among patients with atrial fibrillation who take anticoagulants. And, he said, medicine is still far from the ultimate goal – fully reversing cognitive decline.
Michael Weiner, MD, president of the CTAD22 Scientific Committee, noted in a press release that there is “growing evidence” that some antiamyloid therapies, “especially lecanemab and donanemab” have shown promising results.
“Unfortunately, these treatments are also associated with abnormal differences seen in imaging, including brain swelling and bleeding in the brain,” said Dr. Weiner, professor of radiology, medicine, and neurology at the University of California, San Francisco.
“There is considerable controversy concerning the significance and impact of these findings, including whether or not governments and medical insurance will provide financial coverage for such treatments,” he added.
Rave reviews from the Alzheimer’s Association
In a statement, the Alzheimer’s Association raved about lecanemab and declared that the FDA should approve lecanemab on an accelerated basis. The study “confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease ...” the association said, adding that “it could mean many months more of recognizing their spouse, children and grandchildren.”
The association, which is a staunch supporter of aducanumab, called on the Centers for Medicare & Medicaid Services to cover the drug if the FDA approves it. The association’s statement did not address the drug’s potential high cost, the adverse effects, or the two reported deaths.
The trial was supported by Eisai (regulatory sponsor) with partial funding from Biogen. Dr. van Dyck reports having received research grants from Biogen, Eisai, Biohaven, Cerevel Therapeutics, Eli Lilly, Genentech, Janssen, Novartis, and UCB. He has been a consultant to Cerevel, Eisai, Ono Pharmaceutical, and Roche. Relevant financial relationships for the other investigators are fully listed in the original article.
A version of this article first appeared on Medscape.com.
AT CTAD 2022
Recommending exercise for migraine: Just do it
with high-intensity aerobics coming in second, and both beating top-line migraine medications topiramate and amitriptyline, new research suggests.
The new results should encourage clinicians to recommend patients with migraine engage in strength-training exercise whenever possible, study investigator Yohannes W. Woldeamanuel, MD, a physician-scientist and instructor, department of neurology and neurological sciences, Stanford (Calif.) University, told this news organization.
“Exercise is something patients can do all their lives and use it to prevent migraine attacks instead of taking daily medications or repetitive injections that have several adverse effects.”
The findings were published online in the Journal of Headache and Pain.
Head-to-head comparison
Several clinical trials have shown exercise is effective for migraine management, but to date, there have been no head-to-head comparisons of strength training and aerobic exercise, said Dr. Woldeamanuel.
This new study used a systematic review with network meta-analysis (NMA), which compares multiple interventions and ranks the efficacy of each one.
After a literature search, researchers included 21 clinical trials with an exercise regimen arm and a comparison control arm. All study data reported monthly frequency of migraine at baseline and at the end of the intervention.
The total combined sample size was 1,195 patients with migraine, who were a mean age of 35.5 years, with a female-to-male ratio of 6.7:1. All studies used International Classification of Headache Disorders (ICHD) criteria for migraine diagnosis.
The NMA provided 27 pairwise comparisons and 8 indirect comparisons. The pairwise comparisons provided direct evidence between the different interventions.
Researchers combined strength training, including weightlifting, with resistance training. Both modalities target muscles, while aerobic exercise targets cardiovascular health.
The average number of weeks was 9.3, 9.3, and 10.7, and the average number of hours per session for strength/resistance training, high-intensity aerobic exercise, and moderate-intensity aerobic exercise interventions was 50, 56, and 45.3, respectively.
The analysis showed all exercise interventions were more effective than the placebo groups in reducing the frequency of migraine. In terms of ranking, strength training came out on top, with a mean difference in monthly migraine days of −3.55 (95% confidence interval, −6.15 to −0.95) between the active and placebo groups.
Next was high-intensity aerobic exercise (−3.13; 95% CI, −5.28 to −0.97) and moderate-intensity aerobic exercise (−2.18; 95% CI, −3.25 to −1.11), followed by topiramate, placebo, and then amitriptyline.
Strength/resistance training was superior possibly because it targets muscle strengthening, particularly major muscles in the neck and shoulder area, which can be a source of the pain trigger, said Dr. Woldeamanuel. He added neck pain is highly comorbid with migraine.
Interestingly, patients doing exercises that focus on unaffected muscles – for example, squats – still get the benefits of less migraine burden, said Dr. Woldeamanuel.
Training recommendations
Strength training also increases or preserves lean muscle mass, which is associated with reduced migraine frequency. Research shows preservation of lean body mass combats central sensitization in various pain syndromes, said Dr. Woldeamanuel.
The superior effects of high- versus moderate-intensity aerobic exercise may be due to recruitment of endogenous molecules involved in exercise-mediated hypoalgesia (pain reduction).
The most common pathways are the opioid and endocannabinoid systems, although other systems are also likely involved, said Dr. Woldeamanuel. He noted migraine has been linked to a deficiency of both opioidergic and endocannabinoidergic signaling.
Dr. Woldeamanuel commented on the difficulty of comparing exercise interventions for patients with chronic versus episodic migraine, as many studies include both.
However, the two studies with moderate-intensity aerobic exercise exclusively involving patients with chronic migraine showed large effect sizes (Cohen’s d) of 0.80 and 1.10 in reducing monthly headache frequency.
Based on these new results and their own experience, the researchers recommend strength training start with 50% of repetition maximum (RM) with 2-3 sets of 12-15 repetitions three times a week along with 10 minutes of warm-up, stretching, and cool-down, totaling 45-60 minutes per session. Weight/resistance load can then be increased weekly by 5% of RM if the patient is capable of successfully completing three sets.
They also recommend including active recovery days (low-intensity exercise) between training days. All major muscles, including neck, shoulder, and upper limb muscles, should be trained in a rotation.
For high-intensity aerobic exercise, the authors recommend starting with interval training at 55% VO2max (maximum respiratory capacity), or 50% HRmax (maximal heart rate) for 45-60 minutes per session, including 10 minutes of warm-up and cool-down, three times per week. The intensity can then be increased by 5%-10% each week to reach a maximum target of 80%-90% by week 12.
It is best for patients to start with a trainer for guidance and supervision, but once they master the routines, they can do the exercises independently, said Dr. Woldeamanuel.
Managing flare-ups
Headache flare-ups are normal during exercise, which may be caused by “boom and bust cycles” – exercising excessively when feeling good then completely stopping when feeling bad, said Dr. Woldeamanuel. He noted these flare-ups don’t mean “there’s something wrong with the brain or there’s some injury to muscles.”
The best way to manage such flare-ups is to use a pacing strategy that involves “not going overboard on good days and avoiding excessive rest on bad days,” the investigators note.
Dr. Woldeamanuel noted exercise is a lifestyle-based intervention; it not only helps reduce migraine attacks but also helps control other known comorbidities such as obesity and hypertension.
In a comment, Elizabeth Loder, MD, vice-chair, academic affairs, department of neurology, Brigham and Women’s Hospital, and professor of neurology, Harvard Medical School, both in Boston, said, “It’s useful to collect and summarize all of these studies, and to focus on helping patients and doctors understand the possible value of different kinds of exercise.”
The review was “well done,” said Dr. Loder, adding the researchers “have looked carefully at the quality of included studies.”
The study received support from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. Dr. Woldeamanuel has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
with high-intensity aerobics coming in second, and both beating top-line migraine medications topiramate and amitriptyline, new research suggests.
The new results should encourage clinicians to recommend patients with migraine engage in strength-training exercise whenever possible, study investigator Yohannes W. Woldeamanuel, MD, a physician-scientist and instructor, department of neurology and neurological sciences, Stanford (Calif.) University, told this news organization.
“Exercise is something patients can do all their lives and use it to prevent migraine attacks instead of taking daily medications or repetitive injections that have several adverse effects.”
The findings were published online in the Journal of Headache and Pain.
Head-to-head comparison
Several clinical trials have shown exercise is effective for migraine management, but to date, there have been no head-to-head comparisons of strength training and aerobic exercise, said Dr. Woldeamanuel.
This new study used a systematic review with network meta-analysis (NMA), which compares multiple interventions and ranks the efficacy of each one.
After a literature search, researchers included 21 clinical trials with an exercise regimen arm and a comparison control arm. All study data reported monthly frequency of migraine at baseline and at the end of the intervention.
The total combined sample size was 1,195 patients with migraine, who were a mean age of 35.5 years, with a female-to-male ratio of 6.7:1. All studies used International Classification of Headache Disorders (ICHD) criteria for migraine diagnosis.
The NMA provided 27 pairwise comparisons and 8 indirect comparisons. The pairwise comparisons provided direct evidence between the different interventions.
Researchers combined strength training, including weightlifting, with resistance training. Both modalities target muscles, while aerobic exercise targets cardiovascular health.
The average number of weeks was 9.3, 9.3, and 10.7, and the average number of hours per session for strength/resistance training, high-intensity aerobic exercise, and moderate-intensity aerobic exercise interventions was 50, 56, and 45.3, respectively.
The analysis showed all exercise interventions were more effective than the placebo groups in reducing the frequency of migraine. In terms of ranking, strength training came out on top, with a mean difference in monthly migraine days of −3.55 (95% confidence interval, −6.15 to −0.95) between the active and placebo groups.
Next was high-intensity aerobic exercise (−3.13; 95% CI, −5.28 to −0.97) and moderate-intensity aerobic exercise (−2.18; 95% CI, −3.25 to −1.11), followed by topiramate, placebo, and then amitriptyline.
Strength/resistance training was superior possibly because it targets muscle strengthening, particularly major muscles in the neck and shoulder area, which can be a source of the pain trigger, said Dr. Woldeamanuel. He added neck pain is highly comorbid with migraine.
Interestingly, patients doing exercises that focus on unaffected muscles – for example, squats – still get the benefits of less migraine burden, said Dr. Woldeamanuel.
Training recommendations
Strength training also increases or preserves lean muscle mass, which is associated with reduced migraine frequency. Research shows preservation of lean body mass combats central sensitization in various pain syndromes, said Dr. Woldeamanuel.
The superior effects of high- versus moderate-intensity aerobic exercise may be due to recruitment of endogenous molecules involved in exercise-mediated hypoalgesia (pain reduction).
The most common pathways are the opioid and endocannabinoid systems, although other systems are also likely involved, said Dr. Woldeamanuel. He noted migraine has been linked to a deficiency of both opioidergic and endocannabinoidergic signaling.
Dr. Woldeamanuel commented on the difficulty of comparing exercise interventions for patients with chronic versus episodic migraine, as many studies include both.
However, the two studies with moderate-intensity aerobic exercise exclusively involving patients with chronic migraine showed large effect sizes (Cohen’s d) of 0.80 and 1.10 in reducing monthly headache frequency.
Based on these new results and their own experience, the researchers recommend strength training start with 50% of repetition maximum (RM) with 2-3 sets of 12-15 repetitions three times a week along with 10 minutes of warm-up, stretching, and cool-down, totaling 45-60 minutes per session. Weight/resistance load can then be increased weekly by 5% of RM if the patient is capable of successfully completing three sets.
They also recommend including active recovery days (low-intensity exercise) between training days. All major muscles, including neck, shoulder, and upper limb muscles, should be trained in a rotation.
For high-intensity aerobic exercise, the authors recommend starting with interval training at 55% VO2max (maximum respiratory capacity), or 50% HRmax (maximal heart rate) for 45-60 minutes per session, including 10 minutes of warm-up and cool-down, three times per week. The intensity can then be increased by 5%-10% each week to reach a maximum target of 80%-90% by week 12.
It is best for patients to start with a trainer for guidance and supervision, but once they master the routines, they can do the exercises independently, said Dr. Woldeamanuel.
Managing flare-ups
Headache flare-ups are normal during exercise, which may be caused by “boom and bust cycles” – exercising excessively when feeling good then completely stopping when feeling bad, said Dr. Woldeamanuel. He noted these flare-ups don’t mean “there’s something wrong with the brain or there’s some injury to muscles.”
The best way to manage such flare-ups is to use a pacing strategy that involves “not going overboard on good days and avoiding excessive rest on bad days,” the investigators note.
Dr. Woldeamanuel noted exercise is a lifestyle-based intervention; it not only helps reduce migraine attacks but also helps control other known comorbidities such as obesity and hypertension.
In a comment, Elizabeth Loder, MD, vice-chair, academic affairs, department of neurology, Brigham and Women’s Hospital, and professor of neurology, Harvard Medical School, both in Boston, said, “It’s useful to collect and summarize all of these studies, and to focus on helping patients and doctors understand the possible value of different kinds of exercise.”
The review was “well done,” said Dr. Loder, adding the researchers “have looked carefully at the quality of included studies.”
The study received support from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. Dr. Woldeamanuel has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
with high-intensity aerobics coming in second, and both beating top-line migraine medications topiramate and amitriptyline, new research suggests.
The new results should encourage clinicians to recommend patients with migraine engage in strength-training exercise whenever possible, study investigator Yohannes W. Woldeamanuel, MD, a physician-scientist and instructor, department of neurology and neurological sciences, Stanford (Calif.) University, told this news organization.
“Exercise is something patients can do all their lives and use it to prevent migraine attacks instead of taking daily medications or repetitive injections that have several adverse effects.”
The findings were published online in the Journal of Headache and Pain.
Head-to-head comparison
Several clinical trials have shown exercise is effective for migraine management, but to date, there have been no head-to-head comparisons of strength training and aerobic exercise, said Dr. Woldeamanuel.
This new study used a systematic review with network meta-analysis (NMA), which compares multiple interventions and ranks the efficacy of each one.
After a literature search, researchers included 21 clinical trials with an exercise regimen arm and a comparison control arm. All study data reported monthly frequency of migraine at baseline and at the end of the intervention.
The total combined sample size was 1,195 patients with migraine, who were a mean age of 35.5 years, with a female-to-male ratio of 6.7:1. All studies used International Classification of Headache Disorders (ICHD) criteria for migraine diagnosis.
The NMA provided 27 pairwise comparisons and 8 indirect comparisons. The pairwise comparisons provided direct evidence between the different interventions.
Researchers combined strength training, including weightlifting, with resistance training. Both modalities target muscles, while aerobic exercise targets cardiovascular health.
The average number of weeks was 9.3, 9.3, and 10.7, and the average number of hours per session for strength/resistance training, high-intensity aerobic exercise, and moderate-intensity aerobic exercise interventions was 50, 56, and 45.3, respectively.
The analysis showed all exercise interventions were more effective than the placebo groups in reducing the frequency of migraine. In terms of ranking, strength training came out on top, with a mean difference in monthly migraine days of −3.55 (95% confidence interval, −6.15 to −0.95) between the active and placebo groups.
Next was high-intensity aerobic exercise (−3.13; 95% CI, −5.28 to −0.97) and moderate-intensity aerobic exercise (−2.18; 95% CI, −3.25 to −1.11), followed by topiramate, placebo, and then amitriptyline.
Strength/resistance training was superior possibly because it targets muscle strengthening, particularly major muscles in the neck and shoulder area, which can be a source of the pain trigger, said Dr. Woldeamanuel. He added neck pain is highly comorbid with migraine.
Interestingly, patients doing exercises that focus on unaffected muscles – for example, squats – still get the benefits of less migraine burden, said Dr. Woldeamanuel.
Training recommendations
Strength training also increases or preserves lean muscle mass, which is associated with reduced migraine frequency. Research shows preservation of lean body mass combats central sensitization in various pain syndromes, said Dr. Woldeamanuel.
The superior effects of high- versus moderate-intensity aerobic exercise may be due to recruitment of endogenous molecules involved in exercise-mediated hypoalgesia (pain reduction).
The most common pathways are the opioid and endocannabinoid systems, although other systems are also likely involved, said Dr. Woldeamanuel. He noted migraine has been linked to a deficiency of both opioidergic and endocannabinoidergic signaling.
Dr. Woldeamanuel commented on the difficulty of comparing exercise interventions for patients with chronic versus episodic migraine, as many studies include both.
However, the two studies with moderate-intensity aerobic exercise exclusively involving patients with chronic migraine showed large effect sizes (Cohen’s d) of 0.80 and 1.10 in reducing monthly headache frequency.
Based on these new results and their own experience, the researchers recommend strength training start with 50% of repetition maximum (RM) with 2-3 sets of 12-15 repetitions three times a week along with 10 minutes of warm-up, stretching, and cool-down, totaling 45-60 minutes per session. Weight/resistance load can then be increased weekly by 5% of RM if the patient is capable of successfully completing three sets.
They also recommend including active recovery days (low-intensity exercise) between training days. All major muscles, including neck, shoulder, and upper limb muscles, should be trained in a rotation.
For high-intensity aerobic exercise, the authors recommend starting with interval training at 55% VO2max (maximum respiratory capacity), or 50% HRmax (maximal heart rate) for 45-60 minutes per session, including 10 minutes of warm-up and cool-down, three times per week. The intensity can then be increased by 5%-10% each week to reach a maximum target of 80%-90% by week 12.
It is best for patients to start with a trainer for guidance and supervision, but once they master the routines, they can do the exercises independently, said Dr. Woldeamanuel.
Managing flare-ups
Headache flare-ups are normal during exercise, which may be caused by “boom and bust cycles” – exercising excessively when feeling good then completely stopping when feeling bad, said Dr. Woldeamanuel. He noted these flare-ups don’t mean “there’s something wrong with the brain or there’s some injury to muscles.”
The best way to manage such flare-ups is to use a pacing strategy that involves “not going overboard on good days and avoiding excessive rest on bad days,” the investigators note.
Dr. Woldeamanuel noted exercise is a lifestyle-based intervention; it not only helps reduce migraine attacks but also helps control other known comorbidities such as obesity and hypertension.
In a comment, Elizabeth Loder, MD, vice-chair, academic affairs, department of neurology, Brigham and Women’s Hospital, and professor of neurology, Harvard Medical School, both in Boston, said, “It’s useful to collect and summarize all of these studies, and to focus on helping patients and doctors understand the possible value of different kinds of exercise.”
The review was “well done,” said Dr. Loder, adding the researchers “have looked carefully at the quality of included studies.”
The study received support from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. Dr. Woldeamanuel has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JOURNAL OF HEADACHE AND PAIN
Meet the JCOM Author with Dr. Barkoudah: Neurosurgery Operating Room Efficiency During the COVID-19 Era
AAP issues clinical update to cerebral palsy guidelines
Updated clinical guidelines for the early diagnosis and management of cerebral palsy have been issued by the American Academy of Pediatrics.
Coauthored with the American Academy for Cerebral Palsy and Developmental Medicine, the report builds on new evidence for improved care and outcomes since the 2006 consensus guidelines.
Cerebral palsy, the most common neuromotor disorder of childhood, is often accompanied by cognitive impairments, epilepsy, sensory impairments, behavioral problems, communication difficulties, breathing and sleep problems, gastrointestinal and nutritional problems, and bone and orthopedic problems.
In the United States, the estimated prevalence of cerebral palsy ranges from 1.5 to 4 per 1,000 live births.
“Early identification and initiation of evidence-based motor therapies can improve outcomes by taking advantage of the neuroplasticity in the infant brain,” said the guideline authors in an executive summary.
The guideline, published in Pediatrics, is directed to primary care physicians with pediatrics, family practice, or internal medicine training. “It’s a much more comprehensive overview of the important role that primary care providers play in the lifetime care of people with cerebral palsy,” explained Garey Noritz, MD, chair of the 2021-2022 Executive Committee of the Council on Children with Disabilities. Dr. Noritz, a professor of pediatrics at Ohio State University and division chief of the complex health care program at Nationwide Children’s Hospital, both in Columbus, said: “The combined efforts of the primary care physician and specialty providers are needed to achieve the best outcomes.”
The AAP recommends that primary care pediatricians, neonatologists, and other specialists caring for hospitalized newborns recognize those at high risk of cerebral palsy, diagnose them as early as possible, and promptly refer them for therapy. Primary care physicians are advised to identify motor delays early by formalizing standardized developmental surveillance and screening at 9, 18, and 30 months, and to implement family-centered care across multiple specialists.
“If a motor disorder is suspected, primary care physicians should simultaneously begin a medical evaluation, refer to a specialist for definitive diagnosis, and to therapists for treatment,” Dr. Noritz emphasized.
“The earlier any possible movement disorder is recognized and intervention begins, the better a child can develop a gait pattern and work toward living an independent life, said Manish N. Shah, MD, associate professor of pediatric neurosurgery at the University of Texas, Houston, who was not involved in developing the guidelines.
For children in whom physical therapy and medication have not reduced leg spasticity, a minimally invasive spinal procedure can help release contracted tendons and encourage independent walking. The optimal age for selective dorsal rhizotomy is about 4 years, said Dr. Shah, who is director of the Texas Comprehensive Spasticity Center at Children’s Memorial Hermann Hospital in Houston. “You can turn these children into walkers. As adults, they can get jobs, have their own families. It’s life-changing.”
Importantly, the guidelines address the health care disparities leading to a higher prevalence of cerebral palsy in Black children and in those from families with lower socioeconomic status. “Efforts to combat racism and eliminate barriers to culturally sensitive prenatal, perinatal, and later pediatric care may help to improve outcomes for all children with cerebral palsy,” the authors said.
“Every child with cerebral palsy needs an individual plan, but only 30% or 40% are getting interventions,” said Dr. Shah. The updated guidelines could help payers rethink the 15-20 visits a year that are often approved, compared with the 2-3 visits per week that are needed for speech, physical, and occupational therapy, he pointed out.
“Financial issues often compromise the interdisciplinary and coordinated care associated with favorable outcomes in children with cerebral palsy,” said Heidi Feldman, MD, PhD, a developmental and behavioral pediatric specialist at Stanford (Calif.) Medicine Children’s Health’s Johnson Center for Pregnancy and Newborn Services. “With a new guideline, there may be greater willingness to fund these essential services.”
In the meantime, the AAP recommends that pediatricians advise families about available medical, social, and educational services, such as early intervention services, the Title V Maternal and Child Health block grant program, and special education services through the public school system.
Children with cerebral palsy need the same standardized primary care as any child, including the full schedule of recommended vaccinations and vision and hearing testing. They also need to be monitored and treated for the many problems that commonly co-occur, including chronic pain.
When secondary complications arise, the frequency of visits should increase.
Pneumonia, the leading cause of death in children and adolescents with cerebral palsy, can be prevented or minimized through immunization against respiratory diseases and screening for signs and symptoms of aspiration and sleep-disordered breathing.
The AAP also recommends that symptoms or functional declines undergo full investigation into other potential causes.
Since the sedentary lifestyle associated with cerebral palsy is now known to be related to the higher rates of cardiovascular complications in this patient population, the AAP recommends more attention be paid to physical activity and a healthy diet early in life. Pediatricians are advised to help families locate suitable opportunities for adaptive sports and recreation.
Almost 50% of children and adolescents with cerebral palsy have intellectual disability, 60%-80% have difficulty speaking, and about 25% are nonverbal. To address this, pediatricians should maximize the use of augmentative and alternative communication devices and involve experts in speech and language pathology, according to the guidelines.
“Many individuals with cerebral palsy and severe motor limitations have active, creative minds, and may need assistive technology, such as electronic talking devices, to demonstrate that mental life,” said Dr. Feldman. “Primary care clinicians should advocate for assistive technology.”
For challenging behavior, especially in the patient with limited verbal skills, potential nonbehavioral culprits such as constipation, esophageal reflux disease, and musculoskeletal or dental pain must be ruled out.
In the lead-up to adolescence, youth with cerebral palsy must be prepared for puberty, menstruation, and healthy, safe sexual relationships, much like their nonaffected peers. Since a disproportionate number of children with cerebral palsy experience neglect and physical, sexual, and emotional abuse, however, family stressors should be identified and caregivers referred for support services.
For the transition from pediatric to adult health care, the AAP recommends that structured planning begin between 12 and 14 years of age. Before transfer, the pediatrician should prepare a comprehensive medical summary with the input of the patient, parent/guardian, and pediatric subspecialists.
Without a proper handoff, “there is an increased risk of morbidity, medical complications, unnecessary emergency department visits, hospitalizations, and procedures,” the authors warned.
Transitions are likely to run more smoothly when youth are given the opportunity to understand their medical condition and be involved in decisions about their health. With this in mind, the AAP recommends that pediatricians actively discourage overprotective parents from getting in the way of their child developing “maximal independence.”
No potential conflicts of interest were disclosed by the authors, Dr. Shah, or Dr. Feldman.
*This story was updated on Nov. 28, 2022.
Updated clinical guidelines for the early diagnosis and management of cerebral palsy have been issued by the American Academy of Pediatrics.
Coauthored with the American Academy for Cerebral Palsy and Developmental Medicine, the report builds on new evidence for improved care and outcomes since the 2006 consensus guidelines.
Cerebral palsy, the most common neuromotor disorder of childhood, is often accompanied by cognitive impairments, epilepsy, sensory impairments, behavioral problems, communication difficulties, breathing and sleep problems, gastrointestinal and nutritional problems, and bone and orthopedic problems.
In the United States, the estimated prevalence of cerebral palsy ranges from 1.5 to 4 per 1,000 live births.
“Early identification and initiation of evidence-based motor therapies can improve outcomes by taking advantage of the neuroplasticity in the infant brain,” said the guideline authors in an executive summary.
The guideline, published in Pediatrics, is directed to primary care physicians with pediatrics, family practice, or internal medicine training. “It’s a much more comprehensive overview of the important role that primary care providers play in the lifetime care of people with cerebral palsy,” explained Garey Noritz, MD, chair of the 2021-2022 Executive Committee of the Council on Children with Disabilities. Dr. Noritz, a professor of pediatrics at Ohio State University and division chief of the complex health care program at Nationwide Children’s Hospital, both in Columbus, said: “The combined efforts of the primary care physician and specialty providers are needed to achieve the best outcomes.”
The AAP recommends that primary care pediatricians, neonatologists, and other specialists caring for hospitalized newborns recognize those at high risk of cerebral palsy, diagnose them as early as possible, and promptly refer them for therapy. Primary care physicians are advised to identify motor delays early by formalizing standardized developmental surveillance and screening at 9, 18, and 30 months, and to implement family-centered care across multiple specialists.
“If a motor disorder is suspected, primary care physicians should simultaneously begin a medical evaluation, refer to a specialist for definitive diagnosis, and to therapists for treatment,” Dr. Noritz emphasized.
“The earlier any possible movement disorder is recognized and intervention begins, the better a child can develop a gait pattern and work toward living an independent life, said Manish N. Shah, MD, associate professor of pediatric neurosurgery at the University of Texas, Houston, who was not involved in developing the guidelines.
For children in whom physical therapy and medication have not reduced leg spasticity, a minimally invasive spinal procedure can help release contracted tendons and encourage independent walking. The optimal age for selective dorsal rhizotomy is about 4 years, said Dr. Shah, who is director of the Texas Comprehensive Spasticity Center at Children’s Memorial Hermann Hospital in Houston. “You can turn these children into walkers. As adults, they can get jobs, have their own families. It’s life-changing.”
Importantly, the guidelines address the health care disparities leading to a higher prevalence of cerebral palsy in Black children and in those from families with lower socioeconomic status. “Efforts to combat racism and eliminate barriers to culturally sensitive prenatal, perinatal, and later pediatric care may help to improve outcomes for all children with cerebral palsy,” the authors said.
“Every child with cerebral palsy needs an individual plan, but only 30% or 40% are getting interventions,” said Dr. Shah. The updated guidelines could help payers rethink the 15-20 visits a year that are often approved, compared with the 2-3 visits per week that are needed for speech, physical, and occupational therapy, he pointed out.
“Financial issues often compromise the interdisciplinary and coordinated care associated with favorable outcomes in children with cerebral palsy,” said Heidi Feldman, MD, PhD, a developmental and behavioral pediatric specialist at Stanford (Calif.) Medicine Children’s Health’s Johnson Center for Pregnancy and Newborn Services. “With a new guideline, there may be greater willingness to fund these essential services.”
In the meantime, the AAP recommends that pediatricians advise families about available medical, social, and educational services, such as early intervention services, the Title V Maternal and Child Health block grant program, and special education services through the public school system.
Children with cerebral palsy need the same standardized primary care as any child, including the full schedule of recommended vaccinations and vision and hearing testing. They also need to be monitored and treated for the many problems that commonly co-occur, including chronic pain.
When secondary complications arise, the frequency of visits should increase.
Pneumonia, the leading cause of death in children and adolescents with cerebral palsy, can be prevented or minimized through immunization against respiratory diseases and screening for signs and symptoms of aspiration and sleep-disordered breathing.
The AAP also recommends that symptoms or functional declines undergo full investigation into other potential causes.
Since the sedentary lifestyle associated with cerebral palsy is now known to be related to the higher rates of cardiovascular complications in this patient population, the AAP recommends more attention be paid to physical activity and a healthy diet early in life. Pediatricians are advised to help families locate suitable opportunities for adaptive sports and recreation.
Almost 50% of children and adolescents with cerebral palsy have intellectual disability, 60%-80% have difficulty speaking, and about 25% are nonverbal. To address this, pediatricians should maximize the use of augmentative and alternative communication devices and involve experts in speech and language pathology, according to the guidelines.
“Many individuals with cerebral palsy and severe motor limitations have active, creative minds, and may need assistive technology, such as electronic talking devices, to demonstrate that mental life,” said Dr. Feldman. “Primary care clinicians should advocate for assistive technology.”
For challenging behavior, especially in the patient with limited verbal skills, potential nonbehavioral culprits such as constipation, esophageal reflux disease, and musculoskeletal or dental pain must be ruled out.
In the lead-up to adolescence, youth with cerebral palsy must be prepared for puberty, menstruation, and healthy, safe sexual relationships, much like their nonaffected peers. Since a disproportionate number of children with cerebral palsy experience neglect and physical, sexual, and emotional abuse, however, family stressors should be identified and caregivers referred for support services.
For the transition from pediatric to adult health care, the AAP recommends that structured planning begin between 12 and 14 years of age. Before transfer, the pediatrician should prepare a comprehensive medical summary with the input of the patient, parent/guardian, and pediatric subspecialists.
Without a proper handoff, “there is an increased risk of morbidity, medical complications, unnecessary emergency department visits, hospitalizations, and procedures,” the authors warned.
Transitions are likely to run more smoothly when youth are given the opportunity to understand their medical condition and be involved in decisions about their health. With this in mind, the AAP recommends that pediatricians actively discourage overprotective parents from getting in the way of their child developing “maximal independence.”
No potential conflicts of interest were disclosed by the authors, Dr. Shah, or Dr. Feldman.
*This story was updated on Nov. 28, 2022.
Updated clinical guidelines for the early diagnosis and management of cerebral palsy have been issued by the American Academy of Pediatrics.
Coauthored with the American Academy for Cerebral Palsy and Developmental Medicine, the report builds on new evidence for improved care and outcomes since the 2006 consensus guidelines.
Cerebral palsy, the most common neuromotor disorder of childhood, is often accompanied by cognitive impairments, epilepsy, sensory impairments, behavioral problems, communication difficulties, breathing and sleep problems, gastrointestinal and nutritional problems, and bone and orthopedic problems.
In the United States, the estimated prevalence of cerebral palsy ranges from 1.5 to 4 per 1,000 live births.
“Early identification and initiation of evidence-based motor therapies can improve outcomes by taking advantage of the neuroplasticity in the infant brain,” said the guideline authors in an executive summary.
The guideline, published in Pediatrics, is directed to primary care physicians with pediatrics, family practice, or internal medicine training. “It’s a much more comprehensive overview of the important role that primary care providers play in the lifetime care of people with cerebral palsy,” explained Garey Noritz, MD, chair of the 2021-2022 Executive Committee of the Council on Children with Disabilities. Dr. Noritz, a professor of pediatrics at Ohio State University and division chief of the complex health care program at Nationwide Children’s Hospital, both in Columbus, said: “The combined efforts of the primary care physician and specialty providers are needed to achieve the best outcomes.”
The AAP recommends that primary care pediatricians, neonatologists, and other specialists caring for hospitalized newborns recognize those at high risk of cerebral palsy, diagnose them as early as possible, and promptly refer them for therapy. Primary care physicians are advised to identify motor delays early by formalizing standardized developmental surveillance and screening at 9, 18, and 30 months, and to implement family-centered care across multiple specialists.
“If a motor disorder is suspected, primary care physicians should simultaneously begin a medical evaluation, refer to a specialist for definitive diagnosis, and to therapists for treatment,” Dr. Noritz emphasized.
“The earlier any possible movement disorder is recognized and intervention begins, the better a child can develop a gait pattern and work toward living an independent life, said Manish N. Shah, MD, associate professor of pediatric neurosurgery at the University of Texas, Houston, who was not involved in developing the guidelines.
For children in whom physical therapy and medication have not reduced leg spasticity, a minimally invasive spinal procedure can help release contracted tendons and encourage independent walking. The optimal age for selective dorsal rhizotomy is about 4 years, said Dr. Shah, who is director of the Texas Comprehensive Spasticity Center at Children’s Memorial Hermann Hospital in Houston. “You can turn these children into walkers. As adults, they can get jobs, have their own families. It’s life-changing.”
Importantly, the guidelines address the health care disparities leading to a higher prevalence of cerebral palsy in Black children and in those from families with lower socioeconomic status. “Efforts to combat racism and eliminate barriers to culturally sensitive prenatal, perinatal, and later pediatric care may help to improve outcomes for all children with cerebral palsy,” the authors said.
“Every child with cerebral palsy needs an individual plan, but only 30% or 40% are getting interventions,” said Dr. Shah. The updated guidelines could help payers rethink the 15-20 visits a year that are often approved, compared with the 2-3 visits per week that are needed for speech, physical, and occupational therapy, he pointed out.
“Financial issues often compromise the interdisciplinary and coordinated care associated with favorable outcomes in children with cerebral palsy,” said Heidi Feldman, MD, PhD, a developmental and behavioral pediatric specialist at Stanford (Calif.) Medicine Children’s Health’s Johnson Center for Pregnancy and Newborn Services. “With a new guideline, there may be greater willingness to fund these essential services.”
In the meantime, the AAP recommends that pediatricians advise families about available medical, social, and educational services, such as early intervention services, the Title V Maternal and Child Health block grant program, and special education services through the public school system.
Children with cerebral palsy need the same standardized primary care as any child, including the full schedule of recommended vaccinations and vision and hearing testing. They also need to be monitored and treated for the many problems that commonly co-occur, including chronic pain.
When secondary complications arise, the frequency of visits should increase.
Pneumonia, the leading cause of death in children and adolescents with cerebral palsy, can be prevented or minimized through immunization against respiratory diseases and screening for signs and symptoms of aspiration and sleep-disordered breathing.
The AAP also recommends that symptoms or functional declines undergo full investigation into other potential causes.
Since the sedentary lifestyle associated with cerebral palsy is now known to be related to the higher rates of cardiovascular complications in this patient population, the AAP recommends more attention be paid to physical activity and a healthy diet early in life. Pediatricians are advised to help families locate suitable opportunities for adaptive sports and recreation.
Almost 50% of children and adolescents with cerebral palsy have intellectual disability, 60%-80% have difficulty speaking, and about 25% are nonverbal. To address this, pediatricians should maximize the use of augmentative and alternative communication devices and involve experts in speech and language pathology, according to the guidelines.
“Many individuals with cerebral palsy and severe motor limitations have active, creative minds, and may need assistive technology, such as electronic talking devices, to demonstrate that mental life,” said Dr. Feldman. “Primary care clinicians should advocate for assistive technology.”
For challenging behavior, especially in the patient with limited verbal skills, potential nonbehavioral culprits such as constipation, esophageal reflux disease, and musculoskeletal or dental pain must be ruled out.
In the lead-up to adolescence, youth with cerebral palsy must be prepared for puberty, menstruation, and healthy, safe sexual relationships, much like their nonaffected peers. Since a disproportionate number of children with cerebral palsy experience neglect and physical, sexual, and emotional abuse, however, family stressors should be identified and caregivers referred for support services.
For the transition from pediatric to adult health care, the AAP recommends that structured planning begin between 12 and 14 years of age. Before transfer, the pediatrician should prepare a comprehensive medical summary with the input of the patient, parent/guardian, and pediatric subspecialists.
Without a proper handoff, “there is an increased risk of morbidity, medical complications, unnecessary emergency department visits, hospitalizations, and procedures,” the authors warned.
Transitions are likely to run more smoothly when youth are given the opportunity to understand their medical condition and be involved in decisions about their health. With this in mind, the AAP recommends that pediatricians actively discourage overprotective parents from getting in the way of their child developing “maximal independence.”
No potential conflicts of interest were disclosed by the authors, Dr. Shah, or Dr. Feldman.
*This story was updated on Nov. 28, 2022.
FROM PEDIATRICS