Neurology

ILLUSTRATIVE CASE

A 16-year-old girl with no chronic medical illness presents to your office with her parents after sustaining a head injury at a soccer game over the weekend. She collided with another player while attempting to head the ball. Immediately afterward, she was taken off the field and assessed. She was confused but had a normal level of consciousness and denied vision changes, weakness or tingling in her arms or legs, severe headache, or neck pain. Further testing revealed dizziness and abnormal balance. Her confusion and abnormal balance resolved after 1 day. She has had a mild headache and light sensitivity since the event. She otherwise feels well at rest in the office. She wants to recover quickly but safely and has heard conflicting statements about whether she should completely rest or start back to light activity now.

Sports-related concussions (SRCs) are highly prevalent in the United States, with as many as 3.8 million cases annually. Of those, 1.1 to 1.9 million cases are in children 18 years old or younger.^2,3 SRCs are defined by the Concussion in Sport Group (CISG) 2017 consensus statement as involving the following criteria: (1) direct or indirect trauma anywhere on the body with force transmitted to the head; (2) rapid or delayed symptom presentation, typically with spontaneous resolution; (3) functional rather than structural injury; and (4) occurrence with or without loss of consciousness with stepwise symptom resolution.⁴

SRCs do not have a proven, effective treatment and can have short- or long-term consequences. Initial treatment includes removing athletes from play immediately after an event. The American Academy of Neurology recommends that athletes not return to play until the concussion is resolved, as judged by a health care provider, and the athlete is asymptomatic when off medication.²

The CISG recommends a 6-step approach, with each step taking at least 24 hours.⁴ The final step is a return to normal activity.⁴ This working group recommended extensive study of rehabilitation programs involving subsymptom threshold exercise (ie, exercise performed at a level that does not exacerbate symptoms) before implementation as routine practice. Evidence from a 2015 study suggests that following strict rest for 5 days until complete symptom resolution may prolong recovery compared with rest for only 1 to 2 days.⁵ Additionally, strict rest did not show a difference in neurocognitive or balance outcomes in that study, and the authors noted it may also negatively impact academic, sports, and social function in adolescents.⁵ This study looked at the potential benefit of subsymptom threshold exercise during recovery from SRC.¹

STUDY SUMMARY

Light aerobic exercise may help speed recovery

This multicenter, prospective, parallel, randomized clinical trial compared subsymptom threshold aerobic exercise to ­placebo-like stretching. Patients were included if they were ages 13 to 18 years and presented within 10 days of an SRC, as diagnosed using the CISG criteria. Exclusion criteria included focal neurologic deficits; history of moderate or severe traumatic brain injury; inability to exercise due to orthopedic injury, cervical spine injury, diabetes, or heart disease; increased cardiac risk; or low postconcussion symptom severity. Patients with a diagnosis of and treatment with medication for ­attention-deficit/hyperactivity disorder (ADHD), depression, anxiety, or learning disorder were excluded, as were patients with a history of more than 3 previous concussions.

It’s unclear whether subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with > 3 concussions were excluded from this study.

Patients in the aerobic exercise group were instructed to use a stationary bike or treadmill (or equivalent walking or jogging if they did not have access to this equipment) at a prescribed heart rate. The target heart rate was 80% of the heart rate achieved during initial assessment with the Buffalo Concussion Treadmill Test (BCTT).⁶ Patients in this group were instructed to exercise for 20 minutes or to the point at which their symptoms increased by 2 points (on a 10-point scale) from pre-exercise levels, whichever came first, with rest prescribed at all other times.

For the placebo-like group, a stretching instruction booklet was provided, with the goal of achieving a heart rate that was not significantly elevated. Participants in this group were told to perform the stretches for 20 minutes daily. Of note, researchers ensured the level of physician and research staff attention was similar for each patient, regardless of treatment group, to prevent intervention bias. Additionally, interventions were not initiated prior to 48 hours from the time of injury.

Continue to: The primary outcome...

The primary outcome was number of days to recovery since the date of injury. This was defined as symptom resolution to normal (as evaluated by a physician blinded to the study group) and by the patient’s ability to exercise to exhaustion without symptom exacerbation on the BCTT. Secondary outcomes measured the proportion of patients with delayed recovery (defined as recovery requiring > 30 days) and daily symptom scores.

Of 165 patients meeting the inclusion criteria, 52 patients were excluded prior to randomization (12 patients chose not to participate, 39 were excluded for lack of symptoms, and 1 withdrew due to severe symptoms on the BCTT). A total of 113 were randomized to either group, and 103 patients completed the study (10 patients did not complete the study or had another illness during the intervention). The study analysis included 52 patients in the aerobic exercise group and 51 in the placebo-like stretching group. The study was powered to detect a significant difference in recovery time.

Patients were about equally divided by sex, with a mean age of 15 years. Patients who had no previous concussion made up 50% of the aerobic group and 57% of the stretching group. The average time since injury was similar in the aerobic and stretching groups (4.9 days and 4.8 days, respectively). The aerobic exercise group recovered in a median of 13 days (interquartile range [IQR] = 10-18.5 days) compared with a median of 17 days (IQR = 13-23 days) for the stretching group (P = .009). The incidence of delayed recovery (> 30 days) was higher in the stretching group (n = 7) compared with the aerobic exercise group (n = 2) but was not statistically significant. Daily symptom reporting occurred at a high rate in both groups, with patients stating that they performed their prescribed exercise 89% of the time. No adverse events were reported.

WHAT’S NEW

First high-quality study to support evidence for early light activity

This is the first high-quality study of subsymptom threshold exercise for SRC. Its findings add to the growing body of evidence that early engagement in light aerobic activity that does not provoke symptoms (but not fully returning to sports activity) can aid in recovery from an SRC.

CAVEATS

Narrow study population limits application of findings

It is unclear if subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with more than 3 concussions were excluded from this study. Additionally, patients with comorbidities such as ADHD, depression, anxiety, or learning disorders were not included in this study, which limits the application of these findings. The generalizability of this study is limited in younger children, adults, those with increased cardiovascular risk, and in patients with concussions that are not sports related.

CHALLENGES TO IMPLEMENTATION

More real-world studies needed to confirm benefit

The majority of adolescent athletes in this study completed the subsymptom threshold exercise in a monitored environment with trainers, heart rate monitors, and access to equipment, limiting the study’s generalizability. Additionally, physicians need to be familiar with the BCTT to assign heart rate goals and assess improvement. The study environment may be feasible for some but not others. Studies evaluating real-world settings with athletes self-monitoring for symptom threshold with stepwise evaluations are needed and may be more broadly applicable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 16-year-old girl with no chronic medical illness presents to your office with her parents after sustaining a head injury at a soccer game over the weekend. She collided with another player while attempting to head the ball. Immediately afterward, she was taken off the field and assessed. She was confused but had a normal level of consciousness and denied vision changes, weakness or tingling in her arms or legs, severe headache, or neck pain. Further testing revealed dizziness and abnormal balance. Her confusion and abnormal balance resolved after 1 day. She has had a mild headache and light sensitivity since the event. She otherwise feels well at rest in the office. She wants to recover quickly but safely and has heard conflicting statements about whether she should completely rest or start back to light activity now.

Sports-related concussions (SRCs) are highly prevalent in the United States, with as many as 3.8 million cases annually. Of those, 1.1 to 1.9 million cases are in children 18 years old or younger.^2,3 SRCs are defined by the Concussion in Sport Group (CISG) 2017 consensus statement as involving the following criteria: (1) direct or indirect trauma anywhere on the body with force transmitted to the head; (2) rapid or delayed symptom presentation, typically with spontaneous resolution; (3) functional rather than structural injury; and (4) occurrence with or without loss of consciousness with stepwise symptom resolution.⁴

SRCs do not have a proven, effective treatment and can have short- or long-term consequences. Initial treatment includes removing athletes from play immediately after an event. The American Academy of Neurology recommends that athletes not return to play until the concussion is resolved, as judged by a health care provider, and the athlete is asymptomatic when off medication.²

The CISG recommends a 6-step approach, with each step taking at least 24 hours.⁴ The final step is a return to normal activity.⁴ This working group recommended extensive study of rehabilitation programs involving subsymptom threshold exercise (ie, exercise performed at a level that does not exacerbate symptoms) before implementation as routine practice. Evidence from a 2015 study suggests that following strict rest for 5 days until complete symptom resolution may prolong recovery compared with rest for only 1 to 2 days.⁵ Additionally, strict rest did not show a difference in neurocognitive or balance outcomes in that study, and the authors noted it may also negatively impact academic, sports, and social function in adolescents.⁵ This study looked at the potential benefit of subsymptom threshold exercise during recovery from SRC.¹

STUDY SUMMARY

Light aerobic exercise may help speed recovery

This multicenter, prospective, parallel, randomized clinical trial compared subsymptom threshold aerobic exercise to ­placebo-like stretching. Patients were included if they were ages 13 to 18 years and presented within 10 days of an SRC, as diagnosed using the CISG criteria. Exclusion criteria included focal neurologic deficits; history of moderate or severe traumatic brain injury; inability to exercise due to orthopedic injury, cervical spine injury, diabetes, or heart disease; increased cardiac risk; or low postconcussion symptom severity. Patients with a diagnosis of and treatment with medication for ­attention-deficit/hyperactivity disorder (ADHD), depression, anxiety, or learning disorder were excluded, as were patients with a history of more than 3 previous concussions.

It’s unclear whether subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with > 3 concussions were excluded from this study.

Patients in the aerobic exercise group were instructed to use a stationary bike or treadmill (or equivalent walking or jogging if they did not have access to this equipment) at a prescribed heart rate. The target heart rate was 80% of the heart rate achieved during initial assessment with the Buffalo Concussion Treadmill Test (BCTT).⁶ Patients in this group were instructed to exercise for 20 minutes or to the point at which their symptoms increased by 2 points (on a 10-point scale) from pre-exercise levels, whichever came first, with rest prescribed at all other times.

For the placebo-like group, a stretching instruction booklet was provided, with the goal of achieving a heart rate that was not significantly elevated. Participants in this group were told to perform the stretches for 20 minutes daily. Of note, researchers ensured the level of physician and research staff attention was similar for each patient, regardless of treatment group, to prevent intervention bias. Additionally, interventions were not initiated prior to 48 hours from the time of injury.

Continue to: The primary outcome...

The primary outcome was number of days to recovery since the date of injury. This was defined as symptom resolution to normal (as evaluated by a physician blinded to the study group) and by the patient’s ability to exercise to exhaustion without symptom exacerbation on the BCTT. Secondary outcomes measured the proportion of patients with delayed recovery (defined as recovery requiring > 30 days) and daily symptom scores.

Of 165 patients meeting the inclusion criteria, 52 patients were excluded prior to randomization (12 patients chose not to participate, 39 were excluded for lack of symptoms, and 1 withdrew due to severe symptoms on the BCTT). A total of 113 were randomized to either group, and 103 patients completed the study (10 patients did not complete the study or had another illness during the intervention). The study analysis included 52 patients in the aerobic exercise group and 51 in the placebo-like stretching group. The study was powered to detect a significant difference in recovery time.

Patients were about equally divided by sex, with a mean age of 15 years. Patients who had no previous concussion made up 50% of the aerobic group and 57% of the stretching group. The average time since injury was similar in the aerobic and stretching groups (4.9 days and 4.8 days, respectively). The aerobic exercise group recovered in a median of 13 days (interquartile range [IQR] = 10-18.5 days) compared with a median of 17 days (IQR = 13-23 days) for the stretching group (P = .009). The incidence of delayed recovery (> 30 days) was higher in the stretching group (n = 7) compared with the aerobic exercise group (n = 2) but was not statistically significant. Daily symptom reporting occurred at a high rate in both groups, with patients stating that they performed their prescribed exercise 89% of the time. No adverse events were reported.

WHAT’S NEW

First high-quality study to support evidence for early light activity

This is the first high-quality study of subsymptom threshold exercise for SRC. Its findings add to the growing body of evidence that early engagement in light aerobic activity that does not provoke symptoms (but not fully returning to sports activity) can aid in recovery from an SRC.

CAVEATS

Narrow study population limits application of findings

It is unclear if subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with more than 3 concussions were excluded from this study. Additionally, patients with comorbidities such as ADHD, depression, anxiety, or learning disorders were not included in this study, which limits the application of these findings. The generalizability of this study is limited in younger children, adults, those with increased cardiovascular risk, and in patients with concussions that are not sports related.

CHALLENGES TO IMPLEMENTATION

More real-world studies needed to confirm benefit

The majority of adolescent athletes in this study completed the subsymptom threshold exercise in a monitored environment with trainers, heart rate monitors, and access to equipment, limiting the study’s generalizability. Additionally, physicians need to be familiar with the BCTT to assign heart rate goals and assess improvement. The study environment may be feasible for some but not others. Studies evaluating real-world settings with athletes self-monitoring for symptom threshold with stepwise evaluations are needed and may be more broadly applicable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 16-year-old girl with no chronic medical illness presents to your office with her parents after sustaining a head injury at a soccer game over the weekend. She collided with another player while attempting to head the ball. Immediately afterward, she was taken off the field and assessed. She was confused but had a normal level of consciousness and denied vision changes, weakness or tingling in her arms or legs, severe headache, or neck pain. Further testing revealed dizziness and abnormal balance. Her confusion and abnormal balance resolved after 1 day. She has had a mild headache and light sensitivity since the event. She otherwise feels well at rest in the office. She wants to recover quickly but safely and has heard conflicting statements about whether she should completely rest or start back to light activity now.

Sports-related concussions (SRCs) are highly prevalent in the United States, with as many as 3.8 million cases annually. Of those, 1.1 to 1.9 million cases are in children 18 years old or younger.^2,3 SRCs are defined by the Concussion in Sport Group (CISG) 2017 consensus statement as involving the following criteria: (1) direct or indirect trauma anywhere on the body with force transmitted to the head; (2) rapid or delayed symptom presentation, typically with spontaneous resolution; (3) functional rather than structural injury; and (4) occurrence with or without loss of consciousness with stepwise symptom resolution.⁴

SRCs do not have a proven, effective treatment and can have short- or long-term consequences. Initial treatment includes removing athletes from play immediately after an event. The American Academy of Neurology recommends that athletes not return to play until the concussion is resolved, as judged by a health care provider, and the athlete is asymptomatic when off medication.²

The CISG recommends a 6-step approach, with each step taking at least 24 hours.⁴ The final step is a return to normal activity.⁴ This working group recommended extensive study of rehabilitation programs involving subsymptom threshold exercise (ie, exercise performed at a level that does not exacerbate symptoms) before implementation as routine practice. Evidence from a 2015 study suggests that following strict rest for 5 days until complete symptom resolution may prolong recovery compared with rest for only 1 to 2 days.⁵ Additionally, strict rest did not show a difference in neurocognitive or balance outcomes in that study, and the authors noted it may also negatively impact academic, sports, and social function in adolescents.⁵ This study looked at the potential benefit of subsymptom threshold exercise during recovery from SRC.¹

STUDY SUMMARY

Light aerobic exercise may help speed recovery

This multicenter, prospective, parallel, randomized clinical trial compared subsymptom threshold aerobic exercise to ­placebo-like stretching. Patients were included if they were ages 13 to 18 years and presented within 10 days of an SRC, as diagnosed using the CISG criteria. Exclusion criteria included focal neurologic deficits; history of moderate or severe traumatic brain injury; inability to exercise due to orthopedic injury, cervical spine injury, diabetes, or heart disease; increased cardiac risk; or low postconcussion symptom severity. Patients with a diagnosis of and treatment with medication for ­attention-deficit/hyperactivity disorder (ADHD), depression, anxiety, or learning disorder were excluded, as were patients with a history of more than 3 previous concussions.

It’s unclear whether subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with > 3 concussions were excluded from this study.

Patients in the aerobic exercise group were instructed to use a stationary bike or treadmill (or equivalent walking or jogging if they did not have access to this equipment) at a prescribed heart rate. The target heart rate was 80% of the heart rate achieved during initial assessment with the Buffalo Concussion Treadmill Test (BCTT).⁶ Patients in this group were instructed to exercise for 20 minutes or to the point at which their symptoms increased by 2 points (on a 10-point scale) from pre-exercise levels, whichever came first, with rest prescribed at all other times.

For the placebo-like group, a stretching instruction booklet was provided, with the goal of achieving a heart rate that was not significantly elevated. Participants in this group were told to perform the stretches for 20 minutes daily. Of note, researchers ensured the level of physician and research staff attention was similar for each patient, regardless of treatment group, to prevent intervention bias. Additionally, interventions were not initiated prior to 48 hours from the time of injury.

Continue to: The primary outcome...

The primary outcome was number of days to recovery since the date of injury. This was defined as symptom resolution to normal (as evaluated by a physician blinded to the study group) and by the patient’s ability to exercise to exhaustion without symptom exacerbation on the BCTT. Secondary outcomes measured the proportion of patients with delayed recovery (defined as recovery requiring > 30 days) and daily symptom scores.

Of 165 patients meeting the inclusion criteria, 52 patients were excluded prior to randomization (12 patients chose not to participate, 39 were excluded for lack of symptoms, and 1 withdrew due to severe symptoms on the BCTT). A total of 113 were randomized to either group, and 103 patients completed the study (10 patients did not complete the study or had another illness during the intervention). The study analysis included 52 patients in the aerobic exercise group and 51 in the placebo-like stretching group. The study was powered to detect a significant difference in recovery time.

Patients were about equally divided by sex, with a mean age of 15 years. Patients who had no previous concussion made up 50% of the aerobic group and 57% of the stretching group. The average time since injury was similar in the aerobic and stretching groups (4.9 days and 4.8 days, respectively). The aerobic exercise group recovered in a median of 13 days (interquartile range [IQR] = 10-18.5 days) compared with a median of 17 days (IQR = 13-23 days) for the stretching group (P = .009). The incidence of delayed recovery (> 30 days) was higher in the stretching group (n = 7) compared with the aerobic exercise group (n = 2) but was not statistically significant. Daily symptom reporting occurred at a high rate in both groups, with patients stating that they performed their prescribed exercise 89% of the time. No adverse events were reported.

WHAT’S NEW

First high-quality study to support evidence for early light activity

This is the first high-quality study of subsymptom threshold exercise for SRC. Its findings add to the growing body of evidence that early engagement in light aerobic activity that does not provoke symptoms (but not fully returning to sports activity) can aid in recovery from an SRC.

CAVEATS

Narrow study population limits application of findings

It is unclear if subsymptom threshold exercise is safe and effective in adolescents with a history of multiple concussions, as those with more than 3 concussions were excluded from this study. Additionally, patients with comorbidities such as ADHD, depression, anxiety, or learning disorders were not included in this study, which limits the application of these findings. The generalizability of this study is limited in younger children, adults, those with increased cardiovascular risk, and in patients with concussions that are not sports related.

CHALLENGES TO IMPLEMENTATION

More real-world studies needed to confirm benefit

The majority of adolescent athletes in this study completed the subsymptom threshold exercise in a monitored environment with trainers, heart rate monitors, and access to equipment, limiting the study’s generalizability. Additionally, physicians need to be familiar with the BCTT to assign heart rate goals and assess improvement. The study environment may be feasible for some but not others. Studies evaluating real-world settings with athletes self-monitoring for symptom threshold with stepwise evaluations are needed and may be more broadly applicable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Topiramate, introduced as an antiepileptic drug (AED), is currently most widely used for prevention of migraine headaches.

Because reproductive-aged women represent a population in which migraines are prevalent, clinicians need guidance to help women taking topiramate make sound contraceptive choices.

Several issues are relevant here. First, women who have migraines with aura should avoid estrogen-containing contraceptive pills, patches, and rings. Instead, progestin-only methods, including the contraceptive implant, may be recommended to patients with migraines.

Second, because topiramate, as with a number of other AEDs, is a teratogen, women using this medication need highly effective contraception. This consideration may also lead clinicians to recommend use of the implant in women with migraines.

Finally, topiramate, along with other AEDs (phenytoin, carbamazepine, barbiturates, primidone, and oxcarbazepine) induces hepatic enzymes, which results in reduced serum contraceptive steroid levels.

Because there is uncertainty regarding the degree to which the use of topiramate reduces serum levels of etonogestrel (the progestin released by the implant), investigators performed a prospective study to assess the pharmacokinetic impact of topiramate in women with the implant.

Ongoing users of contraceptive implants who agreed to use additional nonhormonal contraception were recruited to a 6-week study, during which they took topiramate and periodically had blood drawn.

Overall, use of topiramate was found to lower serum etonogestrel levels from baseline on a dose-related basis. At study completion, almost one-third of study participants were found to have serum progestin levels lower than the threshold associated with predictable ovulation suppression.

The results of this carefully conducted study support guidance from the Centers for Disease Control and Prevention that women seeking contraception and using topiramate or other enzyme-inducing AEDs should be encouraged to use intrauterine devices or injectable contraception. The contraceptive efficacy of these latter methods is not diminished by concomitant use of enzyme inducers.

I am Andrew Kaunitz. Please take care of yourself and each other.

Any views expressed above are the author’s own and do not necessarily reflect the views of WebMD or Medscape.

Andrew M. Kaunitz is a professor and Associate Chairman, department of obstetrics and gynecology, University of Florida, Jacksonville.

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

Topiramate, introduced as an antiepileptic drug (AED), is currently most widely used for prevention of migraine headaches.

Because reproductive-aged women represent a population in which migraines are prevalent, clinicians need guidance to help women taking topiramate make sound contraceptive choices.

Several issues are relevant here. First, women who have migraines with aura should avoid estrogen-containing contraceptive pills, patches, and rings. Instead, progestin-only methods, including the contraceptive implant, may be recommended to patients with migraines.

Second, because topiramate, as with a number of other AEDs, is a teratogen, women using this medication need highly effective contraception. This consideration may also lead clinicians to recommend use of the implant in women with migraines.

Finally, topiramate, along with other AEDs (phenytoin, carbamazepine, barbiturates, primidone, and oxcarbazepine) induces hepatic enzymes, which results in reduced serum contraceptive steroid levels.

Because there is uncertainty regarding the degree to which the use of topiramate reduces serum levels of etonogestrel (the progestin released by the implant), investigators performed a prospective study to assess the pharmacokinetic impact of topiramate in women with the implant.

Ongoing users of contraceptive implants who agreed to use additional nonhormonal contraception were recruited to a 6-week study, during which they took topiramate and periodically had blood drawn.

Overall, use of topiramate was found to lower serum etonogestrel levels from baseline on a dose-related basis. At study completion, almost one-third of study participants were found to have serum progestin levels lower than the threshold associated with predictable ovulation suppression.

The results of this carefully conducted study support guidance from the Centers for Disease Control and Prevention that women seeking contraception and using topiramate or other enzyme-inducing AEDs should be encouraged to use intrauterine devices or injectable contraception. The contraceptive efficacy of these latter methods is not diminished by concomitant use of enzyme inducers.

I am Andrew Kaunitz. Please take care of yourself and each other.

Any views expressed above are the author’s own and do not necessarily reflect the views of WebMD or Medscape.

Andrew M. Kaunitz is a professor and Associate Chairman, department of obstetrics and gynecology, University of Florida, Jacksonville.

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

Topiramate, introduced as an antiepileptic drug (AED), is currently most widely used for prevention of migraine headaches.

Because reproductive-aged women represent a population in which migraines are prevalent, clinicians need guidance to help women taking topiramate make sound contraceptive choices.

Several issues are relevant here. First, women who have migraines with aura should avoid estrogen-containing contraceptive pills, patches, and rings. Instead, progestin-only methods, including the contraceptive implant, may be recommended to patients with migraines.

Second, because topiramate, as with a number of other AEDs, is a teratogen, women using this medication need highly effective contraception. This consideration may also lead clinicians to recommend use of the implant in women with migraines.

Finally, topiramate, along with other AEDs (phenytoin, carbamazepine, barbiturates, primidone, and oxcarbazepine) induces hepatic enzymes, which results in reduced serum contraceptive steroid levels.

Because there is uncertainty regarding the degree to which the use of topiramate reduces serum levels of etonogestrel (the progestin released by the implant), investigators performed a prospective study to assess the pharmacokinetic impact of topiramate in women with the implant.

Ongoing users of contraceptive implants who agreed to use additional nonhormonal contraception were recruited to a 6-week study, during which they took topiramate and periodically had blood drawn.

Overall, use of topiramate was found to lower serum etonogestrel levels from baseline on a dose-related basis. At study completion, almost one-third of study participants were found to have serum progestin levels lower than the threshold associated with predictable ovulation suppression.

The results of this carefully conducted study support guidance from the Centers for Disease Control and Prevention that women seeking contraception and using topiramate or other enzyme-inducing AEDs should be encouraged to use intrauterine devices or injectable contraception. The contraceptive efficacy of these latter methods is not diminished by concomitant use of enzyme inducers.

I am Andrew Kaunitz. Please take care of yourself and each other.

Any views expressed above are the author’s own and do not necessarily reflect the views of WebMD or Medscape.

Andrew M. Kaunitz is a professor and Associate Chairman, department of obstetrics and gynecology, University of Florida, Jacksonville.

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

The American Academy of Pediatrics, with funding from the Centers for Disease Control and Prevention, studied the CDC’s “Learn the Signs. Act Early” developmental surveillance milestones for children 0-5 years to update the milestones based on published studies. The goal was to improve this tool for developmental surveillance and use by the public. Developmental surveillance is not just observing a child at a check-up but rather “is a longitudinal process that involves eliciting concerns, taking a developmental history based on milestone attainment, observing milestones and other behaviors, examining the child, and applying clinical judgment during health supervision visits (HSVs).”¹

While the milestones we were trained on were a good start and highlighted the developmental progression central to pediatrics, they were not based on norms or cut scores indicating significant developmental risk unless taught from a validated tool. The CDC was concerned that their public handouts and apps were based on median ages (middle number of the entire range) of attainment not the mode (most common) or even average ages. That means that about half of all typically developing children would “not have attained” that skill at the age noted, potentially evoking unnecessary concern for parents and a “wait-and-see” message from a knowledgeable provider who realized the statistical meaning and the broad range of normal. Another potential problem with using milestones set at the median age is that parents, especially those with several children or experienced friends, may see the provider as an alarmist when they have seen great variation in children who later were normal. This reaction can dampen provider willingness to discuss development or even to screen with validated tools. We have learned the hard way from COVID-19 that it is difficult to convey concepts of risk effectively both balancing fear and stimulating action.

The AAP experts reviewed the English literature for data-based milestones, finding 34 articles, 10 of which had an opinion for at least one milestone. If this sounds like a very small number, you are correct. You may not realize that almost all screening and diagnostic tools have been based on data collected by Gesell in 1928!² While most of health care has changed since then, which milestones are measured in infants has not.

The biggest change from this review was deciding to use as milestones skills reported for 75% of children at each age of typical HSVs, adding ones for 15 and 30 months. The implication is that children not attaining these milestones are all at risk and deserving of more careful history, examination, and administration of a validated screening tool; not true when based on median data. Of the 94 existing CDC milestones retained after the review, one-third were moved to a different age with 21 of 31 assigned to an older age. Domains of functioning for the milestones were consolidated into social emotional, cognitive, language/communication, and motor, to help parents learn to distinguish these areas, and, although many milestones reflect several domains, each was included only once to reduce confusion.

Psychosocial assessment is recommended by the AAP and Bright Futures at every HSV but the fewest milestones with normative data were identified for this domain, often self-help rather than social engagement or emotion regulation skills. The cross-cultural study cited for many of the new milestones was reassuring overall in that the median ages for 67%-88% of milestones in most domains were equivalent across the four countries sampled, but only 22% of self-help skills were equivalent.³ This should remind us that parenting has more influence over psychosocial skills than other domains. Psychosocial and behavioral functioning, especially emotional regulation, also deserve “surveillance” as they have enormous impact on life outcomes but need to be measured and supported differently. Routine use of validated tools such as the Early Childhood Screening Assessment or the Ages & Stages Questionnaires: Social-Emotional for these domains are also needed.

Normal variations in temperament and patterns of attachment can affect many milestones including courage for walking, exploration, social engagement, and prosocial behaviors or self-control for social situations, attention, range of affect, and cooperation. All of these skills are among the 42 total (14 new) social-emotional milestones for 0- to 5-year-olds. Variations in these functions are at the root of the most common “challenging behaviors” in our studies in primary care. They are also the most vulnerable to suboptimal parent-child relationships, adverse childhood experiences, and social determinants of health.

As primary care providers, we not only need to detect children at risk for developmental problems but also promote and celebrate developmental progress. I hope that changing the threshold for concern to 75% will allow for a more positive review with the family (as fewer will be flagged as at risk) and chance to congratulate parents on all that is going well. But I also hope the change will not make us overlook parenting challenges, often from the psychosocial milestones most amenable to our guidance and support.

Early identification is mainly important to obtain the early intervention shown to improve outcomes. However, less than 25% of children with delays or disabilities receive early intervention before age 3 and most with emotional, behavioral, and developmental conditions, other than autism spectrum disorder, not before age 5. Since early intervention services are freely available in all states, we also need to do better at getting children to this care.

Let’s reconsider the process of developmental surveillance in this light of delayed referral: “Eliciting concerns” is key as parents have been shown to be usually correct in their worries. Listening to how they express the concerns can help you connect their specific issues when discussing reasons for referral. While most parent “recall of past milestones” is not accurate, current milestones reported are; thus, the need to have the new more accurate norms for all ages for comparison. When we make observations of a child’s abilities and behaviors ourselves we may not only pick up on issues missed by the parent, but will be more convincing in conveying the need for referral when indicated. When we “examine” the child we can use our professional skills to determine the very important risk factor of the quality of how a skill is performed, not just that it is. The recommended “use of validated screening tools” when the new milestones are not met give us an objective tool to share with parents, more confidence in when referral is warranted, which we will convey to parents (and perhaps skeptical relatives), and baseline documentation from which we can “track” referrals, progress, and, hopefully, better outcomes.

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

References

1. Zubler JM et al. Pediatrics. 2022;149(3):e2021052138.

2. Gessell A et al. Macmillan: New York, 1928.

3. Ertem IO et al. Lancet Glob Health. 2018 Mar;6(3):e279-91.

The American Academy of Pediatrics, with funding from the Centers for Disease Control and Prevention, studied the CDC’s “Learn the Signs. Act Early” developmental surveillance milestones for children 0-5 years to update the milestones based on published studies. The goal was to improve this tool for developmental surveillance and use by the public. Developmental surveillance is not just observing a child at a check-up but rather “is a longitudinal process that involves eliciting concerns, taking a developmental history based on milestone attainment, observing milestones and other behaviors, examining the child, and applying clinical judgment during health supervision visits (HSVs).”¹

While the milestones we were trained on were a good start and highlighted the developmental progression central to pediatrics, they were not based on norms or cut scores indicating significant developmental risk unless taught from a validated tool. The CDC was concerned that their public handouts and apps were based on median ages (middle number of the entire range) of attainment not the mode (most common) or even average ages. That means that about half of all typically developing children would “not have attained” that skill at the age noted, potentially evoking unnecessary concern for parents and a “wait-and-see” message from a knowledgeable provider who realized the statistical meaning and the broad range of normal. Another potential problem with using milestones set at the median age is that parents, especially those with several children or experienced friends, may see the provider as an alarmist when they have seen great variation in children who later were normal. This reaction can dampen provider willingness to discuss development or even to screen with validated tools. We have learned the hard way from COVID-19 that it is difficult to convey concepts of risk effectively both balancing fear and stimulating action.

The AAP experts reviewed the English literature for data-based milestones, finding 34 articles, 10 of which had an opinion for at least one milestone. If this sounds like a very small number, you are correct. You may not realize that almost all screening and diagnostic tools have been based on data collected by Gesell in 1928!² While most of health care has changed since then, which milestones are measured in infants has not.

The biggest change from this review was deciding to use as milestones skills reported for 75% of children at each age of typical HSVs, adding ones for 15 and 30 months. The implication is that children not attaining these milestones are all at risk and deserving of more careful history, examination, and administration of a validated screening tool; not true when based on median data. Of the 94 existing CDC milestones retained after the review, one-third were moved to a different age with 21 of 31 assigned to an older age. Domains of functioning for the milestones were consolidated into social emotional, cognitive, language/communication, and motor, to help parents learn to distinguish these areas, and, although many milestones reflect several domains, each was included only once to reduce confusion.

Psychosocial assessment is recommended by the AAP and Bright Futures at every HSV but the fewest milestones with normative data were identified for this domain, often self-help rather than social engagement or emotion regulation skills. The cross-cultural study cited for many of the new milestones was reassuring overall in that the median ages for 67%-88% of milestones in most domains were equivalent across the four countries sampled, but only 22% of self-help skills were equivalent.³ This should remind us that parenting has more influence over psychosocial skills than other domains. Psychosocial and behavioral functioning, especially emotional regulation, also deserve “surveillance” as they have enormous impact on life outcomes but need to be measured and supported differently. Routine use of validated tools such as the Early Childhood Screening Assessment or the Ages & Stages Questionnaires: Social-Emotional for these domains are also needed.

Normal variations in temperament and patterns of attachment can affect many milestones including courage for walking, exploration, social engagement, and prosocial behaviors or self-control for social situations, attention, range of affect, and cooperation. All of these skills are among the 42 total (14 new) social-emotional milestones for 0- to 5-year-olds. Variations in these functions are at the root of the most common “challenging behaviors” in our studies in primary care. They are also the most vulnerable to suboptimal parent-child relationships, adverse childhood experiences, and social determinants of health.

As primary care providers, we not only need to detect children at risk for developmental problems but also promote and celebrate developmental progress. I hope that changing the threshold for concern to 75% will allow for a more positive review with the family (as fewer will be flagged as at risk) and chance to congratulate parents on all that is going well. But I also hope the change will not make us overlook parenting challenges, often from the psychosocial milestones most amenable to our guidance and support.

Early identification is mainly important to obtain the early intervention shown to improve outcomes. However, less than 25% of children with delays or disabilities receive early intervention before age 3 and most with emotional, behavioral, and developmental conditions, other than autism spectrum disorder, not before age 5. Since early intervention services are freely available in all states, we also need to do better at getting children to this care.

Let’s reconsider the process of developmental surveillance in this light of delayed referral: “Eliciting concerns” is key as parents have been shown to be usually correct in their worries. Listening to how they express the concerns can help you connect their specific issues when discussing reasons for referral. While most parent “recall of past milestones” is not accurate, current milestones reported are; thus, the need to have the new more accurate norms for all ages for comparison. When we make observations of a child’s abilities and behaviors ourselves we may not only pick up on issues missed by the parent, but will be more convincing in conveying the need for referral when indicated. When we “examine” the child we can use our professional skills to determine the very important risk factor of the quality of how a skill is performed, not just that it is. The recommended “use of validated screening tools” when the new milestones are not met give us an objective tool to share with parents, more confidence in when referral is warranted, which we will convey to parents (and perhaps skeptical relatives), and baseline documentation from which we can “track” referrals, progress, and, hopefully, better outcomes.

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

References

1. Zubler JM et al. Pediatrics. 2022;149(3):e2021052138.

2. Gessell A et al. Macmillan: New York, 1928.

3. Ertem IO et al. Lancet Glob Health. 2018 Mar;6(3):e279-91.

The American Academy of Pediatrics, with funding from the Centers for Disease Control and Prevention, studied the CDC’s “Learn the Signs. Act Early” developmental surveillance milestones for children 0-5 years to update the milestones based on published studies. The goal was to improve this tool for developmental surveillance and use by the public. Developmental surveillance is not just observing a child at a check-up but rather “is a longitudinal process that involves eliciting concerns, taking a developmental history based on milestone attainment, observing milestones and other behaviors, examining the child, and applying clinical judgment during health supervision visits (HSVs).”¹

While the milestones we were trained on were a good start and highlighted the developmental progression central to pediatrics, they were not based on norms or cut scores indicating significant developmental risk unless taught from a validated tool. The CDC was concerned that their public handouts and apps were based on median ages (middle number of the entire range) of attainment not the mode (most common) or even average ages. That means that about half of all typically developing children would “not have attained” that skill at the age noted, potentially evoking unnecessary concern for parents and a “wait-and-see” message from a knowledgeable provider who realized the statistical meaning and the broad range of normal. Another potential problem with using milestones set at the median age is that parents, especially those with several children or experienced friends, may see the provider as an alarmist when they have seen great variation in children who later were normal. This reaction can dampen provider willingness to discuss development or even to screen with validated tools. We have learned the hard way from COVID-19 that it is difficult to convey concepts of risk effectively both balancing fear and stimulating action.

The AAP experts reviewed the English literature for data-based milestones, finding 34 articles, 10 of which had an opinion for at least one milestone. If this sounds like a very small number, you are correct. You may not realize that almost all screening and diagnostic tools have been based on data collected by Gesell in 1928!² While most of health care has changed since then, which milestones are measured in infants has not.

The biggest change from this review was deciding to use as milestones skills reported for 75% of children at each age of typical HSVs, adding ones for 15 and 30 months. The implication is that children not attaining these milestones are all at risk and deserving of more careful history, examination, and administration of a validated screening tool; not true when based on median data. Of the 94 existing CDC milestones retained after the review, one-third were moved to a different age with 21 of 31 assigned to an older age. Domains of functioning for the milestones were consolidated into social emotional, cognitive, language/communication, and motor, to help parents learn to distinguish these areas, and, although many milestones reflect several domains, each was included only once to reduce confusion.

Psychosocial assessment is recommended by the AAP and Bright Futures at every HSV but the fewest milestones with normative data were identified for this domain, often self-help rather than social engagement or emotion regulation skills. The cross-cultural study cited for many of the new milestones was reassuring overall in that the median ages for 67%-88% of milestones in most domains were equivalent across the four countries sampled, but only 22% of self-help skills were equivalent.³ This should remind us that parenting has more influence over psychosocial skills than other domains. Psychosocial and behavioral functioning, especially emotional regulation, also deserve “surveillance” as they have enormous impact on life outcomes but need to be measured and supported differently. Routine use of validated tools such as the Early Childhood Screening Assessment or the Ages & Stages Questionnaires: Social-Emotional for these domains are also needed.

Normal variations in temperament and patterns of attachment can affect many milestones including courage for walking, exploration, social engagement, and prosocial behaviors or self-control for social situations, attention, range of affect, and cooperation. All of these skills are among the 42 total (14 new) social-emotional milestones for 0- to 5-year-olds. Variations in these functions are at the root of the most common “challenging behaviors” in our studies in primary care. They are also the most vulnerable to suboptimal parent-child relationships, adverse childhood experiences, and social determinants of health.

As primary care providers, we not only need to detect children at risk for developmental problems but also promote and celebrate developmental progress. I hope that changing the threshold for concern to 75% will allow for a more positive review with the family (as fewer will be flagged as at risk) and chance to congratulate parents on all that is going well. But I also hope the change will not make us overlook parenting challenges, often from the psychosocial milestones most amenable to our guidance and support.

Early identification is mainly important to obtain the early intervention shown to improve outcomes. However, less than 25% of children with delays or disabilities receive early intervention before age 3 and most with emotional, behavioral, and developmental conditions, other than autism spectrum disorder, not before age 5. Since early intervention services are freely available in all states, we also need to do better at getting children to this care.

Let’s reconsider the process of developmental surveillance in this light of delayed referral: “Eliciting concerns” is key as parents have been shown to be usually correct in their worries. Listening to how they express the concerns can help you connect their specific issues when discussing reasons for referral. While most parent “recall of past milestones” is not accurate, current milestones reported are; thus, the need to have the new more accurate norms for all ages for comparison. When we make observations of a child’s abilities and behaviors ourselves we may not only pick up on issues missed by the parent, but will be more convincing in conveying the need for referral when indicated. When we “examine” the child we can use our professional skills to determine the very important risk factor of the quality of how a skill is performed, not just that it is. The recommended “use of validated screening tools” when the new milestones are not met give us an objective tool to share with parents, more confidence in when referral is warranted, which we will convey to parents (and perhaps skeptical relatives), and baseline documentation from which we can “track” referrals, progress, and, hopefully, better outcomes.

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

References

1. Zubler JM et al. Pediatrics. 2022;149(3):e2021052138.

2. Gessell A et al. Macmillan: New York, 1928.

3. Ertem IO et al. Lancet Glob Health. 2018 Mar;6(3):e279-91.

SEATTLE – Multiple sclerosis (MS), sometimes thought of as primarily affecting Whites, is also common among Hispanic and Black people. These populations often have more severe disease, likely driven by socioeconomic factors and health care access, according to a new study that examined neighborhood-level data and disease severity in the United States.

“It has previously been thought that MS is less common among non-European Caucasian White populations, driven partly by the well-known association of incidence with latitude. It is abundantly clear at this point that this idea is not true,” said Christopher Orlando, MD, during a presentation at the 2022 annual meeting of the American Academy of Neurology.

He noted that several U.S. studies with large sample sizes have shown greater disease severity and a higher disability burden among Hispanic and Black patients. “Black patients in particular appear to have a higher incidence of disease and a greater proportion of progressive disease phenotypes,” said Dr. Orlando.

Race and ethnicity are unlikely explanations for this disparity, according to Dr. Orlando. “While much remains to be discovered of the genetic underpinnings of MS, what we do know does not support the idea that minorities would have a predilection to more severe disease. For example, the well-known high-risk allele HLA DRB1*1501 appears to have a lower frequency in African populations, compared with European [populations].”

Instead, evidence suggests that interrelated social causes include access to resources, environmental exposures, and psychosocial stress. “These affect health via a number of pathways including direct physical injury, allostatic load, and access to health care,” said Dr. Orlando.
 

Probing racial and ethnic disparities

Previous studies that corrected for social determinants of health such as socioeconomic and insurance status reduce the association between MS disability and race, but they do not completely explain it.

To get a better understanding of the impacts of these factors, researchers have used neighborhood-level data combined with information on socioeconomic status and social deprivation to identify associations with MS severity.

At the conference, Dr. Orlando presented a new study that is the first to use this methodology in the United States, and it is the first to apply it to the study of racial and ethnic disparities in MS.

The study confirmed more severe disability in Hispanic and Black patients than in White patients. Clinical factors associated with more severe disease were similar across the three groups, with some small differences among individual traits. “More stark differences appeared when we compared social determinants of health. Hispanic patients were less likely to speak English as a primary language or to complete 12 years of education. Black patients were less likely to live in a rural county and more likely to be unemployed. One particularly stark difference was in the number of unemployed specifically due to their MS, with only 1 White patient [1.1%], 7 Hispanic patients [7.8%] and 27 Black patients [31.0%],” said Dr. Orlando.

The researchers found that Black and Hispanic patients tend to live in more vulnerable neighborhoods than White patients. The researchers found no significant association between social vulnerability index (SVI) values and MS severity, though there was an association in a separate analysis that only included White patients. The SVI uses 15 measures taken from the U.S. Census to identify communities that might require additional support during natural disasters.

“It would appear that the sheer complexity both in variety and magnitude of the social determinants of health are such that by far the stronger association is with race and ethnicity, which are surrogates for any number of social determinants and societal inequities,” said Dr. Orlando.
 

What drives the inequity?

Dr. Orlando acknowledged that some might wonder if these results indicate a true biologically intrinsic factor such as genetic predisposition. “I want to warn against that kind of thinking in the strongest possible terms. It is implausible on several levels. It’s not biologically plausible based on our understanding that race and ethnicity are not genetic constructs. And it’s also not numerically plausible based on these data,” said Dr. Orlando.

While some of the drivers of this inequity have been partially examined, many have not been studied. “As long as this is the case, our ability to fulfill our roles as physicians will be limited in several important ways. Our ability to assess our patients’ individual risk will be missing key information, which will limit the efficacy of shared decision-making, which of course is the cornerstone of MS treatment. In addition, we will continue to struggle to include minority patients in our research studies, and the very design and results of those studies may be misguided, as we will either fail to include these populations, or we will fail to adjust for important confounders,” he said.
 

New answers, new questions

The neighborhood-level data examined by Dr. Orlando’s group “brings extra information in terms of the negative impact of social determinants of health. The disparity seen in neighborhood living is quite striking,” said Lilyana Amezcua, MD, who served as a discussant for Dr. Orlando’s presentation. The study reinforces findings of her own group in Hispanic and Latinx individuals with MS. Some comorbidities are more common among these groups, which is exacerbated by poor health access.

“We have noted that almost 30% of them also have this comorbidity of hypertension, but what is also observed is that only 7% of them are aware [that they have hypertension],” said Dr. Amezcua, who is an associate professor of neurology at the University of Southern California, Los Angeles.

The findings should prompt further research to understand the impact of systemic racism and neighborhood factors, such as disinvestment in the public and private sectors, underresourced hospitals and clinics, and negative infrastructure. “We need to start discussing the (patient’s) environment so we can better understand the community resources they may have available, as well as create innovative transitional care services. We need to also recognize and accept that structural racism and imbalanced distribution of resources and neighborhoods does restrict educational and economic opportunities, as well as health care access and the safety of these marginalized communities,” said Dr. Amezcua.

Dr. Amezcua has consulted for, received speaking fees from, or served on steering committees or advisory boards for Biogen Idec, Novartis, Genentech, and EMD Serono. She has received research support from the Bristol-Myers Squibb Foundation and Biogen Idec. Dr. Orlando has no relevant financial disclosures.

SEATTLE – Multiple sclerosis (MS), sometimes thought of as primarily affecting Whites, is also common among Hispanic and Black people. These populations often have more severe disease, likely driven by socioeconomic factors and health care access, according to a new study that examined neighborhood-level data and disease severity in the United States.

“It has previously been thought that MS is less common among non-European Caucasian White populations, driven partly by the well-known association of incidence with latitude. It is abundantly clear at this point that this idea is not true,” said Christopher Orlando, MD, during a presentation at the 2022 annual meeting of the American Academy of Neurology.

He noted that several U.S. studies with large sample sizes have shown greater disease severity and a higher disability burden among Hispanic and Black patients. “Black patients in particular appear to have a higher incidence of disease and a greater proportion of progressive disease phenotypes,” said Dr. Orlando.

Race and ethnicity are unlikely explanations for this disparity, according to Dr. Orlando. “While much remains to be discovered of the genetic underpinnings of MS, what we do know does not support the idea that minorities would have a predilection to more severe disease. For example, the well-known high-risk allele HLA DRB1*1501 appears to have a lower frequency in African populations, compared with European [populations].”

Instead, evidence suggests that interrelated social causes include access to resources, environmental exposures, and psychosocial stress. “These affect health via a number of pathways including direct physical injury, allostatic load, and access to health care,” said Dr. Orlando.
 

Probing racial and ethnic disparities

Previous studies that corrected for social determinants of health such as socioeconomic and insurance status reduce the association between MS disability and race, but they do not completely explain it.

To get a better understanding of the impacts of these factors, researchers have used neighborhood-level data combined with information on socioeconomic status and social deprivation to identify associations with MS severity.

At the conference, Dr. Orlando presented a new study that is the first to use this methodology in the United States, and it is the first to apply it to the study of racial and ethnic disparities in MS.

The study confirmed more severe disability in Hispanic and Black patients than in White patients. Clinical factors associated with more severe disease were similar across the three groups, with some small differences among individual traits. “More stark differences appeared when we compared social determinants of health. Hispanic patients were less likely to speak English as a primary language or to complete 12 years of education. Black patients were less likely to live in a rural county and more likely to be unemployed. One particularly stark difference was in the number of unemployed specifically due to their MS, with only 1 White patient [1.1%], 7 Hispanic patients [7.8%] and 27 Black patients [31.0%],” said Dr. Orlando.

The researchers found that Black and Hispanic patients tend to live in more vulnerable neighborhoods than White patients. The researchers found no significant association between social vulnerability index (SVI) values and MS severity, though there was an association in a separate analysis that only included White patients. The SVI uses 15 measures taken from the U.S. Census to identify communities that might require additional support during natural disasters.

“It would appear that the sheer complexity both in variety and magnitude of the social determinants of health are such that by far the stronger association is with race and ethnicity, which are surrogates for any number of social determinants and societal inequities,” said Dr. Orlando.
 

What drives the inequity?

Dr. Orlando acknowledged that some might wonder if these results indicate a true biologically intrinsic factor such as genetic predisposition. “I want to warn against that kind of thinking in the strongest possible terms. It is implausible on several levels. It’s not biologically plausible based on our understanding that race and ethnicity are not genetic constructs. And it’s also not numerically plausible based on these data,” said Dr. Orlando.

While some of the drivers of this inequity have been partially examined, many have not been studied. “As long as this is the case, our ability to fulfill our roles as physicians will be limited in several important ways. Our ability to assess our patients’ individual risk will be missing key information, which will limit the efficacy of shared decision-making, which of course is the cornerstone of MS treatment. In addition, we will continue to struggle to include minority patients in our research studies, and the very design and results of those studies may be misguided, as we will either fail to include these populations, or we will fail to adjust for important confounders,” he said.
 

New answers, new questions

The neighborhood-level data examined by Dr. Orlando’s group “brings extra information in terms of the negative impact of social determinants of health. The disparity seen in neighborhood living is quite striking,” said Lilyana Amezcua, MD, who served as a discussant for Dr. Orlando’s presentation. The study reinforces findings of her own group in Hispanic and Latinx individuals with MS. Some comorbidities are more common among these groups, which is exacerbated by poor health access.

“We have noted that almost 30% of them also have this comorbidity of hypertension, but what is also observed is that only 7% of them are aware [that they have hypertension],” said Dr. Amezcua, who is an associate professor of neurology at the University of Southern California, Los Angeles.

The findings should prompt further research to understand the impact of systemic racism and neighborhood factors, such as disinvestment in the public and private sectors, underresourced hospitals and clinics, and negative infrastructure. “We need to start discussing the (patient’s) environment so we can better understand the community resources they may have available, as well as create innovative transitional care services. We need to also recognize and accept that structural racism and imbalanced distribution of resources and neighborhoods does restrict educational and economic opportunities, as well as health care access and the safety of these marginalized communities,” said Dr. Amezcua.

Dr. Amezcua has consulted for, received speaking fees from, or served on steering committees or advisory boards for Biogen Idec, Novartis, Genentech, and EMD Serono. She has received research support from the Bristol-Myers Squibb Foundation and Biogen Idec. Dr. Orlando has no relevant financial disclosures.

SEATTLE – Multiple sclerosis (MS), sometimes thought of as primarily affecting Whites, is also common among Hispanic and Black people. These populations often have more severe disease, likely driven by socioeconomic factors and health care access, according to a new study that examined neighborhood-level data and disease severity in the United States.

“It has previously been thought that MS is less common among non-European Caucasian White populations, driven partly by the well-known association of incidence with latitude. It is abundantly clear at this point that this idea is not true,” said Christopher Orlando, MD, during a presentation at the 2022 annual meeting of the American Academy of Neurology.

He noted that several U.S. studies with large sample sizes have shown greater disease severity and a higher disability burden among Hispanic and Black patients. “Black patients in particular appear to have a higher incidence of disease and a greater proportion of progressive disease phenotypes,” said Dr. Orlando.

Race and ethnicity are unlikely explanations for this disparity, according to Dr. Orlando. “While much remains to be discovered of the genetic underpinnings of MS, what we do know does not support the idea that minorities would have a predilection to more severe disease. For example, the well-known high-risk allele HLA DRB1*1501 appears to have a lower frequency in African populations, compared with European [populations].”

Instead, evidence suggests that interrelated social causes include access to resources, environmental exposures, and psychosocial stress. “These affect health via a number of pathways including direct physical injury, allostatic load, and access to health care,” said Dr. Orlando.
 

Probing racial and ethnic disparities

Previous studies that corrected for social determinants of health such as socioeconomic and insurance status reduce the association between MS disability and race, but they do not completely explain it.

To get a better understanding of the impacts of these factors, researchers have used neighborhood-level data combined with information on socioeconomic status and social deprivation to identify associations with MS severity.

At the conference, Dr. Orlando presented a new study that is the first to use this methodology in the United States, and it is the first to apply it to the study of racial and ethnic disparities in MS.

The study confirmed more severe disability in Hispanic and Black patients than in White patients. Clinical factors associated with more severe disease were similar across the three groups, with some small differences among individual traits. “More stark differences appeared when we compared social determinants of health. Hispanic patients were less likely to speak English as a primary language or to complete 12 years of education. Black patients were less likely to live in a rural county and more likely to be unemployed. One particularly stark difference was in the number of unemployed specifically due to their MS, with only 1 White patient [1.1%], 7 Hispanic patients [7.8%] and 27 Black patients [31.0%],” said Dr. Orlando.

The researchers found that Black and Hispanic patients tend to live in more vulnerable neighborhoods than White patients. The researchers found no significant association between social vulnerability index (SVI) values and MS severity, though there was an association in a separate analysis that only included White patients. The SVI uses 15 measures taken from the U.S. Census to identify communities that might require additional support during natural disasters.

“It would appear that the sheer complexity both in variety and magnitude of the social determinants of health are such that by far the stronger association is with race and ethnicity, which are surrogates for any number of social determinants and societal inequities,” said Dr. Orlando.
 

What drives the inequity?

Dr. Orlando acknowledged that some might wonder if these results indicate a true biologically intrinsic factor such as genetic predisposition. “I want to warn against that kind of thinking in the strongest possible terms. It is implausible on several levels. It’s not biologically plausible based on our understanding that race and ethnicity are not genetic constructs. And it’s also not numerically plausible based on these data,” said Dr. Orlando.

While some of the drivers of this inequity have been partially examined, many have not been studied. “As long as this is the case, our ability to fulfill our roles as physicians will be limited in several important ways. Our ability to assess our patients’ individual risk will be missing key information, which will limit the efficacy of shared decision-making, which of course is the cornerstone of MS treatment. In addition, we will continue to struggle to include minority patients in our research studies, and the very design and results of those studies may be misguided, as we will either fail to include these populations, or we will fail to adjust for important confounders,” he said.
 

New answers, new questions

The neighborhood-level data examined by Dr. Orlando’s group “brings extra information in terms of the negative impact of social determinants of health. The disparity seen in neighborhood living is quite striking,” said Lilyana Amezcua, MD, who served as a discussant for Dr. Orlando’s presentation. The study reinforces findings of her own group in Hispanic and Latinx individuals with MS. Some comorbidities are more common among these groups, which is exacerbated by poor health access.

“We have noted that almost 30% of them also have this comorbidity of hypertension, but what is also observed is that only 7% of them are aware [that they have hypertension],” said Dr. Amezcua, who is an associate professor of neurology at the University of Southern California, Los Angeles.

The findings should prompt further research to understand the impact of systemic racism and neighborhood factors, such as disinvestment in the public and private sectors, underresourced hospitals and clinics, and negative infrastructure. “We need to start discussing the (patient’s) environment so we can better understand the community resources they may have available, as well as create innovative transitional care services. We need to also recognize and accept that structural racism and imbalanced distribution of resources and neighborhoods does restrict educational and economic opportunities, as well as health care access and the safety of these marginalized communities,” said Dr. Amezcua.

Dr. Amezcua has consulted for, received speaking fees from, or served on steering committees or advisory boards for Biogen Idec, Novartis, Genentech, and EMD Serono. She has received research support from the Bristol-Myers Squibb Foundation and Biogen Idec. Dr. Orlando has no relevant financial disclosures.

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.

Several of the core medications for patients with heart failure with reduced ejection fraction (HFrEF) come with a well-known risk of causing hyperkalemia, to which many clinicians respond by pulling back on dosing or withdrawing the culprit drug.

But accompanying renin-angiotensin system–inhibiting agents with the potassium-sequestrant patiromer (Veltassa, Vifor Pharma) appears to shield patients against hyperkalemia enough that they can take more RASI medications at higher doses, suggests a randomized, a controlled study.

Catherine Hackett/MDedge News

The DIAMOND trial’s HFrEF patients, who had current or a history of RASI-related hyperkalemia, added either patiromer or placebo to their guideline-directed medical therapy (GDMT), which includes, even emphasizes, the culprit medication. They include ACE inhibitors, angiotensin-receptor blockers (ARBs), angiotensin-receptor/neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs).

Those taking patiromer tolerated more intense RASI therapy – including MRAs, which are especially prone to causing hyperkalemia – than the patients assigned to placebo. They also maintained lower potassium concentrations and experienced fewer clinically important hyperkalemia episodes, reported Javed Butler, MD, MPH, MBA, Baylor Scott and White Research Institute, Dallas, at the annual scientific sessions of the American College of Cardiology.

The apparent benefit from patiromer came in part from an advantage for a composite hyperkalemia-event endpoint that included mortality, Dr. Butler noted. That advantage seemed to hold regardless of age, sex, body mass index, HFrEF symptom severity, or initial natriuretic peptide levels.

Patients who took patiromer, compared with those who took placebo, showed a 37% reduction in risk for hyperkalemia (P = .006), defined as potassium levels exceeding 5.5 mEq/L, over a median follow-up of 27 weeks. They were 38% less likely to have their MRA dosage reduced to below target level (P = .006).

More patients in the patiromer group than in the control group attained at least 50% of target dosage for MRAs and ACE inhibitors, ARBs, or ARNIs (92% vs. 87%; P = .015).

Patients with HFrEF are unlikely to achieve best possible outcomes without GDMT optimization, but failure to optimize is often attributed to hyperkalemia concerns. DIAMOND, Dr. Butler said, suggests that, by adding the potassium sequestrant to GDMT, “you can simultaneously control potassium and optimize RASI therapy.” Many clinicians seem to believe they can achieve only one or the other.

DIAMOND was too underpowered to show whether preventing hyperkalemia with patiromer could improve clinical outcomes. But failure to optimize RASI medication in HFrEF can worsen risk for heart failure events and death. So “it stands to reason that optimization of RASI therapy without a concomitant risk of hyperkalemia may, in the long run, lead to better outcomes for these patients,” Dr. Butler said in an interview.

Given the drug’s ability to keep potassium levels in check during RASI therapy, Dr. Butler said, “hypokalemia should not be a reason for suboptimal therapy.”

Patiromer and other potassium sequestrants have been available in the United States and Europe for 4-6 years, but their value as adjuncts to RASI medication in HFrEF or other heart failure has been unclear.

Courtesy Massachusetts General Hospital

“There’s a good opportunity to expand the use of the drug. The question is, in whom and when?” James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Some HFrEF patients on GDMT “should be treated with patiromer. The bigger question is, should we give someone who has a history of hyperkalemia another chance at GDMT before we treat them with patiromer? Because they may not necessarily develop hyperkalemia a second time,” said Dr. Januzzi, who was on the DIAMOND endpoint-adjudication committee.

Among the most notable findings of the trial, he said, is that the number of people who developed hyperkalemia on RASI medication, although significantly elevated, “wasn’t as high as they expected it would be,” he said. “The data from DIAMOND argue that if a really significant majority does not become hyperkalemic on rechallenge, jumping straight to a potassium-binding drug may be premature.”

Physicians across specialties can differ in how they interpret potassium-level elevation and can use various cut points to flag when to stop RASI medication or at least hold back on up-titration, Dr. Butler observed. “Cardiologists have a different threshold of potassium that they tolerate than say, for instance, a nephrologist.”

Useful, then, might be a way to tell which patients are most likely to develop hyperkalemia with RASI up-titration and so might benefit from a potassium-binding agent right away. But DIAMOND, Dr. Butler said, “does not necessarily define any patient phenotype or any potassium level where we would say that you should use a potassium binder.”

The trial entered 1,642 patients with HFrEF and current or past RASI-related hyperkalemia to a 12-week run-in phase for optimization of GDMT with patiromer. The trial was conducted at nearly 400 centers in 21 countries.

RASI medication could be optimized in 85% of the cohort, from which 878 patients were randomly assigned either to continue optimized GDMT with patiromer or to have the potassium-sequestrant replaced with a placebo.

The patients on patiromer showed a 0.03-mEq/L mean rise in serum potassium levels from randomization to the end of the study, the primary endpoint, compared with a 0.13 mEq/L mean increase for those in the control group (P < .001), Dr. Butler reported.

The win ratio for a RASI-use score hierarchically featuring cardiovascular death and CV hospitalization for hyperkalemia at several levels of severity was 1.25 (95% confidence interval, 1.003-1.564; P = .048), favoring the patiromer group. The win ratio solely for hyperkalemia-related events also favored patients on patiromer, at 1.53 (95% CI, 1.23-1.91; P < .001).

Patiromer also seemed well tolerated, Dr. Butler said.

Hyperkalemia is “one of the most common excuses” from clinicians for failing to up-titrate RASI medicine in patients with heart failure, Dr. Januzzi said. DIAMOND was less about patiromer itself than about ways “to facilitate better GDMT, where we’re really falling short of the mark. During the run-in phase they were able to get the vast majority of individuals to target, which to me is a critically important point, and emblematic of the need for things that facilitate this kind of excellent care.”

DIAMOND was funded by Vifor Pharma. Dr. Butler disclosed receiving consulting fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana Medical, and Vifor Pharma. Dr. Januzzi disclosed receiving consultant fees or honoraria from Abbott Laboratories, Imbria, Jana Care, Novartis, Prevencio, and Roche Diagnostics; serving on a data safety monitoring board for AbbVie, Amgen, Bayer Healthcare Pharmaceuticals, Beyer, CVRx, and Takeda Pharmaceuticals North America; and receiving research grants from Abbott Laboratories, Janssen, and Vifor Pharma.

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

Several of the core medications for patients with heart failure with reduced ejection fraction (HFrEF) come with a well-known risk of causing hyperkalemia, to which many clinicians respond by pulling back on dosing or withdrawing the culprit drug.

But accompanying renin-angiotensin system–inhibiting agents with the potassium-sequestrant patiromer (Veltassa, Vifor Pharma) appears to shield patients against hyperkalemia enough that they can take more RASI medications at higher doses, suggests a randomized, a controlled study.

Catherine Hackett/MDedge News

The DIAMOND trial’s HFrEF patients, who had current or a history of RASI-related hyperkalemia, added either patiromer or placebo to their guideline-directed medical therapy (GDMT), which includes, even emphasizes, the culprit medication. They include ACE inhibitors, angiotensin-receptor blockers (ARBs), angiotensin-receptor/neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs).

Those taking patiromer tolerated more intense RASI therapy – including MRAs, which are especially prone to causing hyperkalemia – than the patients assigned to placebo. They also maintained lower potassium concentrations and experienced fewer clinically important hyperkalemia episodes, reported Javed Butler, MD, MPH, MBA, Baylor Scott and White Research Institute, Dallas, at the annual scientific sessions of the American College of Cardiology.

The apparent benefit from patiromer came in part from an advantage for a composite hyperkalemia-event endpoint that included mortality, Dr. Butler noted. That advantage seemed to hold regardless of age, sex, body mass index, HFrEF symptom severity, or initial natriuretic peptide levels.

Patients who took patiromer, compared with those who took placebo, showed a 37% reduction in risk for hyperkalemia (P = .006), defined as potassium levels exceeding 5.5 mEq/L, over a median follow-up of 27 weeks. They were 38% less likely to have their MRA dosage reduced to below target level (P = .006).

More patients in the patiromer group than in the control group attained at least 50% of target dosage for MRAs and ACE inhibitors, ARBs, or ARNIs (92% vs. 87%; P = .015).

Patients with HFrEF are unlikely to achieve best possible outcomes without GDMT optimization, but failure to optimize is often attributed to hyperkalemia concerns. DIAMOND, Dr. Butler said, suggests that, by adding the potassium sequestrant to GDMT, “you can simultaneously control potassium and optimize RASI therapy.” Many clinicians seem to believe they can achieve only one or the other.

DIAMOND was too underpowered to show whether preventing hyperkalemia with patiromer could improve clinical outcomes. But failure to optimize RASI medication in HFrEF can worsen risk for heart failure events and death. So “it stands to reason that optimization of RASI therapy without a concomitant risk of hyperkalemia may, in the long run, lead to better outcomes for these patients,” Dr. Butler said in an interview.

Given the drug’s ability to keep potassium levels in check during RASI therapy, Dr. Butler said, “hypokalemia should not be a reason for suboptimal therapy.”

Patiromer and other potassium sequestrants have been available in the United States and Europe for 4-6 years, but their value as adjuncts to RASI medication in HFrEF or other heart failure has been unclear.

Courtesy Massachusetts General Hospital

“There’s a good opportunity to expand the use of the drug. The question is, in whom and when?” James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Some HFrEF patients on GDMT “should be treated with patiromer. The bigger question is, should we give someone who has a history of hyperkalemia another chance at GDMT before we treat them with patiromer? Because they may not necessarily develop hyperkalemia a second time,” said Dr. Januzzi, who was on the DIAMOND endpoint-adjudication committee.

Among the most notable findings of the trial, he said, is that the number of people who developed hyperkalemia on RASI medication, although significantly elevated, “wasn’t as high as they expected it would be,” he said. “The data from DIAMOND argue that if a really significant majority does not become hyperkalemic on rechallenge, jumping straight to a potassium-binding drug may be premature.”

Physicians across specialties can differ in how they interpret potassium-level elevation and can use various cut points to flag when to stop RASI medication or at least hold back on up-titration, Dr. Butler observed. “Cardiologists have a different threshold of potassium that they tolerate than say, for instance, a nephrologist.”

Useful, then, might be a way to tell which patients are most likely to develop hyperkalemia with RASI up-titration and so might benefit from a potassium-binding agent right away. But DIAMOND, Dr. Butler said, “does not necessarily define any patient phenotype or any potassium level where we would say that you should use a potassium binder.”

The trial entered 1,642 patients with HFrEF and current or past RASI-related hyperkalemia to a 12-week run-in phase for optimization of GDMT with patiromer. The trial was conducted at nearly 400 centers in 21 countries.

RASI medication could be optimized in 85% of the cohort, from which 878 patients were randomly assigned either to continue optimized GDMT with patiromer or to have the potassium-sequestrant replaced with a placebo.

The patients on patiromer showed a 0.03-mEq/L mean rise in serum potassium levels from randomization to the end of the study, the primary endpoint, compared with a 0.13 mEq/L mean increase for those in the control group (P < .001), Dr. Butler reported.

The win ratio for a RASI-use score hierarchically featuring cardiovascular death and CV hospitalization for hyperkalemia at several levels of severity was 1.25 (95% confidence interval, 1.003-1.564; P = .048), favoring the patiromer group. The win ratio solely for hyperkalemia-related events also favored patients on patiromer, at 1.53 (95% CI, 1.23-1.91; P < .001).

Patiromer also seemed well tolerated, Dr. Butler said.

Hyperkalemia is “one of the most common excuses” from clinicians for failing to up-titrate RASI medicine in patients with heart failure, Dr. Januzzi said. DIAMOND was less about patiromer itself than about ways “to facilitate better GDMT, where we’re really falling short of the mark. During the run-in phase they were able to get the vast majority of individuals to target, which to me is a critically important point, and emblematic of the need for things that facilitate this kind of excellent care.”

DIAMOND was funded by Vifor Pharma. Dr. Butler disclosed receiving consulting fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana Medical, and Vifor Pharma. Dr. Januzzi disclosed receiving consultant fees or honoraria from Abbott Laboratories, Imbria, Jana Care, Novartis, Prevencio, and Roche Diagnostics; serving on a data safety monitoring board for AbbVie, Amgen, Bayer Healthcare Pharmaceuticals, Beyer, CVRx, and Takeda Pharmaceuticals North America; and receiving research grants from Abbott Laboratories, Janssen, and Vifor Pharma.

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

Several of the core medications for patients with heart failure with reduced ejection fraction (HFrEF) come with a well-known risk of causing hyperkalemia, to which many clinicians respond by pulling back on dosing or withdrawing the culprit drug.

But accompanying renin-angiotensin system–inhibiting agents with the potassium-sequestrant patiromer (Veltassa, Vifor Pharma) appears to shield patients against hyperkalemia enough that they can take more RASI medications at higher doses, suggests a randomized, a controlled study.

Catherine Hackett/MDedge News

The DIAMOND trial’s HFrEF patients, who had current or a history of RASI-related hyperkalemia, added either patiromer or placebo to their guideline-directed medical therapy (GDMT), which includes, even emphasizes, the culprit medication. They include ACE inhibitors, angiotensin-receptor blockers (ARBs), angiotensin-receptor/neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs).

Those taking patiromer tolerated more intense RASI therapy – including MRAs, which are especially prone to causing hyperkalemia – than the patients assigned to placebo. They also maintained lower potassium concentrations and experienced fewer clinically important hyperkalemia episodes, reported Javed Butler, MD, MPH, MBA, Baylor Scott and White Research Institute, Dallas, at the annual scientific sessions of the American College of Cardiology.

The apparent benefit from patiromer came in part from an advantage for a composite hyperkalemia-event endpoint that included mortality, Dr. Butler noted. That advantage seemed to hold regardless of age, sex, body mass index, HFrEF symptom severity, or initial natriuretic peptide levels.

Patients who took patiromer, compared with those who took placebo, showed a 37% reduction in risk for hyperkalemia (P = .006), defined as potassium levels exceeding 5.5 mEq/L, over a median follow-up of 27 weeks. They were 38% less likely to have their MRA dosage reduced to below target level (P = .006).

More patients in the patiromer group than in the control group attained at least 50% of target dosage for MRAs and ACE inhibitors, ARBs, or ARNIs (92% vs. 87%; P = .015).

Patients with HFrEF are unlikely to achieve best possible outcomes without GDMT optimization, but failure to optimize is often attributed to hyperkalemia concerns. DIAMOND, Dr. Butler said, suggests that, by adding the potassium sequestrant to GDMT, “you can simultaneously control potassium and optimize RASI therapy.” Many clinicians seem to believe they can achieve only one or the other.

DIAMOND was too underpowered to show whether preventing hyperkalemia with patiromer could improve clinical outcomes. But failure to optimize RASI medication in HFrEF can worsen risk for heart failure events and death. So “it stands to reason that optimization of RASI therapy without a concomitant risk of hyperkalemia may, in the long run, lead to better outcomes for these patients,” Dr. Butler said in an interview.

Given the drug’s ability to keep potassium levels in check during RASI therapy, Dr. Butler said, “hypokalemia should not be a reason for suboptimal therapy.”

Patiromer and other potassium sequestrants have been available in the United States and Europe for 4-6 years, but their value as adjuncts to RASI medication in HFrEF or other heart failure has been unclear.

Courtesy Massachusetts General Hospital

“There’s a good opportunity to expand the use of the drug. The question is, in whom and when?” James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Some HFrEF patients on GDMT “should be treated with patiromer. The bigger question is, should we give someone who has a history of hyperkalemia another chance at GDMT before we treat them with patiromer? Because they may not necessarily develop hyperkalemia a second time,” said Dr. Januzzi, who was on the DIAMOND endpoint-adjudication committee.

Among the most notable findings of the trial, he said, is that the number of people who developed hyperkalemia on RASI medication, although significantly elevated, “wasn’t as high as they expected it would be,” he said. “The data from DIAMOND argue that if a really significant majority does not become hyperkalemic on rechallenge, jumping straight to a potassium-binding drug may be premature.”

Physicians across specialties can differ in how they interpret potassium-level elevation and can use various cut points to flag when to stop RASI medication or at least hold back on up-titration, Dr. Butler observed. “Cardiologists have a different threshold of potassium that they tolerate than say, for instance, a nephrologist.”

Useful, then, might be a way to tell which patients are most likely to develop hyperkalemia with RASI up-titration and so might benefit from a potassium-binding agent right away. But DIAMOND, Dr. Butler said, “does not necessarily define any patient phenotype or any potassium level where we would say that you should use a potassium binder.”

The trial entered 1,642 patients with HFrEF and current or past RASI-related hyperkalemia to a 12-week run-in phase for optimization of GDMT with patiromer. The trial was conducted at nearly 400 centers in 21 countries.

RASI medication could be optimized in 85% of the cohort, from which 878 patients were randomly assigned either to continue optimized GDMT with patiromer or to have the potassium-sequestrant replaced with a placebo.

The patients on patiromer showed a 0.03-mEq/L mean rise in serum potassium levels from randomization to the end of the study, the primary endpoint, compared with a 0.13 mEq/L mean increase for those in the control group (P < .001), Dr. Butler reported.

The win ratio for a RASI-use score hierarchically featuring cardiovascular death and CV hospitalization for hyperkalemia at several levels of severity was 1.25 (95% confidence interval, 1.003-1.564; P = .048), favoring the patiromer group. The win ratio solely for hyperkalemia-related events also favored patients on patiromer, at 1.53 (95% CI, 1.23-1.91; P < .001).

Patiromer also seemed well tolerated, Dr. Butler said.

Hyperkalemia is “one of the most common excuses” from clinicians for failing to up-titrate RASI medicine in patients with heart failure, Dr. Januzzi said. DIAMOND was less about patiromer itself than about ways “to facilitate better GDMT, where we’re really falling short of the mark. During the run-in phase they were able to get the vast majority of individuals to target, which to me is a critically important point, and emblematic of the need for things that facilitate this kind of excellent care.”

DIAMOND was funded by Vifor Pharma. Dr. Butler disclosed receiving consulting fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana Medical, and Vifor Pharma. Dr. Januzzi disclosed receiving consultant fees or honoraria from Abbott Laboratories, Imbria, Jana Care, Novartis, Prevencio, and Roche Diagnostics; serving on a data safety monitoring board for AbbVie, Amgen, Bayer Healthcare Pharmaceuticals, Beyer, CVRx, and Takeda Pharmaceuticals North America; and receiving research grants from Abbott Laboratories, Janssen, and Vifor Pharma.

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

SEATTLE – A novel therapy for ataxia telangiectasia that delivers dexamethasone sodium phosphate (DSP) through autologous red blood cells has shown promise in a phase 3 clinical trial.

The disease is an autosomal recessive disorder caused by mutations in the ATM gene, which is critical to the response to cellular insults such as DNA breaks, oxidative damage, and other forms of stress. The result is clinical manifestations that range from a suppressed immune system to organ damage and neurological symptoms that typically lead patients to be wheelchair bound by their teenage years.

“It’s really multisystem and a very, very difficult disease for people to live with,” Howard M. Lederman, MD, PhD, said in an interview. Dr. Lederman is a coauthor of the study, which was presented by Stefan Zielen, PhD, professor at the University of Goethe, at the 2022 annual meeting of the American Academy of Neurology.

Various therapies have been developed to improve immunodeficiency, lung disease, and some of the other clinical aspects of the condition, but there is no treatment for its neurological effects. “There’s not really been a good animal model, which has been a big problem in trying to test drugs and design treatment trials,” said Dr. Lederman, professor of pediatrics and medicine at Johns Hopkins University, Baltimore.

The new results may change that. “In the children under the age of 9, there was really a very clear slowdown in the neurodegeneration, and specifically the time that it took for them to lose the ability to ambulate. It’s very exciting, because it’s the first time that anybody has really shown in a double-blind, placebo-controlled, large phase 3 study that any drug has been able to do this. And there were really no steroid side effects, which is the other really remarkable thing about this study,” said Dr. Lederman.

The therapy grew out of a study by researchers in Italy who treated pediatric ataxia telangiectasia patients with corticosteroids and found some transitory improvements in gross motor function, but concerns about long-term exposure to steroids limited its application. EryDel, which specializes in encapsulating therapeutics in red blood cells, became interested and developed a formulation using the patient’s own red blood cells infused with DSP. Reinfused to the patients, the red blood cells slowly release the steroid.

It isn’t clear how dexamethasone works. There are data suggesting that it might lead to transcription of small pieces of the ATM protein, “but that has really not been nailed down in any way at this point. Corticosteroids act on all kinds of cells in all kinds of ways, and so there might be a little bit of this so-called mini-ATM that’s produced, but that may or may not be related to the way in which corticosteroids have a beneficial effect on the rate of neurodegeneration,” said Dr. Lederman.

The treatment process is not easy. Children must have 50-60 cc of blood removed. Red blood cells treated to become porous are exposed to DSP, and then resealed. Then the cells are reinfused. “The whole process takes from beginning to end probably about 3 hours, with a really experienced team of people doing it. And it’s limiting because it’s not easy to put in an IV and take 50 or 60 cc of blood out of children much younger than 5 or 6. The process is now being modified to see whether we could do it with 20 to 30 cc instead,” said Dr. Lederman.
 

A ‘promising and impressive’ study

The study is promising, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “They were able to show a slower rate of neurological degeneration or duration on both the lower and higher dose compared with the placebo. This is promising and impressive, in the sense that it’s a really large (trial) for a rare condition,” Dr. Johnson, vice chair of research at Virginia Commonwealth University, Richmond, said in an interview.

The study included 164 patients Europe, Australia, Israel, Tunisia, India, and the United States, who received 5-10 mg dexamethasone, 14-22 mg DSP, or placebo. Mean ages in each group ranged from 9.6 to 10.4 years.

In an intention-to-treat analysis, modified International Cooperative Ataxia Rating Scale (mICARS) scores trended toward improvement in the low-dose (–1.37; P = .0847) and high-dose groups (–1.40; P = .0765) when determined by central raters during the COVID-19 pandemic. There was also a trend toward improvement when determined by local raters in the low dose group (–1.73; P = .0720) and a statistically significant change in the high dose group (–2.11; P = .0277). The researchers noted some inconsistency between local and central raters, due to inconsistency of videography and language challenges for central raters.

An intention-to-treat analysis of a subgroup of 89 patients age 6-9, who were compared with natural history data from 245 patients, found a deterioration of mICARS of 3.7 per year, compared with 0.92 in the high-dose group, for a reduction of 75% (P = .020). In the high-dose group, 51.7% had a minimal or significant improvement compared with baseline according to the Clinical Global Impression of Change, as did 29.0% on low dose, and 27.6% in the placebo group.

SEATTLE – A novel therapy for ataxia telangiectasia that delivers dexamethasone sodium phosphate (DSP) through autologous red blood cells has shown promise in a phase 3 clinical trial.

The disease is an autosomal recessive disorder caused by mutations in the ATM gene, which is critical to the response to cellular insults such as DNA breaks, oxidative damage, and other forms of stress. The result is clinical manifestations that range from a suppressed immune system to organ damage and neurological symptoms that typically lead patients to be wheelchair bound by their teenage years.

“It’s really multisystem and a very, very difficult disease for people to live with,” Howard M. Lederman, MD, PhD, said in an interview. Dr. Lederman is a coauthor of the study, which was presented by Stefan Zielen, PhD, professor at the University of Goethe, at the 2022 annual meeting of the American Academy of Neurology.

Various therapies have been developed to improve immunodeficiency, lung disease, and some of the other clinical aspects of the condition, but there is no treatment for its neurological effects. “There’s not really been a good animal model, which has been a big problem in trying to test drugs and design treatment trials,” said Dr. Lederman, professor of pediatrics and medicine at Johns Hopkins University, Baltimore.

The new results may change that. “In the children under the age of 9, there was really a very clear slowdown in the neurodegeneration, and specifically the time that it took for them to lose the ability to ambulate. It’s very exciting, because it’s the first time that anybody has really shown in a double-blind, placebo-controlled, large phase 3 study that any drug has been able to do this. And there were really no steroid side effects, which is the other really remarkable thing about this study,” said Dr. Lederman.

The therapy grew out of a study by researchers in Italy who treated pediatric ataxia telangiectasia patients with corticosteroids and found some transitory improvements in gross motor function, but concerns about long-term exposure to steroids limited its application. EryDel, which specializes in encapsulating therapeutics in red blood cells, became interested and developed a formulation using the patient’s own red blood cells infused with DSP. Reinfused to the patients, the red blood cells slowly release the steroid.

It isn’t clear how dexamethasone works. There are data suggesting that it might lead to transcription of small pieces of the ATM protein, “but that has really not been nailed down in any way at this point. Corticosteroids act on all kinds of cells in all kinds of ways, and so there might be a little bit of this so-called mini-ATM that’s produced, but that may or may not be related to the way in which corticosteroids have a beneficial effect on the rate of neurodegeneration,” said Dr. Lederman.

The treatment process is not easy. Children must have 50-60 cc of blood removed. Red blood cells treated to become porous are exposed to DSP, and then resealed. Then the cells are reinfused. “The whole process takes from beginning to end probably about 3 hours, with a really experienced team of people doing it. And it’s limiting because it’s not easy to put in an IV and take 50 or 60 cc of blood out of children much younger than 5 or 6. The process is now being modified to see whether we could do it with 20 to 30 cc instead,” said Dr. Lederman.
 

A ‘promising and impressive’ study

The study is promising, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “They were able to show a slower rate of neurological degeneration or duration on both the lower and higher dose compared with the placebo. This is promising and impressive, in the sense that it’s a really large (trial) for a rare condition,” Dr. Johnson, vice chair of research at Virginia Commonwealth University, Richmond, said in an interview.

The study included 164 patients Europe, Australia, Israel, Tunisia, India, and the United States, who received 5-10 mg dexamethasone, 14-22 mg DSP, or placebo. Mean ages in each group ranged from 9.6 to 10.4 years.

In an intention-to-treat analysis, modified International Cooperative Ataxia Rating Scale (mICARS) scores trended toward improvement in the low-dose (–1.37; P = .0847) and high-dose groups (–1.40; P = .0765) when determined by central raters during the COVID-19 pandemic. There was also a trend toward improvement when determined by local raters in the low dose group (–1.73; P = .0720) and a statistically significant change in the high dose group (–2.11; P = .0277). The researchers noted some inconsistency between local and central raters, due to inconsistency of videography and language challenges for central raters.

An intention-to-treat analysis of a subgroup of 89 patients age 6-9, who were compared with natural history data from 245 patients, found a deterioration of mICARS of 3.7 per year, compared with 0.92 in the high-dose group, for a reduction of 75% (P = .020). In the high-dose group, 51.7% had a minimal or significant improvement compared with baseline according to the Clinical Global Impression of Change, as did 29.0% on low dose, and 27.6% in the placebo group.

SEATTLE – A novel therapy for ataxia telangiectasia that delivers dexamethasone sodium phosphate (DSP) through autologous red blood cells has shown promise in a phase 3 clinical trial.

The disease is an autosomal recessive disorder caused by mutations in the ATM gene, which is critical to the response to cellular insults such as DNA breaks, oxidative damage, and other forms of stress. The result is clinical manifestations that range from a suppressed immune system to organ damage and neurological symptoms that typically lead patients to be wheelchair bound by their teenage years.

“It’s really multisystem and a very, very difficult disease for people to live with,” Howard M. Lederman, MD, PhD, said in an interview. Dr. Lederman is a coauthor of the study, which was presented by Stefan Zielen, PhD, professor at the University of Goethe, at the 2022 annual meeting of the American Academy of Neurology.

Various therapies have been developed to improve immunodeficiency, lung disease, and some of the other clinical aspects of the condition, but there is no treatment for its neurological effects. “There’s not really been a good animal model, which has been a big problem in trying to test drugs and design treatment trials,” said Dr. Lederman, professor of pediatrics and medicine at Johns Hopkins University, Baltimore.

The new results may change that. “In the children under the age of 9, there was really a very clear slowdown in the neurodegeneration, and specifically the time that it took for them to lose the ability to ambulate. It’s very exciting, because it’s the first time that anybody has really shown in a double-blind, placebo-controlled, large phase 3 study that any drug has been able to do this. And there were really no steroid side effects, which is the other really remarkable thing about this study,” said Dr. Lederman.

The therapy grew out of a study by researchers in Italy who treated pediatric ataxia telangiectasia patients with corticosteroids and found some transitory improvements in gross motor function, but concerns about long-term exposure to steroids limited its application. EryDel, which specializes in encapsulating therapeutics in red blood cells, became interested and developed a formulation using the patient’s own red blood cells infused with DSP. Reinfused to the patients, the red blood cells slowly release the steroid.

It isn’t clear how dexamethasone works. There are data suggesting that it might lead to transcription of small pieces of the ATM protein, “but that has really not been nailed down in any way at this point. Corticosteroids act on all kinds of cells in all kinds of ways, and so there might be a little bit of this so-called mini-ATM that’s produced, but that may or may not be related to the way in which corticosteroids have a beneficial effect on the rate of neurodegeneration,” said Dr. Lederman.

The treatment process is not easy. Children must have 50-60 cc of blood removed. Red blood cells treated to become porous are exposed to DSP, and then resealed. Then the cells are reinfused. “The whole process takes from beginning to end probably about 3 hours, with a really experienced team of people doing it. And it’s limiting because it’s not easy to put in an IV and take 50 or 60 cc of blood out of children much younger than 5 or 6. The process is now being modified to see whether we could do it with 20 to 30 cc instead,” said Dr. Lederman.
 

A ‘promising and impressive’ study

The study is promising, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “They were able to show a slower rate of neurological degeneration or duration on both the lower and higher dose compared with the placebo. This is promising and impressive, in the sense that it’s a really large (trial) for a rare condition,” Dr. Johnson, vice chair of research at Virginia Commonwealth University, Richmond, said in an interview.

The study included 164 patients Europe, Australia, Israel, Tunisia, India, and the United States, who received 5-10 mg dexamethasone, 14-22 mg DSP, or placebo. Mean ages in each group ranged from 9.6 to 10.4 years.

In an intention-to-treat analysis, modified International Cooperative Ataxia Rating Scale (mICARS) scores trended toward improvement in the low-dose (–1.37; P = .0847) and high-dose groups (–1.40; P = .0765) when determined by central raters during the COVID-19 pandemic. There was also a trend toward improvement when determined by local raters in the low dose group (–1.73; P = .0720) and a statistically significant change in the high dose group (–2.11; P = .0277). The researchers noted some inconsistency between local and central raters, due to inconsistency of videography and language challenges for central raters.

An intention-to-treat analysis of a subgroup of 89 patients age 6-9, who were compared with natural history data from 245 patients, found a deterioration of mICARS of 3.7 per year, compared with 0.92 in the high-dose group, for a reduction of 75% (P = .020). In the high-dose group, 51.7% had a minimal or significant improvement compared with baseline according to the Clinical Global Impression of Change, as did 29.0% on low dose, and 27.6% in the placebo group.

Restless legs syndrome occurred in approximately 40% of adults with X-linked adrenoleukodystrophy, based on data from 32 individuals.

Patients with X-linked adrenoleukodystrophy (ALD), a neurodegenerative disease, often experience gait and balance problems, as well as leg discomfort, sleep disturbances, and pain, wrote John W. Winkelman, MD, of Massachusetts General Hospital, Boston, and colleagues. Restless legs syndrome (RLS) has been associated with neurological conditions including Parkinson’s disease, but the prevalence of RLS in ALD patients has not been examined, they said.

Courtesy Brigham and Women&#039;s Hospital

In a pilot study published in Sleep Medicine, the researchers identified 21 women and 11 men with ALD who were treated at a single center. The median age of the patients was 45.9 years. Twenty-seven patients had symptoms of myelopathy, with a median age of onset of 34 years.

The researchers assessed RLS severity using questionnaires and the Hopkins Telephone Diagnostic Interview (HTDI), a validated RLS assessment tool. They also reviewed patients’ charts for data on neurological examinations, functional gait measures, and laboratory assessments. Functional gait assessments included the 25-Foot Walk test (25-FW), the Timed Up and Go test (TUG), and Six Minute Walk test (6MW).

Thirteen patients (10 women and 3 men) met criteria for RLS based on the HTDI. The median age of RLS onset was 35 years. Six RLS patients (46.2%) reported using medication to relieve symptoms, and eight RLS patients had a history of antidepressant use.

In addition, six patients with RLS reported a history of anemia or iron deficiency. Ferritin levels were available for 14 patients: 8 women with RLS and 4 women and 2 men without RLS; the mean ferritin levels were 74.0 mcg/L in RLS patients and 99.5 mcg/L in those without RLS.

Of the seven ALD patients with brain lesions, all were men, only two were diagnosed with RLS, and all seven cases were mild, the researchers noted.

Overall, patients with RLS had more neurological signs and symptoms than those without RLS; the most significant were pain and gait difficulty. However, patients with RLS also were more likely than were those without RLS to report spasticity, muscle weakness, impaired coordination, hyperreflexia, impaired sensation, and paraesthesia, as well as bladder, bowel, and erectile dysfunction.

The 40.6% prevalence of RLS in patients with ALD is notably higher than that of the general population, in which the prevalence of RLS is 5%-10%, the researchers wrote in their discussion.

“Consistent with patterns observed in the general population, risk factors for RLS in this cohort of adults with ALD included female gender, increased age, lower iron indices, and use of serotonergic antidepressants,” they said.

The study findings were limited by several factors including the small size and the possible contribution of antidepressant use to the high rate of RLS, the researchers noted.

“Awareness of RLS in patients with ALD would allow for its effective treatment, which may improve the functional impairments as well as quality of life, mood, and anxiety issues in those with ALD,” they concluded.

The study received no outside funding.

Dr. Winkelman disclosed ties with Advance Medical, Avadel, Disc Medicine, Eisai, Emalex, Idorsia, Noctrix, UpToDate, and Merck Pharmaceuticals, as well as research support from the National Institute on Drug Abuse and the Baszucki Brain Research Foundation. The study also was supported by grants from the National Institute of Neurological Disorders and Stroke, the European Leukodystrophy Association, the Arrivederci Foundation, the Leblang Foundation, and the Hammer Family Fund Journal Preproof for ALD Research and Therapies for Women.

Restless legs syndrome occurred in approximately 40% of adults with X-linked adrenoleukodystrophy, based on data from 32 individuals.

Patients with X-linked adrenoleukodystrophy (ALD), a neurodegenerative disease, often experience gait and balance problems, as well as leg discomfort, sleep disturbances, and pain, wrote John W. Winkelman, MD, of Massachusetts General Hospital, Boston, and colleagues. Restless legs syndrome (RLS) has been associated with neurological conditions including Parkinson’s disease, but the prevalence of RLS in ALD patients has not been examined, they said.

Courtesy Brigham and Women&#039;s Hospital

In a pilot study published in Sleep Medicine, the researchers identified 21 women and 11 men with ALD who were treated at a single center. The median age of the patients was 45.9 years. Twenty-seven patients had symptoms of myelopathy, with a median age of onset of 34 years.

The researchers assessed RLS severity using questionnaires and the Hopkins Telephone Diagnostic Interview (HTDI), a validated RLS assessment tool. They also reviewed patients’ charts for data on neurological examinations, functional gait measures, and laboratory assessments. Functional gait assessments included the 25-Foot Walk test (25-FW), the Timed Up and Go test (TUG), and Six Minute Walk test (6MW).

Thirteen patients (10 women and 3 men) met criteria for RLS based on the HTDI. The median age of RLS onset was 35 years. Six RLS patients (46.2%) reported using medication to relieve symptoms, and eight RLS patients had a history of antidepressant use.

In addition, six patients with RLS reported a history of anemia or iron deficiency. Ferritin levels were available for 14 patients: 8 women with RLS and 4 women and 2 men without RLS; the mean ferritin levels were 74.0 mcg/L in RLS patients and 99.5 mcg/L in those without RLS.

Of the seven ALD patients with brain lesions, all were men, only two were diagnosed with RLS, and all seven cases were mild, the researchers noted.

Overall, patients with RLS had more neurological signs and symptoms than those without RLS; the most significant were pain and gait difficulty. However, patients with RLS also were more likely than were those without RLS to report spasticity, muscle weakness, impaired coordination, hyperreflexia, impaired sensation, and paraesthesia, as well as bladder, bowel, and erectile dysfunction.

The 40.6% prevalence of RLS in patients with ALD is notably higher than that of the general population, in which the prevalence of RLS is 5%-10%, the researchers wrote in their discussion.

“Consistent with patterns observed in the general population, risk factors for RLS in this cohort of adults with ALD included female gender, increased age, lower iron indices, and use of serotonergic antidepressants,” they said.

The study findings were limited by several factors including the small size and the possible contribution of antidepressant use to the high rate of RLS, the researchers noted.

“Awareness of RLS in patients with ALD would allow for its effective treatment, which may improve the functional impairments as well as quality of life, mood, and anxiety issues in those with ALD,” they concluded.

The study received no outside funding.

Dr. Winkelman disclosed ties with Advance Medical, Avadel, Disc Medicine, Eisai, Emalex, Idorsia, Noctrix, UpToDate, and Merck Pharmaceuticals, as well as research support from the National Institute on Drug Abuse and the Baszucki Brain Research Foundation. The study also was supported by grants from the National Institute of Neurological Disorders and Stroke, the European Leukodystrophy Association, the Arrivederci Foundation, the Leblang Foundation, and the Hammer Family Fund Journal Preproof for ALD Research and Therapies for Women.

Restless legs syndrome occurred in approximately 40% of adults with X-linked adrenoleukodystrophy, based on data from 32 individuals.

Patients with X-linked adrenoleukodystrophy (ALD), a neurodegenerative disease, often experience gait and balance problems, as well as leg discomfort, sleep disturbances, and pain, wrote John W. Winkelman, MD, of Massachusetts General Hospital, Boston, and colleagues. Restless legs syndrome (RLS) has been associated with neurological conditions including Parkinson’s disease, but the prevalence of RLS in ALD patients has not been examined, they said.

Courtesy Brigham and Women&#039;s Hospital

In a pilot study published in Sleep Medicine, the researchers identified 21 women and 11 men with ALD who were treated at a single center. The median age of the patients was 45.9 years. Twenty-seven patients had symptoms of myelopathy, with a median age of onset of 34 years.

The researchers assessed RLS severity using questionnaires and the Hopkins Telephone Diagnostic Interview (HTDI), a validated RLS assessment tool. They also reviewed patients’ charts for data on neurological examinations, functional gait measures, and laboratory assessments. Functional gait assessments included the 25-Foot Walk test (25-FW), the Timed Up and Go test (TUG), and Six Minute Walk test (6MW).

Thirteen patients (10 women and 3 men) met criteria for RLS based on the HTDI. The median age of RLS onset was 35 years. Six RLS patients (46.2%) reported using medication to relieve symptoms, and eight RLS patients had a history of antidepressant use.

In addition, six patients with RLS reported a history of anemia or iron deficiency. Ferritin levels were available for 14 patients: 8 women with RLS and 4 women and 2 men without RLS; the mean ferritin levels were 74.0 mcg/L in RLS patients and 99.5 mcg/L in those without RLS.

Of the seven ALD patients with brain lesions, all were men, only two were diagnosed with RLS, and all seven cases were mild, the researchers noted.

Overall, patients with RLS had more neurological signs and symptoms than those without RLS; the most significant were pain and gait difficulty. However, patients with RLS also were more likely than were those without RLS to report spasticity, muscle weakness, impaired coordination, hyperreflexia, impaired sensation, and paraesthesia, as well as bladder, bowel, and erectile dysfunction.

The 40.6% prevalence of RLS in patients with ALD is notably higher than that of the general population, in which the prevalence of RLS is 5%-10%, the researchers wrote in their discussion.

“Consistent with patterns observed in the general population, risk factors for RLS in this cohort of adults with ALD included female gender, increased age, lower iron indices, and use of serotonergic antidepressants,” they said.

The study findings were limited by several factors including the small size and the possible contribution of antidepressant use to the high rate of RLS, the researchers noted.

“Awareness of RLS in patients with ALD would allow for its effective treatment, which may improve the functional impairments as well as quality of life, mood, and anxiety issues in those with ALD,” they concluded.

The study received no outside funding.

Dr. Winkelman disclosed ties with Advance Medical, Avadel, Disc Medicine, Eisai, Emalex, Idorsia, Noctrix, UpToDate, and Merck Pharmaceuticals, as well as research support from the National Institute on Drug Abuse and the Baszucki Brain Research Foundation. The study also was supported by grants from the National Institute of Neurological Disorders and Stroke, the European Leukodystrophy Association, the Arrivederci Foundation, the Leblang Foundation, and the Hammer Family Fund Journal Preproof for ALD Research and Therapies for Women.

A new study suggests that overgrowth of the amygdala in infants during the first 6-12 months of life is tied to a later diagnosis of autism spectrum disorder (ASD).

“The faster the amygdala grew in infancy, the more social difficulties the child showed when diagnosed with autism a year later,” first author Mark Shen, PhD, assistant professor of psychiatry and neuroscience, University of North Carolina, Chapel Hill, told this news organization.

The study was published online  in the American Journal of Psychiatry.
 

Unique to autism

The amygdala plays a key role in processing memory, emotional responses, and decisionmaking. 

It’s long been known that the amygdala is abnormally large in school-aged children with ASD, but until now, it was not known precisely when aberrant amygdala growth happens, what the clinical consequences may be, and whether amygdala overgrowth is unique to autism.

To investigate, Dr. Shen and colleagues evaluated 1,099 longitudinal MRI scans obtained during natural sleep at 6, 12, and 24 months of age in 408 infants in the Infant Brain Imaging Study (IBIS) Network.

The cohort included 58 infants at high likelihood of developing ASD who were later diagnosed with the disorder, 212 infants at high likelihood of ASD who did not develop ASD, 109 typically-developing control infants, and 29 infants with fragile X syndrome.

At 6 months, infants who developed ASD had typically sized amygdala volumes but showed significantly faster amygdala growth between 6 and 24 months, such that by 12 months the ASD group had significantly larger amygdala volume (Cohen’s d = 0.56), compared with all other groups.

Amygdala growth rate between 6 and 12 months was significantly associated with greater social deficits at 24 months when the children were diagnosed with ASD.

“We found that the amygdala grows too rapidly between 6 and 12 months of age, during a presymptomatic period in autism, prior to when the diagnostic symptoms of autism (social difficulties and repetitive behaviors) are evident and lead to the later diagnosis of autism,” Dr. Shen said in an interview.

This brain growth pattern appears to be unique to autism, as babies with the genetic disorder fragile X syndrome – another neurodevelopmental condition – showed a markedly different brain growth pattern: no differences in amygdala growth but enlargement of a different brain structure, the caudate, which was linked to increased repetitive behaviors, the investigators found.
 

Earlier intervention

Prior research has shown that children who are later diagnosed with ASD often display problems in infancy with how they attend to visual stimuli in their surroundings.

These early problems with processing visual and sensory information may put increased stress on the amygdala, potentially leading to amygdala hyperactivity, deficits in pruning dendritic connections, and overgrowth, Dr. Shen and colleagues hypothesize.

Amygdala overgrowth has also been linked to chronic stress in studies of other psychiatric conditions, such as depression and anxiety, and may provide a clue to understanding this observation in infants who later develop autism.

“This research suggests that an optimal time to begin supports for children who are at the highest likelihood of developing autism may be during the first year of life: to improve early precursors to social development, such as sensory processing, in babies even before social difficulties arise,” Dr. Shen said.

Cyrus A. Raji, MD, PhD, assistant professor of radiology and neurology, Washington University, St. Louis, said, “What makes this study important is the finding of abnormally increased amygdala growth rate in autism using a longitudinal design that focuses on earlier development.”

“While we are typically used to understanding brain structure as abnormally decreasing over time in certain disorders like Alzheimer’s disease, this study challenges us to understand that too much brain volume growth can also be abnormal in specific conditions,” Dr. Raji added.

This research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, and National Institute of Mental Health, along with Autism Speaks and the Simons Foundation. Dr. Shen and Dr. Raji have disclosed no relevant financial relationships.

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

A new study suggests that overgrowth of the amygdala in infants during the first 6-12 months of life is tied to a later diagnosis of autism spectrum disorder (ASD).

“The faster the amygdala grew in infancy, the more social difficulties the child showed when diagnosed with autism a year later,” first author Mark Shen, PhD, assistant professor of psychiatry and neuroscience, University of North Carolina, Chapel Hill, told this news organization.

The study was published online  in the American Journal of Psychiatry.
 

Unique to autism

The amygdala plays a key role in processing memory, emotional responses, and decisionmaking. 

It’s long been known that the amygdala is abnormally large in school-aged children with ASD, but until now, it was not known precisely when aberrant amygdala growth happens, what the clinical consequences may be, and whether amygdala overgrowth is unique to autism.

To investigate, Dr. Shen and colleagues evaluated 1,099 longitudinal MRI scans obtained during natural sleep at 6, 12, and 24 months of age in 408 infants in the Infant Brain Imaging Study (IBIS) Network.

The cohort included 58 infants at high likelihood of developing ASD who were later diagnosed with the disorder, 212 infants at high likelihood of ASD who did not develop ASD, 109 typically-developing control infants, and 29 infants with fragile X syndrome.

At 6 months, infants who developed ASD had typically sized amygdala volumes but showed significantly faster amygdala growth between 6 and 24 months, such that by 12 months the ASD group had significantly larger amygdala volume (Cohen’s d = 0.56), compared with all other groups.

Amygdala growth rate between 6 and 12 months was significantly associated with greater social deficits at 24 months when the children were diagnosed with ASD.

“We found that the amygdala grows too rapidly between 6 and 12 months of age, during a presymptomatic period in autism, prior to when the diagnostic symptoms of autism (social difficulties and repetitive behaviors) are evident and lead to the later diagnosis of autism,” Dr. Shen said in an interview.

This brain growth pattern appears to be unique to autism, as babies with the genetic disorder fragile X syndrome – another neurodevelopmental condition – showed a markedly different brain growth pattern: no differences in amygdala growth but enlargement of a different brain structure, the caudate, which was linked to increased repetitive behaviors, the investigators found.
 

Earlier intervention

Prior research has shown that children who are later diagnosed with ASD often display problems in infancy with how they attend to visual stimuli in their surroundings.

These early problems with processing visual and sensory information may put increased stress on the amygdala, potentially leading to amygdala hyperactivity, deficits in pruning dendritic connections, and overgrowth, Dr. Shen and colleagues hypothesize.

Amygdala overgrowth has also been linked to chronic stress in studies of other psychiatric conditions, such as depression and anxiety, and may provide a clue to understanding this observation in infants who later develop autism.

“This research suggests that an optimal time to begin supports for children who are at the highest likelihood of developing autism may be during the first year of life: to improve early precursors to social development, such as sensory processing, in babies even before social difficulties arise,” Dr. Shen said.

Cyrus A. Raji, MD, PhD, assistant professor of radiology and neurology, Washington University, St. Louis, said, “What makes this study important is the finding of abnormally increased amygdala growth rate in autism using a longitudinal design that focuses on earlier development.”

“While we are typically used to understanding brain structure as abnormally decreasing over time in certain disorders like Alzheimer’s disease, this study challenges us to understand that too much brain volume growth can also be abnormal in specific conditions,” Dr. Raji added.

This research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, and National Institute of Mental Health, along with Autism Speaks and the Simons Foundation. Dr. Shen and Dr. Raji have disclosed no relevant financial relationships.

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

A new study suggests that overgrowth of the amygdala in infants during the first 6-12 months of life is tied to a later diagnosis of autism spectrum disorder (ASD).

“The faster the amygdala grew in infancy, the more social difficulties the child showed when diagnosed with autism a year later,” first author Mark Shen, PhD, assistant professor of psychiatry and neuroscience, University of North Carolina, Chapel Hill, told this news organization.

The study was published online  in the American Journal of Psychiatry.
 

Unique to autism

The amygdala plays a key role in processing memory, emotional responses, and decisionmaking. 

It’s long been known that the amygdala is abnormally large in school-aged children with ASD, but until now, it was not known precisely when aberrant amygdala growth happens, what the clinical consequences may be, and whether amygdala overgrowth is unique to autism.

To investigate, Dr. Shen and colleagues evaluated 1,099 longitudinal MRI scans obtained during natural sleep at 6, 12, and 24 months of age in 408 infants in the Infant Brain Imaging Study (IBIS) Network.

The cohort included 58 infants at high likelihood of developing ASD who were later diagnosed with the disorder, 212 infants at high likelihood of ASD who did not develop ASD, 109 typically-developing control infants, and 29 infants with fragile X syndrome.

At 6 months, infants who developed ASD had typically sized amygdala volumes but showed significantly faster amygdala growth between 6 and 24 months, such that by 12 months the ASD group had significantly larger amygdala volume (Cohen’s d = 0.56), compared with all other groups.

Amygdala growth rate between 6 and 12 months was significantly associated with greater social deficits at 24 months when the children were diagnosed with ASD.

“We found that the amygdala grows too rapidly between 6 and 12 months of age, during a presymptomatic period in autism, prior to when the diagnostic symptoms of autism (social difficulties and repetitive behaviors) are evident and lead to the later diagnosis of autism,” Dr. Shen said in an interview.

This brain growth pattern appears to be unique to autism, as babies with the genetic disorder fragile X syndrome – another neurodevelopmental condition – showed a markedly different brain growth pattern: no differences in amygdala growth but enlargement of a different brain structure, the caudate, which was linked to increased repetitive behaviors, the investigators found.
 

Earlier intervention

Prior research has shown that children who are later diagnosed with ASD often display problems in infancy with how they attend to visual stimuli in their surroundings.

These early problems with processing visual and sensory information may put increased stress on the amygdala, potentially leading to amygdala hyperactivity, deficits in pruning dendritic connections, and overgrowth, Dr. Shen and colleagues hypothesize.

Amygdala overgrowth has also been linked to chronic stress in studies of other psychiatric conditions, such as depression and anxiety, and may provide a clue to understanding this observation in infants who later develop autism.

“This research suggests that an optimal time to begin supports for children who are at the highest likelihood of developing autism may be during the first year of life: to improve early precursors to social development, such as sensory processing, in babies even before social difficulties arise,” Dr. Shen said.

Cyrus A. Raji, MD, PhD, assistant professor of radiology and neurology, Washington University, St. Louis, said, “What makes this study important is the finding of abnormally increased amygdala growth rate in autism using a longitudinal design that focuses on earlier development.”

“While we are typically used to understanding brain structure as abnormally decreasing over time in certain disorders like Alzheimer’s disease, this study challenges us to understand that too much brain volume growth can also be abnormal in specific conditions,” Dr. Raji added.

This research was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, and National Institute of Mental Health, along with Autism Speaks and the Simons Foundation. Dr. Shen and Dr. Raji have disclosed no relevant financial relationships.

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

Physical fitness has been linked to a lower risk of Alzheimer’s disease, but even moderate levels of cardiorespiratory fitness offer some protection, new findings suggest. “One exciting finding of this study is that as people’s fitness improved, their risk of Alzheimer’s disease decreased – it was not an all-or-nothing proposition,” study investigator Edward Zamrini, MD, of the Washington DC VA Medical Center, said in a news release.

The findings suggest that people can work toward making incremental changes and improvements in their physical fitness, which may help decrease their risk of dementia, Dr. Zamrini added.

The findings were presented at the 2022 annual meeting of the American Academy of Neurology.
 

Effective prevention strategy

Using the Veterans Health Administration database, Dr. Zamrini and colleagues identified 649,605 veterans (mean age, 61 years) free of Alzheimer’s disease and related disorders (ADRD) when they completed standardized exercise treadmill tests between 2000 and 2017.

They divided participants into five age-specific fitness groups, from least fit to most fit, based on peak metabolic equivalents (METs) achieved during the treadmill test: lowest-fit (METs, ±3.8), low-fit (METs, ±5.8), moderate-fit (METs, ±7.5), fit (METs, ±9.2), and highest-fit (METs, ±11.7).

In unadjusted analysis, veterans with the lowest cardiorespiratory fitness developed ADRD at a rate of 9.5 cases per 1,000 person-years, compared with a rate of 6.4 cases per 1,000 person-years for the most fit group (P < .001).

After adjusting for factors that could affect risk of ADRD, compared with the lowest-fit group, the highest-fit and fit groups were 33% and 26% less likely to develop ADRD, respectively, while the moderate-fit and low-fit groups were 20% and 13% less likely to develop the disease, respectively.

The next vital sign?

Commenting on the study, Shaheen E. Lakhan, MD, PhD, a neurologist in Boston, noted that “for decades and with increasing body of support from studies like this, we have known that preventing dementia is based on healthy behaviors for the brain including a proper diet (NASH and/or Mediterranean), exercise regimen (aerobic/cardio more than anaerobic/weight-lifting), sleep hygiene, and social and intellectual engagements.”

“Frankly, what’s good for the body is good for the brain,” said Dr. Lakhan.

“It should be noted that the measure studied here is cardiorespiratory fitness, which has been associated with heart disease and resulting death, death from any cause, and now brain health,” Dr. Lakhan said.

“This powerful predictor may in fact be the next vital sign, after your heart rate and blood pressure, from which your primary care provider can make a personalized treatment plan,” he added.

“Accelerating this process, the ability to measure cardiorespiratory fitness traditionally from huge stationary machines down to wearables like a watch or ring, or even your iPhone or Android, is just on the horizon,” Dr. Lakhan said.

“Instead of tracking just your weight, shape, and BMI, personal fitness may be tailored to optimizing this indicator and further empowering individuals to take charge of their health,” he said.

The study was supported by the National Institute on Aging, the National Institutes of Health, the U.S. Department of Veterans Affairs, the Washington DC VA Medical Center, and George Washington University. Dr. Zamrini and Dr. Lakhan have disclosed no relevant financial relationships.

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

Physical fitness has been linked to a lower risk of Alzheimer’s disease, but even moderate levels of cardiorespiratory fitness offer some protection, new findings suggest. “One exciting finding of this study is that as people’s fitness improved, their risk of Alzheimer’s disease decreased – it was not an all-or-nothing proposition,” study investigator Edward Zamrini, MD, of the Washington DC VA Medical Center, said in a news release.

The findings suggest that people can work toward making incremental changes and improvements in their physical fitness, which may help decrease their risk of dementia, Dr. Zamrini added.

The findings were presented at the 2022 annual meeting of the American Academy of Neurology.
 

Effective prevention strategy

Using the Veterans Health Administration database, Dr. Zamrini and colleagues identified 649,605 veterans (mean age, 61 years) free of Alzheimer’s disease and related disorders (ADRD) when they completed standardized exercise treadmill tests between 2000 and 2017.

They divided participants into five age-specific fitness groups, from least fit to most fit, based on peak metabolic equivalents (METs) achieved during the treadmill test: lowest-fit (METs, ±3.8), low-fit (METs, ±5.8), moderate-fit (METs, ±7.5), fit (METs, ±9.2), and highest-fit (METs, ±11.7).

In unadjusted analysis, veterans with the lowest cardiorespiratory fitness developed ADRD at a rate of 9.5 cases per 1,000 person-years, compared with a rate of 6.4 cases per 1,000 person-years for the most fit group (P < .001).

After adjusting for factors that could affect risk of ADRD, compared with the lowest-fit group, the highest-fit and fit groups were 33% and 26% less likely to develop ADRD, respectively, while the moderate-fit and low-fit groups were 20% and 13% less likely to develop the disease, respectively.

The next vital sign?

Commenting on the study, Shaheen E. Lakhan, MD, PhD, a neurologist in Boston, noted that “for decades and with increasing body of support from studies like this, we have known that preventing dementia is based on healthy behaviors for the brain including a proper diet (NASH and/or Mediterranean), exercise regimen (aerobic/cardio more than anaerobic/weight-lifting), sleep hygiene, and social and intellectual engagements.”

“Frankly, what’s good for the body is good for the brain,” said Dr. Lakhan.

“It should be noted that the measure studied here is cardiorespiratory fitness, which has been associated with heart disease and resulting death, death from any cause, and now brain health,” Dr. Lakhan said.

“This powerful predictor may in fact be the next vital sign, after your heart rate and blood pressure, from which your primary care provider can make a personalized treatment plan,” he added.

“Accelerating this process, the ability to measure cardiorespiratory fitness traditionally from huge stationary machines down to wearables like a watch or ring, or even your iPhone or Android, is just on the horizon,” Dr. Lakhan said.

“Instead of tracking just your weight, shape, and BMI, personal fitness may be tailored to optimizing this indicator and further empowering individuals to take charge of their health,” he said.

The study was supported by the National Institute on Aging, the National Institutes of Health, the U.S. Department of Veterans Affairs, the Washington DC VA Medical Center, and George Washington University. Dr. Zamrini and Dr. Lakhan have disclosed no relevant financial relationships.

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

Physical fitness has been linked to a lower risk of Alzheimer’s disease, but even moderate levels of cardiorespiratory fitness offer some protection, new findings suggest. “One exciting finding of this study is that as people’s fitness improved, their risk of Alzheimer’s disease decreased – it was not an all-or-nothing proposition,” study investigator Edward Zamrini, MD, of the Washington DC VA Medical Center, said in a news release.

The findings suggest that people can work toward making incremental changes and improvements in their physical fitness, which may help decrease their risk of dementia, Dr. Zamrini added.

The findings were presented at the 2022 annual meeting of the American Academy of Neurology.
 

Effective prevention strategy

Using the Veterans Health Administration database, Dr. Zamrini and colleagues identified 649,605 veterans (mean age, 61 years) free of Alzheimer’s disease and related disorders (ADRD) when they completed standardized exercise treadmill tests between 2000 and 2017.

They divided participants into five age-specific fitness groups, from least fit to most fit, based on peak metabolic equivalents (METs) achieved during the treadmill test: lowest-fit (METs, ±3.8), low-fit (METs, ±5.8), moderate-fit (METs, ±7.5), fit (METs, ±9.2), and highest-fit (METs, ±11.7).

In unadjusted analysis, veterans with the lowest cardiorespiratory fitness developed ADRD at a rate of 9.5 cases per 1,000 person-years, compared with a rate of 6.4 cases per 1,000 person-years for the most fit group (P < .001).

After adjusting for factors that could affect risk of ADRD, compared with the lowest-fit group, the highest-fit and fit groups were 33% and 26% less likely to develop ADRD, respectively, while the moderate-fit and low-fit groups were 20% and 13% less likely to develop the disease, respectively.

The next vital sign?

Commenting on the study, Shaheen E. Lakhan, MD, PhD, a neurologist in Boston, noted that “for decades and with increasing body of support from studies like this, we have known that preventing dementia is based on healthy behaviors for the brain including a proper diet (NASH and/or Mediterranean), exercise regimen (aerobic/cardio more than anaerobic/weight-lifting), sleep hygiene, and social and intellectual engagements.”

“Frankly, what’s good for the body is good for the brain,” said Dr. Lakhan.

“It should be noted that the measure studied here is cardiorespiratory fitness, which has been associated with heart disease and resulting death, death from any cause, and now brain health,” Dr. Lakhan said.

“This powerful predictor may in fact be the next vital sign, after your heart rate and blood pressure, from which your primary care provider can make a personalized treatment plan,” he added.

“Accelerating this process, the ability to measure cardiorespiratory fitness traditionally from huge stationary machines down to wearables like a watch or ring, or even your iPhone or Android, is just on the horizon,” Dr. Lakhan said.

“Instead of tracking just your weight, shape, and BMI, personal fitness may be tailored to optimizing this indicator and further empowering individuals to take charge of their health,” he said.

The study was supported by the National Institute on Aging, the National Institutes of Health, the U.S. Department of Veterans Affairs, the Washington DC VA Medical Center, and George Washington University. Dr. Zamrini and Dr. Lakhan have disclosed no relevant financial relationships.

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