Neurology

Children at risk of neonatal hypoglycemia who were screened and treated if needed showed no difference in educational achievement from controls at age 9-10 years, based on data from 480 children.

Previous studies have shown an increased risk of poor executive and visual-motor function in children with neonatal hypoglycemia, but the effect on later childhood academic performance remains unclear, wrote Rajesh Shah, PhD, of the University of Auckland, New Zealand, and colleagues.

In a prospective cohort study published in JAMA, the researchers enrolled moderate to late preterm and term infants born at increased risk for hypoglycemia; those with episodes of hypoglycemia were treated to maintain a blood glucose concentration of at least 47 mg/dL.

The study population was enrolled between 2006 and 2010 at a regional perinatal center in New Zealand, and their educational achievement was assessed 9-10 years later. The primary outcome of low educational achievement was defined as performing below the normal curriculum level in standardized tests of reading comprehension or math. The researchers also identified 47 secondary outcomes related to executive function, visual-motor function, psychosocial adaptation, and general health.

Rates of low educational achievement were not significantly different for children with and without neonatal hypoglycemia (47% vs. 48%, adjusted risk ratio 0.95).

No significant differences appeared between the two groups for any secondary outcomes, including reading comprehension, math, behavior manifestations of executive function, fine motor function, autism traits, and overall well-being, the researchers noted.

However, children with neonatal hypoglycemia were significantly less likely to be rated as below or well below reading curriculum level by teachers compared to those without neonatal hypoglycemia (24% vs. 31%).

The researchers cited a previous study of the same patient cohort at age 4.5 years, which suggested an association between adverse neurodevelopmental outcomes and infant hypoglycemia. However, the reason this association did not persist at age 9-10 years remains unclear, the researchers wrote in their discussion. “Early disturbances in brain development may have diminishing effects over time due to neuroplasticity, that is, reorganization of neural networks, or delayed maturation with mid-childhood catch-up in neurocognitive function,” they said.

The study findings were limited by several factors including the lack of data on several measures of cognition, notably processing speed, and a lack of adjustment for intelligence quotient at age 4.5 years, the lack of data on any treatment for developmental impairment, and the inclusion of a population with well-managed hypoglycemia, the researchers said.

However, the results were strengthened by having a sample size large enough to detect associations, the prospective design, and the accurate measure of neonatal glycemic exposure, they said. Although the results suggest that at-risk children reach similar endpoints by the end of primary school, “efforts to prevent and optimize adverse pregnancy conditions remain important, and developmental surveillance after birth should be considered for at-risk infants,” they concluded.

In a related study published in JAMA, Taygen Edwards and colleagues found that prophylactic oral dextrose gel had no significant effect on neurosensory function.

The study, a prospective follow-up of a multicenter randomized trial, included 1,197 later preterm or term infants deemed at risk for neonatal hypoglycemia. The infants (49% of whom were female) were randomized to prophylactic 40% dextrose gel or a placebo, massaged into the buccal mucosa at 1 hour after birth.

The primary outcome was neurosensory impairment at 2 years of age, which was assessed by neurologic examination, parent-reported medical questionnaires, Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), performance-based executive function, Behavior Rating Inventory of Executive Function–Preschool Version, motion coherence thresholds, growth, and body composition.

At 2 years of age, the prevalence of neurosensory impairment was 21% and 19%, respectively, in infants randomized to prophylactic oral dextrose gel and placebo, a nonsignificant difference. No differences between the two groups were noted for cognitive and language delays, or low performance-based overall executive function. However, infants randomized to dextrose gel had significantly higher risk of motor delay compared to placebo (2.5% vs. 0.7%) and significantly lower Bayley-III composite scores for cognitive, language, and motor performance.

No significant differences were noted between the groups in the areas of moderate or severe neurosensory impairment, hearing impairment, cerebral palsy, developmental delay, above-average development, socioemotional and adaptive behavior, questionnaire-based executive function, low visual processing, history of seizures, allergic and infectious diseases, growth, and body composition.

The results are consistent with previous studies on the safety of dextrose gel, the researchers wrote in their discussion. However, the absolute difference of 7% in the primary outcome may be clinically important, they noted. “Caution is warranted before using prophylactic dextrose gel,” they said.

The researchers noted the results of a dose-finding trial that suggested improved scores on language, executive function, and motor skills in unadjusted analysis with higher doses of dextrose gel, but the reason for these findings remains unknown, they said.

The study findings were limited by the potential underpowering to detect small, but significant differences, and possible lack of generalizability because the majority of the participants were children of mothers with diabetes.

The results were strengthened by the high follow-up rate and comprehensive assessments, and highlight the need for additional research with longer follow-up, the researchers said.
 

Findings fuel further exploration

Although hypoglycemia is common in newborns, its management and potential outcomes remain subjects for debate, Paul J. Rozance, MD, of the University of Colorado, Aurora, wrote in an editorial accompanying both studies.

“Often, the same features that increase the risk of hypoglycemia in newborns also increase the risk for poor outcomes independent of hypoglycemia,” he said.

The study by Shah and colleagues was not a randomized trial of a specific management strategy, Dr. Rozance noted. However, the high rate of low educational attainment in children not exposed to dextrose gel emphasizes the need for more effective management of infant hypoglycemia, he said. “The findings also suggest that antenatal conditions that are associated with increased risk of hypoglycemia among newborns are associated with increased risk for impaired neurodevelopment and educational achievement, independent of neonatal hypoglycemia,” he said. The study findings contrast with those of an earlier study showing low academic achievement association with early transient hypoglycemia, which could argue for earlier intervention, he noted.

The study by Edwards and colleagues addressed the potential value of dextrose gel as an early intervention to prevent neonatal hypoglycemia, said Dr. Rozance.

“The 95% CI for the primary outcome of neurosensory impairment included up to a 7% increased risk for neurosensory impairment in the prophylactic dextrose gel group. The 7% increased risk was defined by the investigators as potentially clinically important, and the study may have been underpowered to detect small differences in the primary outcome,” he wrote.

Although the reasons for adverse outcomes in children given prophylactic dextrose gel remain unclear, “incorporation of prophylactic dextrose gel into clinical practice should await further research,” he said.

Regarding such research, Dr. Rozance proposed an “ideal study,” that would “randomize newborns with hypoglycemia to treatment or no treatment, although equipoise and ethical support for such a study are lacking. Another strategy would be to randomize newborns with hypoglycemia to receive low- or high-treatment glucose concentration goals,” he noted.

The relationship between hypoglycemia and impaired neurodevelopment is yet to be determined, but the two studies provide new evidence for the clinical importance and need for management of neonatal hypoglycemia and subsequent neurodevelopmental outcomes, he concluded.

The study by Shah and colleagues was supported by the Health Research Council of New Zealand and the Maurice and Phyllis Paykel Trust. Dr. Shah disclosed a doctoral fellowship from the University of Auckland. The study by Edwards and colleagues was supported by the Health Research Council of New Zealand and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Ms. Edwards had no financial conflicts to disclose. Dr. Rozance disclosed receiving a StatStrip from Nova Biomedical for use in his laboratory.

Children at risk of neonatal hypoglycemia who were screened and treated if needed showed no difference in educational achievement from controls at age 9-10 years, based on data from 480 children.

Previous studies have shown an increased risk of poor executive and visual-motor function in children with neonatal hypoglycemia, but the effect on later childhood academic performance remains unclear, wrote Rajesh Shah, PhD, of the University of Auckland, New Zealand, and colleagues.

In a prospective cohort study published in JAMA, the researchers enrolled moderate to late preterm and term infants born at increased risk for hypoglycemia; those with episodes of hypoglycemia were treated to maintain a blood glucose concentration of at least 47 mg/dL.

The study population was enrolled between 2006 and 2010 at a regional perinatal center in New Zealand, and their educational achievement was assessed 9-10 years later. The primary outcome of low educational achievement was defined as performing below the normal curriculum level in standardized tests of reading comprehension or math. The researchers also identified 47 secondary outcomes related to executive function, visual-motor function, psychosocial adaptation, and general health.

Rates of low educational achievement were not significantly different for children with and without neonatal hypoglycemia (47% vs. 48%, adjusted risk ratio 0.95).

No significant differences appeared between the two groups for any secondary outcomes, including reading comprehension, math, behavior manifestations of executive function, fine motor function, autism traits, and overall well-being, the researchers noted.

However, children with neonatal hypoglycemia were significantly less likely to be rated as below or well below reading curriculum level by teachers compared to those without neonatal hypoglycemia (24% vs. 31%).

The researchers cited a previous study of the same patient cohort at age 4.5 years, which suggested an association between adverse neurodevelopmental outcomes and infant hypoglycemia. However, the reason this association did not persist at age 9-10 years remains unclear, the researchers wrote in their discussion. “Early disturbances in brain development may have diminishing effects over time due to neuroplasticity, that is, reorganization of neural networks, or delayed maturation with mid-childhood catch-up in neurocognitive function,” they said.

The study findings were limited by several factors including the lack of data on several measures of cognition, notably processing speed, and a lack of adjustment for intelligence quotient at age 4.5 years, the lack of data on any treatment for developmental impairment, and the inclusion of a population with well-managed hypoglycemia, the researchers said.

However, the results were strengthened by having a sample size large enough to detect associations, the prospective design, and the accurate measure of neonatal glycemic exposure, they said. Although the results suggest that at-risk children reach similar endpoints by the end of primary school, “efforts to prevent and optimize adverse pregnancy conditions remain important, and developmental surveillance after birth should be considered for at-risk infants,” they concluded.

In a related study published in JAMA, Taygen Edwards and colleagues found that prophylactic oral dextrose gel had no significant effect on neurosensory function.

The study, a prospective follow-up of a multicenter randomized trial, included 1,197 later preterm or term infants deemed at risk for neonatal hypoglycemia. The infants (49% of whom were female) were randomized to prophylactic 40% dextrose gel or a placebo, massaged into the buccal mucosa at 1 hour after birth.

The primary outcome was neurosensory impairment at 2 years of age, which was assessed by neurologic examination, parent-reported medical questionnaires, Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), performance-based executive function, Behavior Rating Inventory of Executive Function–Preschool Version, motion coherence thresholds, growth, and body composition.

At 2 years of age, the prevalence of neurosensory impairment was 21% and 19%, respectively, in infants randomized to prophylactic oral dextrose gel and placebo, a nonsignificant difference. No differences between the two groups were noted for cognitive and language delays, or low performance-based overall executive function. However, infants randomized to dextrose gel had significantly higher risk of motor delay compared to placebo (2.5% vs. 0.7%) and significantly lower Bayley-III composite scores for cognitive, language, and motor performance.

No significant differences were noted between the groups in the areas of moderate or severe neurosensory impairment, hearing impairment, cerebral palsy, developmental delay, above-average development, socioemotional and adaptive behavior, questionnaire-based executive function, low visual processing, history of seizures, allergic and infectious diseases, growth, and body composition.

The results are consistent with previous studies on the safety of dextrose gel, the researchers wrote in their discussion. However, the absolute difference of 7% in the primary outcome may be clinically important, they noted. “Caution is warranted before using prophylactic dextrose gel,” they said.

The researchers noted the results of a dose-finding trial that suggested improved scores on language, executive function, and motor skills in unadjusted analysis with higher doses of dextrose gel, but the reason for these findings remains unknown, they said.

The study findings were limited by the potential underpowering to detect small, but significant differences, and possible lack of generalizability because the majority of the participants were children of mothers with diabetes.

The results were strengthened by the high follow-up rate and comprehensive assessments, and highlight the need for additional research with longer follow-up, the researchers said.
 

Findings fuel further exploration

Although hypoglycemia is common in newborns, its management and potential outcomes remain subjects for debate, Paul J. Rozance, MD, of the University of Colorado, Aurora, wrote in an editorial accompanying both studies.

“Often, the same features that increase the risk of hypoglycemia in newborns also increase the risk for poor outcomes independent of hypoglycemia,” he said.

The study by Shah and colleagues was not a randomized trial of a specific management strategy, Dr. Rozance noted. However, the high rate of low educational attainment in children not exposed to dextrose gel emphasizes the need for more effective management of infant hypoglycemia, he said. “The findings also suggest that antenatal conditions that are associated with increased risk of hypoglycemia among newborns are associated with increased risk for impaired neurodevelopment and educational achievement, independent of neonatal hypoglycemia,” he said. The study findings contrast with those of an earlier study showing low academic achievement association with early transient hypoglycemia, which could argue for earlier intervention, he noted.

The study by Edwards and colleagues addressed the potential value of dextrose gel as an early intervention to prevent neonatal hypoglycemia, said Dr. Rozance.

“The 95% CI for the primary outcome of neurosensory impairment included up to a 7% increased risk for neurosensory impairment in the prophylactic dextrose gel group. The 7% increased risk was defined by the investigators as potentially clinically important, and the study may have been underpowered to detect small differences in the primary outcome,” he wrote.

Although the reasons for adverse outcomes in children given prophylactic dextrose gel remain unclear, “incorporation of prophylactic dextrose gel into clinical practice should await further research,” he said.

Regarding such research, Dr. Rozance proposed an “ideal study,” that would “randomize newborns with hypoglycemia to treatment or no treatment, although equipoise and ethical support for such a study are lacking. Another strategy would be to randomize newborns with hypoglycemia to receive low- or high-treatment glucose concentration goals,” he noted.

The relationship between hypoglycemia and impaired neurodevelopment is yet to be determined, but the two studies provide new evidence for the clinical importance and need for management of neonatal hypoglycemia and subsequent neurodevelopmental outcomes, he concluded.

The study by Shah and colleagues was supported by the Health Research Council of New Zealand and the Maurice and Phyllis Paykel Trust. Dr. Shah disclosed a doctoral fellowship from the University of Auckland. The study by Edwards and colleagues was supported by the Health Research Council of New Zealand and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Ms. Edwards had no financial conflicts to disclose. Dr. Rozance disclosed receiving a StatStrip from Nova Biomedical for use in his laboratory.

Children at risk of neonatal hypoglycemia who were screened and treated if needed showed no difference in educational achievement from controls at age 9-10 years, based on data from 480 children.

Previous studies have shown an increased risk of poor executive and visual-motor function in children with neonatal hypoglycemia, but the effect on later childhood academic performance remains unclear, wrote Rajesh Shah, PhD, of the University of Auckland, New Zealand, and colleagues.

In a prospective cohort study published in JAMA, the researchers enrolled moderate to late preterm and term infants born at increased risk for hypoglycemia; those with episodes of hypoglycemia were treated to maintain a blood glucose concentration of at least 47 mg/dL.

The study population was enrolled between 2006 and 2010 at a regional perinatal center in New Zealand, and their educational achievement was assessed 9-10 years later. The primary outcome of low educational achievement was defined as performing below the normal curriculum level in standardized tests of reading comprehension or math. The researchers also identified 47 secondary outcomes related to executive function, visual-motor function, psychosocial adaptation, and general health.

Rates of low educational achievement were not significantly different for children with and without neonatal hypoglycemia (47% vs. 48%, adjusted risk ratio 0.95).

No significant differences appeared between the two groups for any secondary outcomes, including reading comprehension, math, behavior manifestations of executive function, fine motor function, autism traits, and overall well-being, the researchers noted.

However, children with neonatal hypoglycemia were significantly less likely to be rated as below or well below reading curriculum level by teachers compared to those without neonatal hypoglycemia (24% vs. 31%).

The researchers cited a previous study of the same patient cohort at age 4.5 years, which suggested an association between adverse neurodevelopmental outcomes and infant hypoglycemia. However, the reason this association did not persist at age 9-10 years remains unclear, the researchers wrote in their discussion. “Early disturbances in brain development may have diminishing effects over time due to neuroplasticity, that is, reorganization of neural networks, or delayed maturation with mid-childhood catch-up in neurocognitive function,” they said.

The study findings were limited by several factors including the lack of data on several measures of cognition, notably processing speed, and a lack of adjustment for intelligence quotient at age 4.5 years, the lack of data on any treatment for developmental impairment, and the inclusion of a population with well-managed hypoglycemia, the researchers said.

However, the results were strengthened by having a sample size large enough to detect associations, the prospective design, and the accurate measure of neonatal glycemic exposure, they said. Although the results suggest that at-risk children reach similar endpoints by the end of primary school, “efforts to prevent and optimize adverse pregnancy conditions remain important, and developmental surveillance after birth should be considered for at-risk infants,” they concluded.

In a related study published in JAMA, Taygen Edwards and colleagues found that prophylactic oral dextrose gel had no significant effect on neurosensory function.

The study, a prospective follow-up of a multicenter randomized trial, included 1,197 later preterm or term infants deemed at risk for neonatal hypoglycemia. The infants (49% of whom were female) were randomized to prophylactic 40% dextrose gel or a placebo, massaged into the buccal mucosa at 1 hour after birth.

The primary outcome was neurosensory impairment at 2 years of age, which was assessed by neurologic examination, parent-reported medical questionnaires, Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), performance-based executive function, Behavior Rating Inventory of Executive Function–Preschool Version, motion coherence thresholds, growth, and body composition.

At 2 years of age, the prevalence of neurosensory impairment was 21% and 19%, respectively, in infants randomized to prophylactic oral dextrose gel and placebo, a nonsignificant difference. No differences between the two groups were noted for cognitive and language delays, or low performance-based overall executive function. However, infants randomized to dextrose gel had significantly higher risk of motor delay compared to placebo (2.5% vs. 0.7%) and significantly lower Bayley-III composite scores for cognitive, language, and motor performance.

No significant differences were noted between the groups in the areas of moderate or severe neurosensory impairment, hearing impairment, cerebral palsy, developmental delay, above-average development, socioemotional and adaptive behavior, questionnaire-based executive function, low visual processing, history of seizures, allergic and infectious diseases, growth, and body composition.

The results are consistent with previous studies on the safety of dextrose gel, the researchers wrote in their discussion. However, the absolute difference of 7% in the primary outcome may be clinically important, they noted. “Caution is warranted before using prophylactic dextrose gel,” they said.

The researchers noted the results of a dose-finding trial that suggested improved scores on language, executive function, and motor skills in unadjusted analysis with higher doses of dextrose gel, but the reason for these findings remains unknown, they said.

The study findings were limited by the potential underpowering to detect small, but significant differences, and possible lack of generalizability because the majority of the participants were children of mothers with diabetes.

The results were strengthened by the high follow-up rate and comprehensive assessments, and highlight the need for additional research with longer follow-up, the researchers said.
 

Findings fuel further exploration

Although hypoglycemia is common in newborns, its management and potential outcomes remain subjects for debate, Paul J. Rozance, MD, of the University of Colorado, Aurora, wrote in an editorial accompanying both studies.

“Often, the same features that increase the risk of hypoglycemia in newborns also increase the risk for poor outcomes independent of hypoglycemia,” he said.

The study by Shah and colleagues was not a randomized trial of a specific management strategy, Dr. Rozance noted. However, the high rate of low educational attainment in children not exposed to dextrose gel emphasizes the need for more effective management of infant hypoglycemia, he said. “The findings also suggest that antenatal conditions that are associated with increased risk of hypoglycemia among newborns are associated with increased risk for impaired neurodevelopment and educational achievement, independent of neonatal hypoglycemia,” he said. The study findings contrast with those of an earlier study showing low academic achievement association with early transient hypoglycemia, which could argue for earlier intervention, he noted.

The study by Edwards and colleagues addressed the potential value of dextrose gel as an early intervention to prevent neonatal hypoglycemia, said Dr. Rozance.

“The 95% CI for the primary outcome of neurosensory impairment included up to a 7% increased risk for neurosensory impairment in the prophylactic dextrose gel group. The 7% increased risk was defined by the investigators as potentially clinically important, and the study may have been underpowered to detect small differences in the primary outcome,” he wrote.

Although the reasons for adverse outcomes in children given prophylactic dextrose gel remain unclear, “incorporation of prophylactic dextrose gel into clinical practice should await further research,” he said.

Regarding such research, Dr. Rozance proposed an “ideal study,” that would “randomize newborns with hypoglycemia to treatment or no treatment, although equipoise and ethical support for such a study are lacking. Another strategy would be to randomize newborns with hypoglycemia to receive low- or high-treatment glucose concentration goals,” he noted.

The relationship between hypoglycemia and impaired neurodevelopment is yet to be determined, but the two studies provide new evidence for the clinical importance and need for management of neonatal hypoglycemia and subsequent neurodevelopmental outcomes, he concluded.

The study by Shah and colleagues was supported by the Health Research Council of New Zealand and the Maurice and Phyllis Paykel Trust. Dr. Shah disclosed a doctoral fellowship from the University of Auckland. The study by Edwards and colleagues was supported by the Health Research Council of New Zealand and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Ms. Edwards had no financial conflicts to disclose. Dr. Rozance disclosed receiving a StatStrip from Nova Biomedical for use in his laboratory.

Hospitalized COVID-19 survivors showed greater cognitive impairment 6 months later, compared with patients hospitalized for other causes, but the overall disease burden was similar, based on data from 85 adults with COVID-19.

Previous studies have shown that cognitive and neuropsychiatric symptoms can occur from 2-6 months after COVID-19 recovery, and such symptoms are known to be associated with hospitalization for other severe medical conditions, Vardan Nersesjan, MD, of Copenhagen University Hospital, and colleagues wrote.

However, it remains unknown if COVID-19 is associated with a unique pattern of cognitive and mental impairment compared with other similarly severe medical conditions, they said.

In a study published in JAMA Psychiatry (2022 Mar 23. doi: 10.1001/jamapsychiatry.2022.0284), the researchers identified 85 adult COVID-19 survivors and 61 controls with non-COVID medical conditions who were treated and released between July 2020 and July 2021. The COVID-19 patients and controls were matched for age, sex, and ICU status. Cognitive impairment was assessed using the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semistructured interview to determine subjective symptoms.

The primary outcomes were the total scores on the MoCA and any new-onset psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses such as depression, neurologic examination findings, and self-reported neuropsychiatric and cognitive symptoms. The mean age of the COVID-19 patients was 56.8 years, and 42% were women.

At 6 months’ follow-up, cognitive status was significantly lower in COVID-19 survivors, compared with controls, based on total geometric mean MoCA scores (26.7 vs. 27.5, P = .01). However, cognitive status improved significantly from 19.2 at hospital discharge to 26.1 at 6 months in 15 of the COVID-19 patients (P = .004), the researchers noted.

New-onset psychiatric diagnoses occurred in 16 COVID-19 patients and 12 of the controls (19% vs. 20%); this difference was not significant.

Secondary outcomes were not significantly different at 6 months between the groups, with the exception of anosmia, which was significantly more common in the COVID-19 patients; however, the significance disappeared in adjusted analysis, the researchers said.

The study findings were limited by several factors including the inability to prove causality because of the case-control feature and by the inability to detect small differences in neuropsychiatric outcomes, the researchers noted.

However, the results were strengthened by the use of a prospectively matched control group with similar disease severity admitted to the same hospital in the same time frame. Although the overall burden of neuropsychiatric and neurologic symptoms and diagnoses appeared similar in COVID-19 patients and those with other medical conditions, more research in larger populations is needed to determine smaller differences in neuropsychiatric profiles, the researchers noted.

Study fills research gap

The study is important at this time because, although prolonged neuropsychiatric and cognitive symptoms have been reported after COVID-19, the field lacked prospective case-control studies with well-matched controls to investigate whether these outcomes differed from those seen in other critical illnesses that had also required hospitalization, corresponding author Michael E. Benros, MD, of the Mental Health Center, Copenhagen, said in an interview.

“I was surprised that there was a significant worse cognitive functioning among COVID-19 patients 6 months after symptom onset also when compared to this well-matched control group that had been hospitalized for non–COVID-19 illness, although the absolute difference between the groups in cognition score were small,” said Dr. Benros. “Another notable finding is the large improvement in cognitive functioning from discharge to follow-up,” he added on behalf of himself and fellow corresponding author Daniel Kondziella, MD.

The study results show that cognitive function affected by COVID-19 and critical illness as observed at discharge showed a substantial improvement at 6 months after symptom onset, said Dr. Benros. “However, the cognitive function was significantly worse among severely ill COVID-19 patients 6 months after symptom onset when compared to a matched control group of individuals hospitalized for non–COVID-19 illness, although this difference in cognitive function was rather small in absolute numbers, and smaller than what had been suggested by other studies that lacked control groups. Strikingly, neuropsychiatric disorders were similar across the two groups, which was also the case when looking at neuropsychiatric symptoms.

“Larger prospective case-control studies of neuropsychiatric and cognitive functioning after COVID-19, compared with matched controls are still needed to detect smaller differences, and more detailed cognitive domains, and with longer follow-up time, which we are currently conducting,” Dr. Benros said.  
 

Controlled studies will help planning

“Lingering neuropsychiatric complications are common after COVID-19, but only controlled studies can tell us whether these complications are specific to COVID-19, rather than a general effect of having been medically ill,” Alasdair G. Rooney, MRCPsych MD PhD, of the University of Edinburgh, said in an interview. “The answer matters ultimately because COVID-19 is a new disease; societies and health care services need to be able to plan for its specific consequences.”

The health status of the control group is important as well. “Most previous studies had compared COVID-19 survivors against healthy controls or patients from a historical database. This new study compared COVID-19 survivors against those hospitalized for other medical causes over the same period,” Dr. Rooney said. “This is a more stringent test of whether COVID-19 has specific neurocognitive and neuropsychiatric consequences.

“The study found that new-onset neuropsychiatric diagnoses and symptoms were no more likely to occur after COVID-19 than after similarly severe medical illnesses,” Dr. Rooney said. “This negative finding runs counter to some earlier studies and may surprise some.” The findings need to be replicated in larger samples, but the current study shows the importance of prospectively recruiting active controls.

“In a subgroup analysis, some patients showed good improvement in cognitive scores between discharge and follow-up. While unsurprising, this is encouraging and suggests that the early postdischarge months are an important time for neurocognitive recovery,” Dr. Rooney noted.

“The findings suggest that COVID-19 may impair attention more selectively than other medical causes of hospitalization. COVID-19 survivors may also be at higher risk of significant overall cognitive impairment than survivors of similarly severe medical illnesses, after a similar duration,” said Dr. Rooney. “If the results are replicated by other prospective studies, they would suggest that there is something about COVID-19 that causes clinically significant neurocognitive difficulties in a minority of survivors.

“Larger well-controlled studies are required, with longer follow-up and more detailed neurocognitive testing,” as the duration of impairment and scope for further recovery are not known, Dr. Rooney added. Also unknown is whether COVID-19 affects attention permanently, or whether recovery is simply slower after COVID-19 compared to other medical illnesses.

“Knowing who is at the greatest risk of severe cognitive impairment after COVID-19 is important and likely to allow tailoring of more effective shielding strategies,” said Dr. Rooney. “This study was conducted before the widespread availability of vaccines for COVID-19. Long-term neuropsychiatric outcomes in vaccinated patients remain largely unknown. Arguably, these are now more important to understand, as future COVID-19 waves will occur mainly among vaccinated individuals.”

The study was supported by the Lundbeck Foundation and the Novo Nordisk Foundation. Lead author Dr. Nersesjan had no financial conflicts to disclose. Dr. Benros reported grants from Lundbeck Foundation and Novo Nordisk Foundation during the conduct of the study. Dr. Rooney had no financial conflicts to disclose.

This article was updated 3/25/22.

Hospitalized COVID-19 survivors showed greater cognitive impairment 6 months later, compared with patients hospitalized for other causes, but the overall disease burden was similar, based on data from 85 adults with COVID-19.

Previous studies have shown that cognitive and neuropsychiatric symptoms can occur from 2-6 months after COVID-19 recovery, and such symptoms are known to be associated with hospitalization for other severe medical conditions, Vardan Nersesjan, MD, of Copenhagen University Hospital, and colleagues wrote.

However, it remains unknown if COVID-19 is associated with a unique pattern of cognitive and mental impairment compared with other similarly severe medical conditions, they said.

In a study published in JAMA Psychiatry (2022 Mar 23. doi: 10.1001/jamapsychiatry.2022.0284), the researchers identified 85 adult COVID-19 survivors and 61 controls with non-COVID medical conditions who were treated and released between July 2020 and July 2021. The COVID-19 patients and controls were matched for age, sex, and ICU status. Cognitive impairment was assessed using the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semistructured interview to determine subjective symptoms.

The primary outcomes were the total scores on the MoCA and any new-onset psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses such as depression, neurologic examination findings, and self-reported neuropsychiatric and cognitive symptoms. The mean age of the COVID-19 patients was 56.8 years, and 42% were women.

At 6 months’ follow-up, cognitive status was significantly lower in COVID-19 survivors, compared with controls, based on total geometric mean MoCA scores (26.7 vs. 27.5, P = .01). However, cognitive status improved significantly from 19.2 at hospital discharge to 26.1 at 6 months in 15 of the COVID-19 patients (P = .004), the researchers noted.

New-onset psychiatric diagnoses occurred in 16 COVID-19 patients and 12 of the controls (19% vs. 20%); this difference was not significant.

Secondary outcomes were not significantly different at 6 months between the groups, with the exception of anosmia, which was significantly more common in the COVID-19 patients; however, the significance disappeared in adjusted analysis, the researchers said.

The study findings were limited by several factors including the inability to prove causality because of the case-control feature and by the inability to detect small differences in neuropsychiatric outcomes, the researchers noted.

However, the results were strengthened by the use of a prospectively matched control group with similar disease severity admitted to the same hospital in the same time frame. Although the overall burden of neuropsychiatric and neurologic symptoms and diagnoses appeared similar in COVID-19 patients and those with other medical conditions, more research in larger populations is needed to determine smaller differences in neuropsychiatric profiles, the researchers noted.

Study fills research gap

The study is important at this time because, although prolonged neuropsychiatric and cognitive symptoms have been reported after COVID-19, the field lacked prospective case-control studies with well-matched controls to investigate whether these outcomes differed from those seen in other critical illnesses that had also required hospitalization, corresponding author Michael E. Benros, MD, of the Mental Health Center, Copenhagen, said in an interview.

“I was surprised that there was a significant worse cognitive functioning among COVID-19 patients 6 months after symptom onset also when compared to this well-matched control group that had been hospitalized for non–COVID-19 illness, although the absolute difference between the groups in cognition score were small,” said Dr. Benros. “Another notable finding is the large improvement in cognitive functioning from discharge to follow-up,” he added on behalf of himself and fellow corresponding author Daniel Kondziella, MD.

The study results show that cognitive function affected by COVID-19 and critical illness as observed at discharge showed a substantial improvement at 6 months after symptom onset, said Dr. Benros. “However, the cognitive function was significantly worse among severely ill COVID-19 patients 6 months after symptom onset when compared to a matched control group of individuals hospitalized for non–COVID-19 illness, although this difference in cognitive function was rather small in absolute numbers, and smaller than what had been suggested by other studies that lacked control groups. Strikingly, neuropsychiatric disorders were similar across the two groups, which was also the case when looking at neuropsychiatric symptoms.

“Larger prospective case-control studies of neuropsychiatric and cognitive functioning after COVID-19, compared with matched controls are still needed to detect smaller differences, and more detailed cognitive domains, and with longer follow-up time, which we are currently conducting,” Dr. Benros said.  
 

Controlled studies will help planning

“Lingering neuropsychiatric complications are common after COVID-19, but only controlled studies can tell us whether these complications are specific to COVID-19, rather than a general effect of having been medically ill,” Alasdair G. Rooney, MRCPsych MD PhD, of the University of Edinburgh, said in an interview. “The answer matters ultimately because COVID-19 is a new disease; societies and health care services need to be able to plan for its specific consequences.”

The health status of the control group is important as well. “Most previous studies had compared COVID-19 survivors against healthy controls or patients from a historical database. This new study compared COVID-19 survivors against those hospitalized for other medical causes over the same period,” Dr. Rooney said. “This is a more stringent test of whether COVID-19 has specific neurocognitive and neuropsychiatric consequences.

“The study found that new-onset neuropsychiatric diagnoses and symptoms were no more likely to occur after COVID-19 than after similarly severe medical illnesses,” Dr. Rooney said. “This negative finding runs counter to some earlier studies and may surprise some.” The findings need to be replicated in larger samples, but the current study shows the importance of prospectively recruiting active controls.

“In a subgroup analysis, some patients showed good improvement in cognitive scores between discharge and follow-up. While unsurprising, this is encouraging and suggests that the early postdischarge months are an important time for neurocognitive recovery,” Dr. Rooney noted.

“The findings suggest that COVID-19 may impair attention more selectively than other medical causes of hospitalization. COVID-19 survivors may also be at higher risk of significant overall cognitive impairment than survivors of similarly severe medical illnesses, after a similar duration,” said Dr. Rooney. “If the results are replicated by other prospective studies, they would suggest that there is something about COVID-19 that causes clinically significant neurocognitive difficulties in a minority of survivors.

“Larger well-controlled studies are required, with longer follow-up and more detailed neurocognitive testing,” as the duration of impairment and scope for further recovery are not known, Dr. Rooney added. Also unknown is whether COVID-19 affects attention permanently, or whether recovery is simply slower after COVID-19 compared to other medical illnesses.

“Knowing who is at the greatest risk of severe cognitive impairment after COVID-19 is important and likely to allow tailoring of more effective shielding strategies,” said Dr. Rooney. “This study was conducted before the widespread availability of vaccines for COVID-19. Long-term neuropsychiatric outcomes in vaccinated patients remain largely unknown. Arguably, these are now more important to understand, as future COVID-19 waves will occur mainly among vaccinated individuals.”

The study was supported by the Lundbeck Foundation and the Novo Nordisk Foundation. Lead author Dr. Nersesjan had no financial conflicts to disclose. Dr. Benros reported grants from Lundbeck Foundation and Novo Nordisk Foundation during the conduct of the study. Dr. Rooney had no financial conflicts to disclose.

This article was updated 3/25/22.

Hospitalized COVID-19 survivors showed greater cognitive impairment 6 months later, compared with patients hospitalized for other causes, but the overall disease burden was similar, based on data from 85 adults with COVID-19.

Previous studies have shown that cognitive and neuropsychiatric symptoms can occur from 2-6 months after COVID-19 recovery, and such symptoms are known to be associated with hospitalization for other severe medical conditions, Vardan Nersesjan, MD, of Copenhagen University Hospital, and colleagues wrote.

However, it remains unknown if COVID-19 is associated with a unique pattern of cognitive and mental impairment compared with other similarly severe medical conditions, they said.

In a study published in JAMA Psychiatry (2022 Mar 23. doi: 10.1001/jamapsychiatry.2022.0284), the researchers identified 85 adult COVID-19 survivors and 61 controls with non-COVID medical conditions who were treated and released between July 2020 and July 2021. The COVID-19 patients and controls were matched for age, sex, and ICU status. Cognitive impairment was assessed using the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semistructured interview to determine subjective symptoms.

The primary outcomes were the total scores on the MoCA and any new-onset psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses such as depression, neurologic examination findings, and self-reported neuropsychiatric and cognitive symptoms. The mean age of the COVID-19 patients was 56.8 years, and 42% were women.

At 6 months’ follow-up, cognitive status was significantly lower in COVID-19 survivors, compared with controls, based on total geometric mean MoCA scores (26.7 vs. 27.5, P = .01). However, cognitive status improved significantly from 19.2 at hospital discharge to 26.1 at 6 months in 15 of the COVID-19 patients (P = .004), the researchers noted.

New-onset psychiatric diagnoses occurred in 16 COVID-19 patients and 12 of the controls (19% vs. 20%); this difference was not significant.

Secondary outcomes were not significantly different at 6 months between the groups, with the exception of anosmia, which was significantly more common in the COVID-19 patients; however, the significance disappeared in adjusted analysis, the researchers said.

The study findings were limited by several factors including the inability to prove causality because of the case-control feature and by the inability to detect small differences in neuropsychiatric outcomes, the researchers noted.

However, the results were strengthened by the use of a prospectively matched control group with similar disease severity admitted to the same hospital in the same time frame. Although the overall burden of neuropsychiatric and neurologic symptoms and diagnoses appeared similar in COVID-19 patients and those with other medical conditions, more research in larger populations is needed to determine smaller differences in neuropsychiatric profiles, the researchers noted.

Study fills research gap

The study is important at this time because, although prolonged neuropsychiatric and cognitive symptoms have been reported after COVID-19, the field lacked prospective case-control studies with well-matched controls to investigate whether these outcomes differed from those seen in other critical illnesses that had also required hospitalization, corresponding author Michael E. Benros, MD, of the Mental Health Center, Copenhagen, said in an interview.

“I was surprised that there was a significant worse cognitive functioning among COVID-19 patients 6 months after symptom onset also when compared to this well-matched control group that had been hospitalized for non–COVID-19 illness, although the absolute difference between the groups in cognition score were small,” said Dr. Benros. “Another notable finding is the large improvement in cognitive functioning from discharge to follow-up,” he added on behalf of himself and fellow corresponding author Daniel Kondziella, MD.

The study results show that cognitive function affected by COVID-19 and critical illness as observed at discharge showed a substantial improvement at 6 months after symptom onset, said Dr. Benros. “However, the cognitive function was significantly worse among severely ill COVID-19 patients 6 months after symptom onset when compared to a matched control group of individuals hospitalized for non–COVID-19 illness, although this difference in cognitive function was rather small in absolute numbers, and smaller than what had been suggested by other studies that lacked control groups. Strikingly, neuropsychiatric disorders were similar across the two groups, which was also the case when looking at neuropsychiatric symptoms.

“Larger prospective case-control studies of neuropsychiatric and cognitive functioning after COVID-19, compared with matched controls are still needed to detect smaller differences, and more detailed cognitive domains, and with longer follow-up time, which we are currently conducting,” Dr. Benros said.  
 

Controlled studies will help planning

“Lingering neuropsychiatric complications are common after COVID-19, but only controlled studies can tell us whether these complications are specific to COVID-19, rather than a general effect of having been medically ill,” Alasdair G. Rooney, MRCPsych MD PhD, of the University of Edinburgh, said in an interview. “The answer matters ultimately because COVID-19 is a new disease; societies and health care services need to be able to plan for its specific consequences.”

The health status of the control group is important as well. “Most previous studies had compared COVID-19 survivors against healthy controls or patients from a historical database. This new study compared COVID-19 survivors against those hospitalized for other medical causes over the same period,” Dr. Rooney said. “This is a more stringent test of whether COVID-19 has specific neurocognitive and neuropsychiatric consequences.

“The study found that new-onset neuropsychiatric diagnoses and symptoms were no more likely to occur after COVID-19 than after similarly severe medical illnesses,” Dr. Rooney said. “This negative finding runs counter to some earlier studies and may surprise some.” The findings need to be replicated in larger samples, but the current study shows the importance of prospectively recruiting active controls.

“In a subgroup analysis, some patients showed good improvement in cognitive scores between discharge and follow-up. While unsurprising, this is encouraging and suggests that the early postdischarge months are an important time for neurocognitive recovery,” Dr. Rooney noted.

“The findings suggest that COVID-19 may impair attention more selectively than other medical causes of hospitalization. COVID-19 survivors may also be at higher risk of significant overall cognitive impairment than survivors of similarly severe medical illnesses, after a similar duration,” said Dr. Rooney. “If the results are replicated by other prospective studies, they would suggest that there is something about COVID-19 that causes clinically significant neurocognitive difficulties in a minority of survivors.

“Larger well-controlled studies are required, with longer follow-up and more detailed neurocognitive testing,” as the duration of impairment and scope for further recovery are not known, Dr. Rooney added. Also unknown is whether COVID-19 affects attention permanently, or whether recovery is simply slower after COVID-19 compared to other medical illnesses.

“Knowing who is at the greatest risk of severe cognitive impairment after COVID-19 is important and likely to allow tailoring of more effective shielding strategies,” said Dr. Rooney. “This study was conducted before the widespread availability of vaccines for COVID-19. Long-term neuropsychiatric outcomes in vaccinated patients remain largely unknown. Arguably, these are now more important to understand, as future COVID-19 waves will occur mainly among vaccinated individuals.”

The study was supported by the Lundbeck Foundation and the Novo Nordisk Foundation. Lead author Dr. Nersesjan had no financial conflicts to disclose. Dr. Benros reported grants from Lundbeck Foundation and Novo Nordisk Foundation during the conduct of the study. Dr. Rooney had no financial conflicts to disclose.

This article was updated 3/25/22.

As the controversial Alzheimer’s disease (AD) drug aducanumab (Aduhelm) begins its integration into clinical practice, some physicians are concerned the drug’s prescribing label does not include adequate brain imaging recommendations to detect amyloid-related imaging abnormalities (ARIA).

Specifically, the drug’s label calls for three MRI brain scans before, and during, the titration period. The problem is the trial data used for the drug’s approval by the U.S. Food and Drug Administration included five MRIs to screen for ARIA.

“We recommend proceeding as per the clinical trials,” said Meghan Riddle, MD, associate director, Memory and Aging program, Butler Hospital, and assistant professor of psychiatry and human behavior, Brown University, Providence, R.I.

Dr. Riddle shared her team’s clinical experience with aducanumab, as well as information on four ARIA cases from their clinic, during a presentation at the American Association for Geriatric Psychiatry (AAGP) 2022 Annual Meeting.
 

Significant safety risk?

As previously reported by this news organization, the FDA granted accelerated approval of aducanumab for AD last year.

ARIA is the most common risk associated with aducanumab and has two types: ARIA-E (with edema) and ARIA-H (with hemosiderin). These can co-occur, particularly in areas of high amyloid burden, Dr. Riddle noted during her presentation.

ARIA is often detected incidentally via MRI. Patients are usually asymptomatic, but when they do have symptoms, headache, dizziness, and vision changes are the most common complaints. However, these are generally mild, said Dr. Riddle.

Nevertheless, in some cases, there can be severe sequelae, including severe edema or bleeding and seizures, she added.

A major risk factor for ARIA is apolipoprotein 4 (APOE ε4) status. Carriers are twice as likely to develop ARIA as non-carriers.

“If you’re heterozygote for APOE ε4, you have about a 40% chance of developing ARIA, and if you’re homozygote, you have about a 66% chance of developing ARIA,” Dr. Riddle said.

Given the high rate of ARIA in APOE ε4 carriers, the team from Butler Hospital recommends APOE testing prior to treatment with aducanumab.

The risk for developing ARIA is highest within the year of dose titration, Dr. Riddle noted. The current FDA label recommends obtaining a recent brain MRI, within 1 year, and then scans before the 7th and 12th infusions. However, the protocol during the clinical trials of aducanumab included MRI at baseline and prior to the 5th, 7th, 9th, and 12th infusions.

Dr. Riddle’s group has opted to continue the research protocol with new patients. “There’s concern that the decreased MRI monitoring based on the current FDA label may pose a significant safety risk, particularly among those who we know are already at a higher risk of developing ARIA,” she said.

Dr. Riddle also shared how her team selects aducanumab candidates. They need to have mild cognitive impairment (MCI), a mini-mental state examination (MMSE) score of 24 to 30, and a recent MRI to review for eligibility and APOE testing.

The most common reason for treatment exclusion is advanced disease and comorbidity, such as stroke.

Once approved for treatment, patients receive monthly infusions titrated over 6 months – 1 mg/kg for 2 months, 3 mg/kg for 2 months, 6 mg/kg for 2 months, then 10 mg/kg.

Patients are monitored to ensure safety and tolerability and regular review of MRI findings. In addition, patients and their families receive ongoing education about the drug.

Dr. Riddle and her team permanently discontinue the aducanumab if patients develop microhemorrhage, more than one area of superficial siderosis, more than 10 microhemorrhages, more than two episodes of ARIA, or severe symptoms of ARIA.
 

Four cases

Of the 11 patients who were candidates for aducanumab treatment, four developed ARIA. All are APOE ε4 carriers, with two homozygotes and two heterozygotes. All had severe radiographic ARIA-E, with one developing ARIA-H.

“Importantly, they were all initially asymptomatic and the ARIA was just picked up on their regular surveillance MRI,” said Dr. Riddle. She added that the drug was discontinued in all four cases.

Three of the ARIA cases were detected prior to the 5th scan, which is “concerning,” said Dr. Riddle. “Based on the current FDA label of safety monitoring, they don’t recommend doing that MRI. So [clinicians] would have dosed through that ARIA, which could put someone at much greater risk of developing severe symptoms.”

In addition, 14 patients at the center are receiving treatment with aducanumab. However, at this point they have not yet received their first MRI screen.

Dr. Riddle noted that when patients are told they are not candidates for treatment, or when treatment is discontinued, they are upset. However, she added, there is also a substantial level of understanding.

“We have a very layered discussion that includes the simple fact that we still aren’t sure if this is going to provide any clinical benefit, that this decision [to approve the drug] was accelerated, and that data are still being gathered,” Dr. Riddle added.

Dr. Riddle noted that the risk of ARIA is highest during the dose titration period: “There’s a signal that once you get to the 10 mg/kg dose, that plateaus.”

None of the patients at her center have reached that 12-month treatment mark. “The current plan is to do the MRI at 12 months then to give serial MRIs but less frequently, and whether that’s at 6 months or annually is yet to be determined.”

“We’re kind of writing these protocols as information evolves,” Dr. Riddle said.

The Memory and Aging Program receives grants from NIH-ADNI, Alzheimer’s Association, Fain Family Foundation, Joukowsky Family Foundation, Winter Family, Rhode Island Foundation, Goodman Family Foundation, and Global Alzheimer Platform Foundation; and clinical trials include: Lilly, Biogen, Genentech, Avid, Roche, Eisai, and Novartis. Dr. Riddle has disclosed no relevant financial relationships.

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

As the controversial Alzheimer’s disease (AD) drug aducanumab (Aduhelm) begins its integration into clinical practice, some physicians are concerned the drug’s prescribing label does not include adequate brain imaging recommendations to detect amyloid-related imaging abnormalities (ARIA).

Specifically, the drug’s label calls for three MRI brain scans before, and during, the titration period. The problem is the trial data used for the drug’s approval by the U.S. Food and Drug Administration included five MRIs to screen for ARIA.

“We recommend proceeding as per the clinical trials,” said Meghan Riddle, MD, associate director, Memory and Aging program, Butler Hospital, and assistant professor of psychiatry and human behavior, Brown University, Providence, R.I.

Dr. Riddle shared her team’s clinical experience with aducanumab, as well as information on four ARIA cases from their clinic, during a presentation at the American Association for Geriatric Psychiatry (AAGP) 2022 Annual Meeting.
 

Significant safety risk?

As previously reported by this news organization, the FDA granted accelerated approval of aducanumab for AD last year.

ARIA is the most common risk associated with aducanumab and has two types: ARIA-E (with edema) and ARIA-H (with hemosiderin). These can co-occur, particularly in areas of high amyloid burden, Dr. Riddle noted during her presentation.

ARIA is often detected incidentally via MRI. Patients are usually asymptomatic, but when they do have symptoms, headache, dizziness, and vision changes are the most common complaints. However, these are generally mild, said Dr. Riddle.

Nevertheless, in some cases, there can be severe sequelae, including severe edema or bleeding and seizures, she added.

A major risk factor for ARIA is apolipoprotein 4 (APOE ε4) status. Carriers are twice as likely to develop ARIA as non-carriers.

“If you’re heterozygote for APOE ε4, you have about a 40% chance of developing ARIA, and if you’re homozygote, you have about a 66% chance of developing ARIA,” Dr. Riddle said.

Given the high rate of ARIA in APOE ε4 carriers, the team from Butler Hospital recommends APOE testing prior to treatment with aducanumab.

The risk for developing ARIA is highest within the year of dose titration, Dr. Riddle noted. The current FDA label recommends obtaining a recent brain MRI, within 1 year, and then scans before the 7th and 12th infusions. However, the protocol during the clinical trials of aducanumab included MRI at baseline and prior to the 5th, 7th, 9th, and 12th infusions.

Dr. Riddle’s group has opted to continue the research protocol with new patients. “There’s concern that the decreased MRI monitoring based on the current FDA label may pose a significant safety risk, particularly among those who we know are already at a higher risk of developing ARIA,” she said.

Dr. Riddle also shared how her team selects aducanumab candidates. They need to have mild cognitive impairment (MCI), a mini-mental state examination (MMSE) score of 24 to 30, and a recent MRI to review for eligibility and APOE testing.

The most common reason for treatment exclusion is advanced disease and comorbidity, such as stroke.

Once approved for treatment, patients receive monthly infusions titrated over 6 months – 1 mg/kg for 2 months, 3 mg/kg for 2 months, 6 mg/kg for 2 months, then 10 mg/kg.

Patients are monitored to ensure safety and tolerability and regular review of MRI findings. In addition, patients and their families receive ongoing education about the drug.

Dr. Riddle and her team permanently discontinue the aducanumab if patients develop microhemorrhage, more than one area of superficial siderosis, more than 10 microhemorrhages, more than two episodes of ARIA, or severe symptoms of ARIA.
 

Four cases

Of the 11 patients who were candidates for aducanumab treatment, four developed ARIA. All are APOE ε4 carriers, with two homozygotes and two heterozygotes. All had severe radiographic ARIA-E, with one developing ARIA-H.

“Importantly, they were all initially asymptomatic and the ARIA was just picked up on their regular surveillance MRI,” said Dr. Riddle. She added that the drug was discontinued in all four cases.

Three of the ARIA cases were detected prior to the 5th scan, which is “concerning,” said Dr. Riddle. “Based on the current FDA label of safety monitoring, they don’t recommend doing that MRI. So [clinicians] would have dosed through that ARIA, which could put someone at much greater risk of developing severe symptoms.”

In addition, 14 patients at the center are receiving treatment with aducanumab. However, at this point they have not yet received their first MRI screen.

Dr. Riddle noted that when patients are told they are not candidates for treatment, or when treatment is discontinued, they are upset. However, she added, there is also a substantial level of understanding.

“We have a very layered discussion that includes the simple fact that we still aren’t sure if this is going to provide any clinical benefit, that this decision [to approve the drug] was accelerated, and that data are still being gathered,” Dr. Riddle added.

Dr. Riddle noted that the risk of ARIA is highest during the dose titration period: “There’s a signal that once you get to the 10 mg/kg dose, that plateaus.”

None of the patients at her center have reached that 12-month treatment mark. “The current plan is to do the MRI at 12 months then to give serial MRIs but less frequently, and whether that’s at 6 months or annually is yet to be determined.”

“We’re kind of writing these protocols as information evolves,” Dr. Riddle said.

The Memory and Aging Program receives grants from NIH-ADNI, Alzheimer’s Association, Fain Family Foundation, Joukowsky Family Foundation, Winter Family, Rhode Island Foundation, Goodman Family Foundation, and Global Alzheimer Platform Foundation; and clinical trials include: Lilly, Biogen, Genentech, Avid, Roche, Eisai, and Novartis. Dr. Riddle has disclosed no relevant financial relationships.

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

As the controversial Alzheimer’s disease (AD) drug aducanumab (Aduhelm) begins its integration into clinical practice, some physicians are concerned the drug’s prescribing label does not include adequate brain imaging recommendations to detect amyloid-related imaging abnormalities (ARIA).

Specifically, the drug’s label calls for three MRI brain scans before, and during, the titration period. The problem is the trial data used for the drug’s approval by the U.S. Food and Drug Administration included five MRIs to screen for ARIA.

“We recommend proceeding as per the clinical trials,” said Meghan Riddle, MD, associate director, Memory and Aging program, Butler Hospital, and assistant professor of psychiatry and human behavior, Brown University, Providence, R.I.

Dr. Riddle shared her team’s clinical experience with aducanumab, as well as information on four ARIA cases from their clinic, during a presentation at the American Association for Geriatric Psychiatry (AAGP) 2022 Annual Meeting.
 

Significant safety risk?

As previously reported by this news organization, the FDA granted accelerated approval of aducanumab for AD last year.

ARIA is the most common risk associated with aducanumab and has two types: ARIA-E (with edema) and ARIA-H (with hemosiderin). These can co-occur, particularly in areas of high amyloid burden, Dr. Riddle noted during her presentation.

ARIA is often detected incidentally via MRI. Patients are usually asymptomatic, but when they do have symptoms, headache, dizziness, and vision changes are the most common complaints. However, these are generally mild, said Dr. Riddle.

Nevertheless, in some cases, there can be severe sequelae, including severe edema or bleeding and seizures, she added.

A major risk factor for ARIA is apolipoprotein 4 (APOE ε4) status. Carriers are twice as likely to develop ARIA as non-carriers.

“If you’re heterozygote for APOE ε4, you have about a 40% chance of developing ARIA, and if you’re homozygote, you have about a 66% chance of developing ARIA,” Dr. Riddle said.

Given the high rate of ARIA in APOE ε4 carriers, the team from Butler Hospital recommends APOE testing prior to treatment with aducanumab.

The risk for developing ARIA is highest within the year of dose titration, Dr. Riddle noted. The current FDA label recommends obtaining a recent brain MRI, within 1 year, and then scans before the 7th and 12th infusions. However, the protocol during the clinical trials of aducanumab included MRI at baseline and prior to the 5th, 7th, 9th, and 12th infusions.

Dr. Riddle’s group has opted to continue the research protocol with new patients. “There’s concern that the decreased MRI monitoring based on the current FDA label may pose a significant safety risk, particularly among those who we know are already at a higher risk of developing ARIA,” she said.

Dr. Riddle also shared how her team selects aducanumab candidates. They need to have mild cognitive impairment (MCI), a mini-mental state examination (MMSE) score of 24 to 30, and a recent MRI to review for eligibility and APOE testing.

The most common reason for treatment exclusion is advanced disease and comorbidity, such as stroke.

Once approved for treatment, patients receive monthly infusions titrated over 6 months – 1 mg/kg for 2 months, 3 mg/kg for 2 months, 6 mg/kg for 2 months, then 10 mg/kg.

Patients are monitored to ensure safety and tolerability and regular review of MRI findings. In addition, patients and their families receive ongoing education about the drug.

Dr. Riddle and her team permanently discontinue the aducanumab if patients develop microhemorrhage, more than one area of superficial siderosis, more than 10 microhemorrhages, more than two episodes of ARIA, or severe symptoms of ARIA.
 

Four cases

Of the 11 patients who were candidates for aducanumab treatment, four developed ARIA. All are APOE ε4 carriers, with two homozygotes and two heterozygotes. All had severe radiographic ARIA-E, with one developing ARIA-H.

“Importantly, they were all initially asymptomatic and the ARIA was just picked up on their regular surveillance MRI,” said Dr. Riddle. She added that the drug was discontinued in all four cases.

Three of the ARIA cases were detected prior to the 5th scan, which is “concerning,” said Dr. Riddle. “Based on the current FDA label of safety monitoring, they don’t recommend doing that MRI. So [clinicians] would have dosed through that ARIA, which could put someone at much greater risk of developing severe symptoms.”

In addition, 14 patients at the center are receiving treatment with aducanumab. However, at this point they have not yet received their first MRI screen.

Dr. Riddle noted that when patients are told they are not candidates for treatment, or when treatment is discontinued, they are upset. However, she added, there is also a substantial level of understanding.

“We have a very layered discussion that includes the simple fact that we still aren’t sure if this is going to provide any clinical benefit, that this decision [to approve the drug] was accelerated, and that data are still being gathered,” Dr. Riddle added.

Dr. Riddle noted that the risk of ARIA is highest during the dose titration period: “There’s a signal that once you get to the 10 mg/kg dose, that plateaus.”

None of the patients at her center have reached that 12-month treatment mark. “The current plan is to do the MRI at 12 months then to give serial MRIs but less frequently, and whether that’s at 6 months or annually is yet to be determined.”

“We’re kind of writing these protocols as information evolves,” Dr. Riddle said.

The Memory and Aging Program receives grants from NIH-ADNI, Alzheimer’s Association, Fain Family Foundation, Joukowsky Family Foundation, Winter Family, Rhode Island Foundation, Goodman Family Foundation, and Global Alzheimer Platform Foundation; and clinical trials include: Lilly, Biogen, Genentech, Avid, Roche, Eisai, and Novartis. Dr. Riddle has disclosed no relevant financial relationships.

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

A large registry-based cohort study in Sweden has revealed that 75% of children born before 24 weeks of gestation had neurodevelopmental disorders, including intellectual disabilities and autism, and required habilitative services.

In addition, somatic disorders such as asthma and failure to thrive/short stature were diagnosed in 88% of the cohort. The findings, published in Acta Paediatrica, emphasize the need for further study of this population, especially as survival rates continue to increase.

“The primary aim of this large, retrospective, national study was to report clinical diagnoses registered after children born before 24 weeks were discharged from neonatal care,” explained lead author Eva Morsing, MD, PhD, of Lund (Sweden) University, and colleagues.

Data on diagnoses of neurodevelopmental disorders and selected somatic diagnoses were obtained from national Swedish registries. Study participants’ individual medical files were also examined by the researchers.
 

Results

The study cohort comprised 383 infants born at a median of 23.3 weeks of gestation (range, 21.9-23.9 weeks). The median birthweight of participants was 565 grams (range, 340-874 grams), with a median birthweight standard deviation (SD) of −0.40 (range, −3.63–3.17).

The majority (75%) of infants had a neurodevelopmental disorder, including speech disorders (52%), intellectual disabilities (40%), attention-deficit/hyperactivity disorder (30%), autism spectrum disorder (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%), and hearing impairment (5%).

With respect to gender, a greater number of boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%; P < .01) and visual impairment (25% vs. 14%; P < .01). Moreover, 55% of the participants were referred for habilitative services.

With respect to somatic diagnoses, failure to thrive/short stature was diagnosed in 39% of the cohort, and it occurred more often in those born at 21 and 22 weeks than in those born at 23 weeks (49% vs. 36%; P < .05).

In addition, asthma and childhood bronchopulmonary dysplasia, pulmonary hypertension, and vocal cord paresis were diagnosed in 63%, 12%, and 13% of participants, respectively.

“Several studies have reported higher rates of preterm morbidities, and poor neurodevelopmental outcomes after extremely preterm birth in boys rather than girls,” study author Ann Hellström, MD, PhD, of the University of Gothenburg, Sweden, said in an interview.

“While the reasons for this were not studied in the present paper, reports in the literature suggest that boys have a higher average growth rate than girls and appear to be more sensitive to suboptimal neonatal nutrition than girls,” Dr. Hellström explained.

“We also know that sex steroids differ in relation to intrauterine life depending on the sex after preterm birth,” Dr. Hellström added.

In an accompanying editorial, Neil Marlow, MD, of University College London, wrote, “One headline from this study [that is interesting] is the high prevalence of autistic spectrum disorders recorded.

“This is a particular finding in extremely preterm cohorts from Sweden, who record more diagnoses than in other longitudinal studies,” Dr. Marlow added. “It certainly warrants further investigation and understanding.”

The researchers acknowledged that a key limitation of the study was the broad age range at the most recent follow-up visit, which ranged from 2 to 13 years, explaining that some diagnoses may occur later in childhood.

“Neonatal clinical practice needs to adopt a long-term perspective and clinicians treating children and adults should be aware of the complicated health problems of children born before 24 weeks,” they concluded.

This study was supported by the Swedish Medical Research Council, the Gothenburg Medical Society, and by grant funding from the Swedish government. The authors reported no relevant disclosures.

A large registry-based cohort study in Sweden has revealed that 75% of children born before 24 weeks of gestation had neurodevelopmental disorders, including intellectual disabilities and autism, and required habilitative services.

In addition, somatic disorders such as asthma and failure to thrive/short stature were diagnosed in 88% of the cohort. The findings, published in Acta Paediatrica, emphasize the need for further study of this population, especially as survival rates continue to increase.

“The primary aim of this large, retrospective, national study was to report clinical diagnoses registered after children born before 24 weeks were discharged from neonatal care,” explained lead author Eva Morsing, MD, PhD, of Lund (Sweden) University, and colleagues.

Data on diagnoses of neurodevelopmental disorders and selected somatic diagnoses were obtained from national Swedish registries. Study participants’ individual medical files were also examined by the researchers.
 

Results

The study cohort comprised 383 infants born at a median of 23.3 weeks of gestation (range, 21.9-23.9 weeks). The median birthweight of participants was 565 grams (range, 340-874 grams), with a median birthweight standard deviation (SD) of −0.40 (range, −3.63–3.17).

The majority (75%) of infants had a neurodevelopmental disorder, including speech disorders (52%), intellectual disabilities (40%), attention-deficit/hyperactivity disorder (30%), autism spectrum disorder (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%), and hearing impairment (5%).

With respect to gender, a greater number of boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%; P < .01) and visual impairment (25% vs. 14%; P < .01). Moreover, 55% of the participants were referred for habilitative services.

With respect to somatic diagnoses, failure to thrive/short stature was diagnosed in 39% of the cohort, and it occurred more often in those born at 21 and 22 weeks than in those born at 23 weeks (49% vs. 36%; P < .05).

In addition, asthma and childhood bronchopulmonary dysplasia, pulmonary hypertension, and vocal cord paresis were diagnosed in 63%, 12%, and 13% of participants, respectively.

“Several studies have reported higher rates of preterm morbidities, and poor neurodevelopmental outcomes after extremely preterm birth in boys rather than girls,” study author Ann Hellström, MD, PhD, of the University of Gothenburg, Sweden, said in an interview.

“While the reasons for this were not studied in the present paper, reports in the literature suggest that boys have a higher average growth rate than girls and appear to be more sensitive to suboptimal neonatal nutrition than girls,” Dr. Hellström explained.

“We also know that sex steroids differ in relation to intrauterine life depending on the sex after preterm birth,” Dr. Hellström added.

In an accompanying editorial, Neil Marlow, MD, of University College London, wrote, “One headline from this study [that is interesting] is the high prevalence of autistic spectrum disorders recorded.

“This is a particular finding in extremely preterm cohorts from Sweden, who record more diagnoses than in other longitudinal studies,” Dr. Marlow added. “It certainly warrants further investigation and understanding.”

The researchers acknowledged that a key limitation of the study was the broad age range at the most recent follow-up visit, which ranged from 2 to 13 years, explaining that some diagnoses may occur later in childhood.

“Neonatal clinical practice needs to adopt a long-term perspective and clinicians treating children and adults should be aware of the complicated health problems of children born before 24 weeks,” they concluded.

This study was supported by the Swedish Medical Research Council, the Gothenburg Medical Society, and by grant funding from the Swedish government. The authors reported no relevant disclosures.

A large registry-based cohort study in Sweden has revealed that 75% of children born before 24 weeks of gestation had neurodevelopmental disorders, including intellectual disabilities and autism, and required habilitative services.

In addition, somatic disorders such as asthma and failure to thrive/short stature were diagnosed in 88% of the cohort. The findings, published in Acta Paediatrica, emphasize the need for further study of this population, especially as survival rates continue to increase.

“The primary aim of this large, retrospective, national study was to report clinical diagnoses registered after children born before 24 weeks were discharged from neonatal care,” explained lead author Eva Morsing, MD, PhD, of Lund (Sweden) University, and colleagues.

Data on diagnoses of neurodevelopmental disorders and selected somatic diagnoses were obtained from national Swedish registries. Study participants’ individual medical files were also examined by the researchers.
 

Results

The study cohort comprised 383 infants born at a median of 23.3 weeks of gestation (range, 21.9-23.9 weeks). The median birthweight of participants was 565 grams (range, 340-874 grams), with a median birthweight standard deviation (SD) of −0.40 (range, −3.63–3.17).

The majority (75%) of infants had a neurodevelopmental disorder, including speech disorders (52%), intellectual disabilities (40%), attention-deficit/hyperactivity disorder (30%), autism spectrum disorder (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%), and hearing impairment (5%).

With respect to gender, a greater number of boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%; P < .01) and visual impairment (25% vs. 14%; P < .01). Moreover, 55% of the participants were referred for habilitative services.

With respect to somatic diagnoses, failure to thrive/short stature was diagnosed in 39% of the cohort, and it occurred more often in those born at 21 and 22 weeks than in those born at 23 weeks (49% vs. 36%; P < .05).

In addition, asthma and childhood bronchopulmonary dysplasia, pulmonary hypertension, and vocal cord paresis were diagnosed in 63%, 12%, and 13% of participants, respectively.

“Several studies have reported higher rates of preterm morbidities, and poor neurodevelopmental outcomes after extremely preterm birth in boys rather than girls,” study author Ann Hellström, MD, PhD, of the University of Gothenburg, Sweden, said in an interview.

“While the reasons for this were not studied in the present paper, reports in the literature suggest that boys have a higher average growth rate than girls and appear to be more sensitive to suboptimal neonatal nutrition than girls,” Dr. Hellström explained.

“We also know that sex steroids differ in relation to intrauterine life depending on the sex after preterm birth,” Dr. Hellström added.

In an accompanying editorial, Neil Marlow, MD, of University College London, wrote, “One headline from this study [that is interesting] is the high prevalence of autistic spectrum disorders recorded.

“This is a particular finding in extremely preterm cohorts from Sweden, who record more diagnoses than in other longitudinal studies,” Dr. Marlow added. “It certainly warrants further investigation and understanding.”

The researchers acknowledged that a key limitation of the study was the broad age range at the most recent follow-up visit, which ranged from 2 to 13 years, explaining that some diagnoses may occur later in childhood.

“Neonatal clinical practice needs to adopt a long-term perspective and clinicians treating children and adults should be aware of the complicated health problems of children born before 24 weeks,” they concluded.

This study was supported by the Swedish Medical Research Council, the Gothenburg Medical Society, and by grant funding from the Swedish government. The authors reported no relevant disclosures.

The stress of living through a pandemic may cause brain inflammation even in those uninfected with SARS-CoV-2, a study suggests.

Healthy individuals who tested negative for the virus that causes COVID-19 had elevated levels of inflammatory markers known to be involved in depression, stress, and mental fatigue. The study indicates a possible link between pandemic-associated stressors and neuroimmune responses.

“The most important finding is the evidence of neuroinflammation in noninfected, otherwise healthy participants, which may explain the variety of sickness-behavior-like symptoms experienced by many during the pandemic,” lead author Ludovica Brusaferri, PhD, a postdoctoral research fellow at Massachusetts General Hospital and Harvard Medical School in Boston, told this news organization.

The study was published online Feb. 16 in Brain, Behavior, and Immunity.
 

Impact of pandemic stress?

Reports of psychological distress have increased considerably in the United States during the pandemic, including among those not infected with SARS-CoV-2.

To better understand the effects of the pandemic on brain and mental health, the investigators retrospectively analyzed data collected from 57 people who were enrolled as control subjects for unrelated studies before the pandemic began.

They also enrolled 15 people living in Massachusetts during that state’s 2-month lockdown/stay-at-home order from March to May 2020, all of whom had tested negative for COVID-19 antibodies.

The investigators used PET and MRI imaging and blood sample analyses to investigate whether there were any differences in the brains of healthy people before and during the pandemic following the lockdown.

Compared with the control group, the pandemic cohort had elevated levels of 18 kDa translocator protein (TSPO) and myoinositol, inflammatory markers in the brain. Increased TSPO has been associated with depression and suicidal thoughts and elevated myoinositol has been linked to schizophrenia.

Blood levels of two inflammatory markers, interleukin-16 and monocyte chemoattractant protein-1, were also elevated in the pandemic cohort, although to a lesser extent.

TSPO levels were especially high in participants in the pandemic cohort who reported moodiness and mental and physical fatigue, compared with those reporting few or no symptoms.

“These findings provide support to a role for neuroinflammation in stress, an observation that, if replicated, might help guide the development of novel treatments focused on the reduction of brain inflammation,” study author Marco Loggia, PhD, codirector of the Center for Integrative Pain NeuroImaging at Mass General and Harvard Medical School, told this news organization.

Although the data showing increased neuroinflammation were collected when participants were under a stay-at-home order, the researchers said it’s not clear that this was the cause.

“We’re not saying it is the lockdown that was causing it,” Dr. Loggia said. “It could have been social isolation, changes in diet, or changes in exercise patterns. We don’t know exactly what the cause was so, maybe.”
 

A significant contribution

Commenting on the study for this news organization, Ning Quan, PhD, professor of biomedical science at Florida Atlantic University, Boca Raton, said although questions remain, the findings offer valuable information.

“This study contributes significantly to our understanding of how pandemic stress might impact our brain and behavior,” Dr. Quan said. “The main advance that this paper provides is that fatigue or brain fog could be induced in individuals with COVID infection during the pandemic.”

However, Dr. Quan added, the study has a number of limitations, including a small sample size, which makes it difficult to generalize the results.

“Another issue is the subjects of the study all lived in Massachusetts,” Dr. Quan added. “Subjects from different states or different countries could yield different results.”

The study was funded by the National Institutes of Health and by the Landreth Family Foundation. The study authors and Dr. Quan have disclosed no relevant financial relationships.

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

The stress of living through a pandemic may cause brain inflammation even in those uninfected with SARS-CoV-2, a study suggests.

Healthy individuals who tested negative for the virus that causes COVID-19 had elevated levels of inflammatory markers known to be involved in depression, stress, and mental fatigue. The study indicates a possible link between pandemic-associated stressors and neuroimmune responses.

“The most important finding is the evidence of neuroinflammation in noninfected, otherwise healthy participants, which may explain the variety of sickness-behavior-like symptoms experienced by many during the pandemic,” lead author Ludovica Brusaferri, PhD, a postdoctoral research fellow at Massachusetts General Hospital and Harvard Medical School in Boston, told this news organization.

The study was published online Feb. 16 in Brain, Behavior, and Immunity.
 

Impact of pandemic stress?

Reports of psychological distress have increased considerably in the United States during the pandemic, including among those not infected with SARS-CoV-2.

To better understand the effects of the pandemic on brain and mental health, the investigators retrospectively analyzed data collected from 57 people who were enrolled as control subjects for unrelated studies before the pandemic began.

They also enrolled 15 people living in Massachusetts during that state’s 2-month lockdown/stay-at-home order from March to May 2020, all of whom had tested negative for COVID-19 antibodies.

The investigators used PET and MRI imaging and blood sample analyses to investigate whether there were any differences in the brains of healthy people before and during the pandemic following the lockdown.

Compared with the control group, the pandemic cohort had elevated levels of 18 kDa translocator protein (TSPO) and myoinositol, inflammatory markers in the brain. Increased TSPO has been associated with depression and suicidal thoughts and elevated myoinositol has been linked to schizophrenia.

Blood levels of two inflammatory markers, interleukin-16 and monocyte chemoattractant protein-1, were also elevated in the pandemic cohort, although to a lesser extent.

TSPO levels were especially high in participants in the pandemic cohort who reported moodiness and mental and physical fatigue, compared with those reporting few or no symptoms.

“These findings provide support to a role for neuroinflammation in stress, an observation that, if replicated, might help guide the development of novel treatments focused on the reduction of brain inflammation,” study author Marco Loggia, PhD, codirector of the Center for Integrative Pain NeuroImaging at Mass General and Harvard Medical School, told this news organization.

Although the data showing increased neuroinflammation were collected when participants were under a stay-at-home order, the researchers said it’s not clear that this was the cause.

“We’re not saying it is the lockdown that was causing it,” Dr. Loggia said. “It could have been social isolation, changes in diet, or changes in exercise patterns. We don’t know exactly what the cause was so, maybe.”
 

A significant contribution

Commenting on the study for this news organization, Ning Quan, PhD, professor of biomedical science at Florida Atlantic University, Boca Raton, said although questions remain, the findings offer valuable information.

“This study contributes significantly to our understanding of how pandemic stress might impact our brain and behavior,” Dr. Quan said. “The main advance that this paper provides is that fatigue or brain fog could be induced in individuals with COVID infection during the pandemic.”

However, Dr. Quan added, the study has a number of limitations, including a small sample size, which makes it difficult to generalize the results.

“Another issue is the subjects of the study all lived in Massachusetts,” Dr. Quan added. “Subjects from different states or different countries could yield different results.”

The study was funded by the National Institutes of Health and by the Landreth Family Foundation. The study authors and Dr. Quan have disclosed no relevant financial relationships.

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

The stress of living through a pandemic may cause brain inflammation even in those uninfected with SARS-CoV-2, a study suggests.

Healthy individuals who tested negative for the virus that causes COVID-19 had elevated levels of inflammatory markers known to be involved in depression, stress, and mental fatigue. The study indicates a possible link between pandemic-associated stressors and neuroimmune responses.

“The most important finding is the evidence of neuroinflammation in noninfected, otherwise healthy participants, which may explain the variety of sickness-behavior-like symptoms experienced by many during the pandemic,” lead author Ludovica Brusaferri, PhD, a postdoctoral research fellow at Massachusetts General Hospital and Harvard Medical School in Boston, told this news organization.

The study was published online Feb. 16 in Brain, Behavior, and Immunity.
 

Impact of pandemic stress?

Reports of psychological distress have increased considerably in the United States during the pandemic, including among those not infected with SARS-CoV-2.

To better understand the effects of the pandemic on brain and mental health, the investigators retrospectively analyzed data collected from 57 people who were enrolled as control subjects for unrelated studies before the pandemic began.

They also enrolled 15 people living in Massachusetts during that state’s 2-month lockdown/stay-at-home order from March to May 2020, all of whom had tested negative for COVID-19 antibodies.

The investigators used PET and MRI imaging and blood sample analyses to investigate whether there were any differences in the brains of healthy people before and during the pandemic following the lockdown.

Compared with the control group, the pandemic cohort had elevated levels of 18 kDa translocator protein (TSPO) and myoinositol, inflammatory markers in the brain. Increased TSPO has been associated with depression and suicidal thoughts and elevated myoinositol has been linked to schizophrenia.

Blood levels of two inflammatory markers, interleukin-16 and monocyte chemoattractant protein-1, were also elevated in the pandemic cohort, although to a lesser extent.

TSPO levels were especially high in participants in the pandemic cohort who reported moodiness and mental and physical fatigue, compared with those reporting few or no symptoms.

“These findings provide support to a role for neuroinflammation in stress, an observation that, if replicated, might help guide the development of novel treatments focused on the reduction of brain inflammation,” study author Marco Loggia, PhD, codirector of the Center for Integrative Pain NeuroImaging at Mass General and Harvard Medical School, told this news organization.

Although the data showing increased neuroinflammation were collected when participants were under a stay-at-home order, the researchers said it’s not clear that this was the cause.

“We’re not saying it is the lockdown that was causing it,” Dr. Loggia said. “It could have been social isolation, changes in diet, or changes in exercise patterns. We don’t know exactly what the cause was so, maybe.”
 

A significant contribution

Commenting on the study for this news organization, Ning Quan, PhD, professor of biomedical science at Florida Atlantic University, Boca Raton, said although questions remain, the findings offer valuable information.

“This study contributes significantly to our understanding of how pandemic stress might impact our brain and behavior,” Dr. Quan said. “The main advance that this paper provides is that fatigue or brain fog could be induced in individuals with COVID infection during the pandemic.”

However, Dr. Quan added, the study has a number of limitations, including a small sample size, which makes it difficult to generalize the results.

“Another issue is the subjects of the study all lived in Massachusetts,” Dr. Quan added. “Subjects from different states or different countries could yield different results.”

The study was funded by the National Institutes of Health and by the Landreth Family Foundation. The study authors and Dr. Quan have disclosed no relevant financial relationships.

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

Differing state regulations and a paucity of research has made it difficult to develop consensus guidelines for the use of cannabinoids in treating drug-resistant epilepsy. A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.

The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.

“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.

“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
 

Appropriate patient populations

Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.

Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.

“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”

Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.

No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.

The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.

The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
 

Considerations for unapproved cannabinoids

The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.

The guidance document notes several reasons to use a regulated medication instead of an unregulated product:

• Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
• Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
• More scientific evidence is available for regulated products.
• Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
• Nonregulated products are rarely covered by insurance or other reimbursement.

Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.

The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.

Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”

“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
 

Dosing and adverse effects

Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.

“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.

The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.

Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.

“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”

Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.

“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”

Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.

Differing state regulations and a paucity of research has made it difficult to develop consensus guidelines for the use of cannabinoids in treating drug-resistant epilepsy. A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.

The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.

“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.

“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
 

Appropriate patient populations

Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.

Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.

“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”

Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.

No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.

The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.

The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
 

Considerations for unapproved cannabinoids

The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.

The guidance document notes several reasons to use a regulated medication instead of an unregulated product:

• Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
• Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
• More scientific evidence is available for regulated products.
• Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
• Nonregulated products are rarely covered by insurance or other reimbursement.

Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.

The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.

Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”

“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
 

Dosing and adverse effects

Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.

“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.

The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.

Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.

“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”

Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.

“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”

Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.

Differing state regulations and a paucity of research has made it difficult to develop consensus guidelines for the use of cannabinoids in treating drug-resistant epilepsy. A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.

The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.

“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.

“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
 

Appropriate patient populations

Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.

Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.

“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”

Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.

No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.

The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.

The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
 

Considerations for unapproved cannabinoids

The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.

The guidance document notes several reasons to use a regulated medication instead of an unregulated product:

• Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
• Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
• More scientific evidence is available for regulated products.
• Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
• Nonregulated products are rarely covered by insurance or other reimbursement.

Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.

The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.

Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”

“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
 

Dosing and adverse effects

Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.

“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.

The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.

Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.

“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”

Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.

“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”

Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.

In his first State of the Union address in early March, President Joe Biden broached a tax policy question that neuroscientists and pediatricians also see as a scientific one.

President Biden urged lawmakers to extend the Child Tax Credit “so no one has to raise a family in poverty.”

Apart from the usual political and budgetary calculus, physicians and social scientists are actively examining the ramifications that such policies could have on child development and long-term health outcomes.

To do so, they have turned to brain scans and rigorous studies to better understand the effects of being raised in poverty and whether giving families more cash makes a difference.

Initial results from an ongoing study known as Baby’s First Years suggest that providing extra money to mothers may influence brain activity in infants in ways that reflect improvements in cognitive ability.

Researchers, doctors, and advocates say the findings cement the case for policies such as the expanded Child Tax Credit. Others argue that reducing child poverty is a social good on its own, regardless of what brain scans show.

The new findings were published Jan. 24 in Proceedings of the National Academy of Sciences (PNAS), as lawmakers were weighing whether to resume an expansion of the tax credit, which had temporarily provided monthly payments akin to the $333 a month looked at in the study.

The expiration of the expanded credit in December left some 3.6 million more children in poverty, bringing the total number to more than 12.5 million and pushing the child poverty rate to 17%.

Philanthropists and research teams have partnered to conduct other guaranteed income experiments around the United States, including one in New York called the Bridge Project, which is evaluating different levels of financial support for mothers with babies.

Some mothers are receiving $500 per month, others twice that amount.

Angelina Matos, 18, receives $1,000 a month, allowing her to attend college and pay for necessities like diapers, clothes, and toys for her nearly 1-year-old daughter.

As one of 600 mothers participating in the project, Ms. Matos periodically answers questions about her daughter’s progress, like whether she is eating solid foods.

Megha Agarwal, BS, executive director of the Bridge Project and its funder the Monarch Foundation, said she was thrilled to see the early results from Baby’s First Years. “We are looking for ways in which we can strengthen our future generations,” she said. “It is exciting to see that direct cash and a guaranteed income might be part of the solution.”
 

A scientific perspective

Growing up in poverty is well-known to increase the likelihood of lower academic achievement and chronic conditions such as asthma and obesity. Relative to higher income levels, poverty is associated with differences in the structure and function of the developing brain. But whether interventions to reduce poverty can influence how newborns develop is less clear.

“There would be plenty of people who would say, ‘Well, it’s not poverty. It’s all the things associated with poverty. It’s the choices you make that are actually leading to differences in outcomes,’” said Kimberly Noble, MD, PhD, a neuroscientist at Columbia University, New York, and a coauthor of the PNAS study. Regardless of ideology, she said, the best way to address that question from a scientific perspective is through a randomized controlled trial.

“You can’t, and wouldn’t want to, randomize kids to living in poverty or not, but you can take a group of families who are unfortunately living in poverty and randomize them to receive different levels of economic support,” Dr. Noble said.
 

$333 per month

Baby’s First Years has done just that. Researchers gave 1,000 low-income mothers with newborns a cash gift of $333 per month or a smaller gift of $20 per month, disbursed on debit cards, starting in 2018. Participants live in four metropolitan areas – New York City, greater New Orleans, Minneapolis-Saint Paul, and Omaha – and were recruited at the time of their child’s birth. Investigators currently have funding to continue the cash support until the children turn 4 years old.

When the infants were about 1 year old, investigators measured their resting brain activity using EEG.

The COVID-19 pandemic disrupted the ability to conduct in-person testing, so the number of children with EEG data was smaller than planned. Still, the researchers analyzed data from 251 kids in the group that received the smaller cash gift and 184 kids in the group that received the larger amount. Patterns of brain activity largely tracked those seen in earlier observational studies: more mid- and high-frequency activity (alpha-, beta-, and gamma-bands) and less low-frequency activity (theta-bands) among children in the households that received more money.

Faster brain activity is associated with better scores on measures of language, cognition, and social-emotional development. Slower activity has been linked to problems with behavior, attention, and learning.

“We predicted that our poverty reduction intervention would mitigate the neurobiological signal of poverty,” Dr. Noble said. “And that’s exactly what we report in this paper.”

The study builds on decades of work showing that poverty can harm child development, said Joan Luby, MD, with Washington University School of Medicine, St. Louis, who served as a peer reviewer for the PNAS paper.

More follow-up data and information about the babies’ cognitive function and behavior over time are needed, but the study shows a signal that cannot be ignored, Dr. Luby said.

Dr. Luby began exploring the effects of poverty on brain development in earnest while working on a study that was meant to focus on another variable altogether: early childhood depression. The investigators on that 2013 study found that poverty had a “very, very big effect in our sample, and we realized we had to learn more about it,” she said.

The American Academy of Pediatrics likewise has recognized poverty as an important determinant of health. A policy statement that the group published in 2016 and reaffirmed in 2021 outlines ways pediatricians and social programs can address poverty.

Benard Dreyer, MD, director of pediatrics at Bellevue Hospital, New York, was president of the AAP when it published this guidance.

One lingering question has been how much low income worsens educational outcomes, Dr. Dreyer said. Perhaps other issues, such as single motherhood, a lack of parental education, or living in neighborhoods with more crime may be the cause. If so, simply giving more money to parents might not overcome those barriers.

Natural experiments have hinted that money itself can influence child development. For example, families on an American Indian reservation in North Carolina started receiving a share of casino profits after a casino opened there.

The new infusion of funds arrived in the middle of a study in which researchers were examining the development of mental illness in children.

Among children who were no longer poor as a result of the casino payments, symptoms of conduct and oppositional defiant disorders decreased.
 

Guaranteeing income

How extra money affects families across different levels of income also interests researchers and policymakers.

“One of the policy debates in Washington is to what degree should it be to everyone,” Ajay Chaudry, PhD, a research scholar at New York University who is advising the Bridge Project, said.

Guaranteed income programs may need to be available to most of the population out of political necessity, even if the benefits turn out to be the most pronounced at lower income levels, added Dr. Chaudry, who served in the Obama administration as deputy assistant secretary for human services policy.

If giving moms money affects babies’ brains, Dr. Dreyer pointed to two pathways that could explain the link: more resources and less family stress.

Money helps families buy toys and books, which in turn could support a child’s cognitive development. Meanwhile, low-income mothers and fathers may experience worries about eviction, adequate food, and the loss of heat and electricity, which could detract from their ability to parent.

Of course, many ways to support a child’s development do not require money. Engaging with children in a warm and nurturing way, having conversations with them, and reading with them are all important.

If the pattern in the PNAS study holds, individual experiences and outcomes will still vary, Dr. Noble said. Many children in the group that received the smaller gift had fast-paced brain activity, whereas some babies in the group that received the larger gift showed slower brain activity. Knowing family income would not allow you to accurately predict anything about an individual child’s brain, Dr. Noble said.

“I certainly wouldn’t want the message to be that money is the only thing that matters,” Dr. Noble said. “Money is something that can be easily manipulated by policy, which is why I think this is important.”

For the 18-year-old new mom Ms. Matos, accepting assistance “makes me feel less of myself. But honestly, I feel like mothers shouldn’t be afraid to ask for help or reach out for help or apply to programs like these.”

The sources reported a variety of funders, including federal agencies and foundations and donors.

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

In his first State of the Union address in early March, President Joe Biden broached a tax policy question that neuroscientists and pediatricians also see as a scientific one.

President Biden urged lawmakers to extend the Child Tax Credit “so no one has to raise a family in poverty.”

Apart from the usual political and budgetary calculus, physicians and social scientists are actively examining the ramifications that such policies could have on child development and long-term health outcomes.

To do so, they have turned to brain scans and rigorous studies to better understand the effects of being raised in poverty and whether giving families more cash makes a difference.

Initial results from an ongoing study known as Baby’s First Years suggest that providing extra money to mothers may influence brain activity in infants in ways that reflect improvements in cognitive ability.

Researchers, doctors, and advocates say the findings cement the case for policies such as the expanded Child Tax Credit. Others argue that reducing child poverty is a social good on its own, regardless of what brain scans show.

The new findings were published Jan. 24 in Proceedings of the National Academy of Sciences (PNAS), as lawmakers were weighing whether to resume an expansion of the tax credit, which had temporarily provided monthly payments akin to the $333 a month looked at in the study.

The expiration of the expanded credit in December left some 3.6 million more children in poverty, bringing the total number to more than 12.5 million and pushing the child poverty rate to 17%.

Philanthropists and research teams have partnered to conduct other guaranteed income experiments around the United States, including one in New York called the Bridge Project, which is evaluating different levels of financial support for mothers with babies.

Some mothers are receiving $500 per month, others twice that amount.

Angelina Matos, 18, receives $1,000 a month, allowing her to attend college and pay for necessities like diapers, clothes, and toys for her nearly 1-year-old daughter.

As one of 600 mothers participating in the project, Ms. Matos periodically answers questions about her daughter’s progress, like whether she is eating solid foods.

Megha Agarwal, BS, executive director of the Bridge Project and its funder the Monarch Foundation, said she was thrilled to see the early results from Baby’s First Years. “We are looking for ways in which we can strengthen our future generations,” she said. “It is exciting to see that direct cash and a guaranteed income might be part of the solution.”
 

A scientific perspective

Growing up in poverty is well-known to increase the likelihood of lower academic achievement and chronic conditions such as asthma and obesity. Relative to higher income levels, poverty is associated with differences in the structure and function of the developing brain. But whether interventions to reduce poverty can influence how newborns develop is less clear.

“There would be plenty of people who would say, ‘Well, it’s not poverty. It’s all the things associated with poverty. It’s the choices you make that are actually leading to differences in outcomes,’” said Kimberly Noble, MD, PhD, a neuroscientist at Columbia University, New York, and a coauthor of the PNAS study. Regardless of ideology, she said, the best way to address that question from a scientific perspective is through a randomized controlled trial.

“You can’t, and wouldn’t want to, randomize kids to living in poverty or not, but you can take a group of families who are unfortunately living in poverty and randomize them to receive different levels of economic support,” Dr. Noble said.
 

$333 per month

Baby’s First Years has done just that. Researchers gave 1,000 low-income mothers with newborns a cash gift of $333 per month or a smaller gift of $20 per month, disbursed on debit cards, starting in 2018. Participants live in four metropolitan areas – New York City, greater New Orleans, Minneapolis-Saint Paul, and Omaha – and were recruited at the time of their child’s birth. Investigators currently have funding to continue the cash support until the children turn 4 years old.

When the infants were about 1 year old, investigators measured their resting brain activity using EEG.

The COVID-19 pandemic disrupted the ability to conduct in-person testing, so the number of children with EEG data was smaller than planned. Still, the researchers analyzed data from 251 kids in the group that received the smaller cash gift and 184 kids in the group that received the larger amount. Patterns of brain activity largely tracked those seen in earlier observational studies: more mid- and high-frequency activity (alpha-, beta-, and gamma-bands) and less low-frequency activity (theta-bands) among children in the households that received more money.

Faster brain activity is associated with better scores on measures of language, cognition, and social-emotional development. Slower activity has been linked to problems with behavior, attention, and learning.

“We predicted that our poverty reduction intervention would mitigate the neurobiological signal of poverty,” Dr. Noble said. “And that’s exactly what we report in this paper.”

The study builds on decades of work showing that poverty can harm child development, said Joan Luby, MD, with Washington University School of Medicine, St. Louis, who served as a peer reviewer for the PNAS paper.

More follow-up data and information about the babies’ cognitive function and behavior over time are needed, but the study shows a signal that cannot be ignored, Dr. Luby said.

Dr. Luby began exploring the effects of poverty on brain development in earnest while working on a study that was meant to focus on another variable altogether: early childhood depression. The investigators on that 2013 study found that poverty had a “very, very big effect in our sample, and we realized we had to learn more about it,” she said.

The American Academy of Pediatrics likewise has recognized poverty as an important determinant of health. A policy statement that the group published in 2016 and reaffirmed in 2021 outlines ways pediatricians and social programs can address poverty.

Benard Dreyer, MD, director of pediatrics at Bellevue Hospital, New York, was president of the AAP when it published this guidance.

One lingering question has been how much low income worsens educational outcomes, Dr. Dreyer said. Perhaps other issues, such as single motherhood, a lack of parental education, or living in neighborhoods with more crime may be the cause. If so, simply giving more money to parents might not overcome those barriers.

Natural experiments have hinted that money itself can influence child development. For example, families on an American Indian reservation in North Carolina started receiving a share of casino profits after a casino opened there.

The new infusion of funds arrived in the middle of a study in which researchers were examining the development of mental illness in children.

Among children who were no longer poor as a result of the casino payments, symptoms of conduct and oppositional defiant disorders decreased.
 

Guaranteeing income

How extra money affects families across different levels of income also interests researchers and policymakers.

“One of the policy debates in Washington is to what degree should it be to everyone,” Ajay Chaudry, PhD, a research scholar at New York University who is advising the Bridge Project, said.

Guaranteed income programs may need to be available to most of the population out of political necessity, even if the benefits turn out to be the most pronounced at lower income levels, added Dr. Chaudry, who served in the Obama administration as deputy assistant secretary for human services policy.

If giving moms money affects babies’ brains, Dr. Dreyer pointed to two pathways that could explain the link: more resources and less family stress.

Money helps families buy toys and books, which in turn could support a child’s cognitive development. Meanwhile, low-income mothers and fathers may experience worries about eviction, adequate food, and the loss of heat and electricity, which could detract from their ability to parent.

Of course, many ways to support a child’s development do not require money. Engaging with children in a warm and nurturing way, having conversations with them, and reading with them are all important.

If the pattern in the PNAS study holds, individual experiences and outcomes will still vary, Dr. Noble said. Many children in the group that received the smaller gift had fast-paced brain activity, whereas some babies in the group that received the larger gift showed slower brain activity. Knowing family income would not allow you to accurately predict anything about an individual child’s brain, Dr. Noble said.

“I certainly wouldn’t want the message to be that money is the only thing that matters,” Dr. Noble said. “Money is something that can be easily manipulated by policy, which is why I think this is important.”

For the 18-year-old new mom Ms. Matos, accepting assistance “makes me feel less of myself. But honestly, I feel like mothers shouldn’t be afraid to ask for help or reach out for help or apply to programs like these.”

The sources reported a variety of funders, including federal agencies and foundations and donors.

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

In his first State of the Union address in early March, President Joe Biden broached a tax policy question that neuroscientists and pediatricians also see as a scientific one.

President Biden urged lawmakers to extend the Child Tax Credit “so no one has to raise a family in poverty.”

Apart from the usual political and budgetary calculus, physicians and social scientists are actively examining the ramifications that such policies could have on child development and long-term health outcomes.

To do so, they have turned to brain scans and rigorous studies to better understand the effects of being raised in poverty and whether giving families more cash makes a difference.

Initial results from an ongoing study known as Baby’s First Years suggest that providing extra money to mothers may influence brain activity in infants in ways that reflect improvements in cognitive ability.

Researchers, doctors, and advocates say the findings cement the case for policies such as the expanded Child Tax Credit. Others argue that reducing child poverty is a social good on its own, regardless of what brain scans show.

The new findings were published Jan. 24 in Proceedings of the National Academy of Sciences (PNAS), as lawmakers were weighing whether to resume an expansion of the tax credit, which had temporarily provided monthly payments akin to the $333 a month looked at in the study.

The expiration of the expanded credit in December left some 3.6 million more children in poverty, bringing the total number to more than 12.5 million and pushing the child poverty rate to 17%.

Philanthropists and research teams have partnered to conduct other guaranteed income experiments around the United States, including one in New York called the Bridge Project, which is evaluating different levels of financial support for mothers with babies.

Some mothers are receiving $500 per month, others twice that amount.

Angelina Matos, 18, receives $1,000 a month, allowing her to attend college and pay for necessities like diapers, clothes, and toys for her nearly 1-year-old daughter.

As one of 600 mothers participating in the project, Ms. Matos periodically answers questions about her daughter’s progress, like whether she is eating solid foods.

Megha Agarwal, BS, executive director of the Bridge Project and its funder the Monarch Foundation, said she was thrilled to see the early results from Baby’s First Years. “We are looking for ways in which we can strengthen our future generations,” she said. “It is exciting to see that direct cash and a guaranteed income might be part of the solution.”
 

A scientific perspective

Growing up in poverty is well-known to increase the likelihood of lower academic achievement and chronic conditions such as asthma and obesity. Relative to higher income levels, poverty is associated with differences in the structure and function of the developing brain. But whether interventions to reduce poverty can influence how newborns develop is less clear.

“There would be plenty of people who would say, ‘Well, it’s not poverty. It’s all the things associated with poverty. It’s the choices you make that are actually leading to differences in outcomes,’” said Kimberly Noble, MD, PhD, a neuroscientist at Columbia University, New York, and a coauthor of the PNAS study. Regardless of ideology, she said, the best way to address that question from a scientific perspective is through a randomized controlled trial.

“You can’t, and wouldn’t want to, randomize kids to living in poverty or not, but you can take a group of families who are unfortunately living in poverty and randomize them to receive different levels of economic support,” Dr. Noble said.
 

$333 per month

Baby’s First Years has done just that. Researchers gave 1,000 low-income mothers with newborns a cash gift of $333 per month or a smaller gift of $20 per month, disbursed on debit cards, starting in 2018. Participants live in four metropolitan areas – New York City, greater New Orleans, Minneapolis-Saint Paul, and Omaha – and were recruited at the time of their child’s birth. Investigators currently have funding to continue the cash support until the children turn 4 years old.

When the infants were about 1 year old, investigators measured their resting brain activity using EEG.

The COVID-19 pandemic disrupted the ability to conduct in-person testing, so the number of children with EEG data was smaller than planned. Still, the researchers analyzed data from 251 kids in the group that received the smaller cash gift and 184 kids in the group that received the larger amount. Patterns of brain activity largely tracked those seen in earlier observational studies: more mid- and high-frequency activity (alpha-, beta-, and gamma-bands) and less low-frequency activity (theta-bands) among children in the households that received more money.

Faster brain activity is associated with better scores on measures of language, cognition, and social-emotional development. Slower activity has been linked to problems with behavior, attention, and learning.

“We predicted that our poverty reduction intervention would mitigate the neurobiological signal of poverty,” Dr. Noble said. “And that’s exactly what we report in this paper.”

The study builds on decades of work showing that poverty can harm child development, said Joan Luby, MD, with Washington University School of Medicine, St. Louis, who served as a peer reviewer for the PNAS paper.

More follow-up data and information about the babies’ cognitive function and behavior over time are needed, but the study shows a signal that cannot be ignored, Dr. Luby said.

Dr. Luby began exploring the effects of poverty on brain development in earnest while working on a study that was meant to focus on another variable altogether: early childhood depression. The investigators on that 2013 study found that poverty had a “very, very big effect in our sample, and we realized we had to learn more about it,” she said.

The American Academy of Pediatrics likewise has recognized poverty as an important determinant of health. A policy statement that the group published in 2016 and reaffirmed in 2021 outlines ways pediatricians and social programs can address poverty.

Benard Dreyer, MD, director of pediatrics at Bellevue Hospital, New York, was president of the AAP when it published this guidance.

One lingering question has been how much low income worsens educational outcomes, Dr. Dreyer said. Perhaps other issues, such as single motherhood, a lack of parental education, or living in neighborhoods with more crime may be the cause. If so, simply giving more money to parents might not overcome those barriers.

Natural experiments have hinted that money itself can influence child development. For example, families on an American Indian reservation in North Carolina started receiving a share of casino profits after a casino opened there.

The new infusion of funds arrived in the middle of a study in which researchers were examining the development of mental illness in children.

Among children who were no longer poor as a result of the casino payments, symptoms of conduct and oppositional defiant disorders decreased.
 

Guaranteeing income

How extra money affects families across different levels of income also interests researchers and policymakers.

“One of the policy debates in Washington is to what degree should it be to everyone,” Ajay Chaudry, PhD, a research scholar at New York University who is advising the Bridge Project, said.

Guaranteed income programs may need to be available to most of the population out of political necessity, even if the benefits turn out to be the most pronounced at lower income levels, added Dr. Chaudry, who served in the Obama administration as deputy assistant secretary for human services policy.

If giving moms money affects babies’ brains, Dr. Dreyer pointed to two pathways that could explain the link: more resources and less family stress.

Money helps families buy toys and books, which in turn could support a child’s cognitive development. Meanwhile, low-income mothers and fathers may experience worries about eviction, adequate food, and the loss of heat and electricity, which could detract from their ability to parent.

Of course, many ways to support a child’s development do not require money. Engaging with children in a warm and nurturing way, having conversations with them, and reading with them are all important.

If the pattern in the PNAS study holds, individual experiences and outcomes will still vary, Dr. Noble said. Many children in the group that received the smaller gift had fast-paced brain activity, whereas some babies in the group that received the larger gift showed slower brain activity. Knowing family income would not allow you to accurately predict anything about an individual child’s brain, Dr. Noble said.

“I certainly wouldn’t want the message to be that money is the only thing that matters,” Dr. Noble said. “Money is something that can be easily manipulated by policy, which is why I think this is important.”

For the 18-year-old new mom Ms. Matos, accepting assistance “makes me feel less of myself. But honestly, I feel like mothers shouldn’t be afraid to ask for help or reach out for help or apply to programs like these.”

The sources reported a variety of funders, including federal agencies and foundations and donors.

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

Pediatricians are increasingly expert in the assessment and treatment of attention-deficit/hyperactivity disorder. But what do you do when adolescents present to your office saying they think they have ADHD? While ADHD is a common and treatable disorder of youth, it is important to take special care when assessing an adolescent. Difficulties with attention and concentration are common symptoms for many different challenges of adolescence, and for ADHD to be the underlying cause, those symptoms must have started prior to adolescence (according to DSM-5, prior to the age of 12). When your adolescent patients or their parents come to your office complaining of inattention, it is important to consider the full range of possible explanations.

Sleep

We have written in this column previously about the challenges that adolescents face in getting adequate sleep consistently. Teenagers, on average, need more than 9 hours of sleep nightly and American teenagers get fewer than 6. This mismatch is because of physiologic shifts that move their natural sleep onset time significantly later, while school still starts early. It’s often compounded by other demands on their time, including homework, extracurricular activities, and the gravitational pull of social connections. Independent teenagers make their own decisions about how to manage their time and may feel sleep is optional, or manage their fatigue with naps and caffeine, both of which will further compromise the quality and efficiency of sleep.

Chronic sleep deprivation will present with difficulties with focus, attention, memory, and cognitive performance. Treatment of this problem with stimulants is likely to make the underlying poor sleep habits even worse. When your patient presents complaining of difficulty concentrating and worsening school performance, be sure to start with a thorough sleep history, and always provide guidance about the body’s need for sleep and healthy sleep habits.
 

Anxiety

Anxiety disorders are the most common psychiatric illnesses of youth, with estimates of as many as 30% of children and adolescents experiencing one. The true prevalence of ADHD is estimated to be about 4% of the population. Whether social phobia, generalized anxiety disorder, or even posttraumatic stress disorder, anxiety disorders interfere with attention as ruminative worry tends to distract those experiencing it. It can also affect attention and focus indirectly by interfering with restful sleep. Anxiety disorders can be difficult to identify, as the sufferers typically internalize their symptoms. But inquire about specific worries (such as speaking in front of others, meeting new people, or an illness or accident striking themselves or a loved one) and how much time they take up. Explore if worries fill their thoughts during quiet or downtime, and explore more about their worries. You may use a screening instrument such as the Pediatric Symptom Checklist or the SCARED, both of which will indicate a likely problem with anxiety. While it is possible to have comorbid ADHD with an anxiety disorder, the anxiety disorder will likely worsen with stimulants and should be treated first. These are usually curable illnesses and you may find that remission of anxiety symptoms resolves the attentional problems.

Depression

Mood disorders are less common than anxiety disorders in youth, but far more prevalent than ADHD. And depression is usually marked by serious difficulty concentrating across settings (including for things that were previously very interesting). A sullen teenager who is deeply self-critical about school performance would benefit from exploration of associated changes in mood, interests, energy, appetite, sleep, and for feelings of worthlessness, guilt, and suicidal thoughts. The PHQ9A is a simple, free screening instrument that is reasonable to use with every sick visit (and well-check) with your adolescent patients, given the risks of undetected and untreated depression. If your patient presents complaining of poor school performance, always screen for depression. As with anxiety disorders, comorbid ADHD is possible, but it is always recommended to treat the mood disorder first and then to assess for residual ADHD symptoms once the mood disorder is in remission.

Substance abuse

Adolescence is a time of exploration, and drug and alcohol use is common. While attentional impairment will happen with intoxication, occasional or rare use should not lead to consistent impairment in school. But when parents are more worried than their children about a significant change in school performance, it is important to screen for substance abuse. A child with a secret substance use disorder will often present with behavioral changes and deteriorating school performance and might deny any drug or alcohol use to parents. Indeed, stimulants have some street value and some patients may be seeking a stimulant prescription to sell or trade for other drugs. Regular marijuana use may present with only deteriorating school performance and no irritability or other noticeable behavioral changes. Marijuana is seen as safe and even healthy by many teenagers (and even many parents), and some youth may be using it recreationally or to manage difficulties with sleep, anxiety, or mood symptoms.

But there is compelling evidence that marijuana use causes cognitive impairment, including difficulty with sustaining attention, short-term memory, and processing speed, for as long as 24 hours after use. If a teenager is using marijuana daily after school, it is certainly going to interfere, in a dose-dependent manner, with attention and cognitive function. Sustained heavy use can lead to permanent cognitive deficits. It can also trigger or worsen anxiety or mood symptoms (contrary to much popular opinion).

Gathering a thorough substance use history is essential when assessing a teenager for difficulties with focus or attention, especially when these are accompanied by change in behavior and school performance. Remember, it is critical to interview these children without their parents present to invite them to be forthcoming with you.
 

History

While true ADHD should have been present throughout childhood, it is possible that the symptoms have become noticeable only in adolescence. For patients with very high intelligence and lower levels of impulsivity and hyperactivity, they might easily have “flown under the radar” during their elementary and even middle school years. Their difficulties with attention and focus might become apparent only when the volume and difficulty of schoolwork both are great enough that their intelligence is not enough to get good grades. That is, their problems with executive function, prioritizing, shifting sets, and completing tasks in a timely way make it impossible to keep up good grades when the work gets harder.

Your history should reveal a long history of dreaminess or distractibility, a tendency to lose and forget things, and the other symptoms of inattention. Did they often seem to not be listening when they were younger? Forget to hand in homework? Leave chores unfinished? Leave messes behind everywhere they went? These will not be definitive, but they do reassure that symptoms may have been present for a long time, even if school performance was considered fine until the workload got too large. If such problems were not present before puberty, consider whether a subtle learning disability could be impairing them as they face more challenging academic subjects.

If you have ruled out anxiety, mood, and substance use concerns, and helped them to address a sleep deficit, then you can proceed. It is worthwhile to get Vanderbilt Assessments as you would for a younger child. If they meet criteria, discuss the risks and benefits of medication, executive skills coaching, and environmental adjustments (extra time for tests, a less stimulating environment) that can help them explore academic challenges without the discouragement that ADHD can bring.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

Pediatricians are increasingly expert in the assessment and treatment of attention-deficit/hyperactivity disorder. But what do you do when adolescents present to your office saying they think they have ADHD? While ADHD is a common and treatable disorder of youth, it is important to take special care when assessing an adolescent. Difficulties with attention and concentration are common symptoms for many different challenges of adolescence, and for ADHD to be the underlying cause, those symptoms must have started prior to adolescence (according to DSM-5, prior to the age of 12). When your adolescent patients or their parents come to your office complaining of inattention, it is important to consider the full range of possible explanations.

Sleep

We have written in this column previously about the challenges that adolescents face in getting adequate sleep consistently. Teenagers, on average, need more than 9 hours of sleep nightly and American teenagers get fewer than 6. This mismatch is because of physiologic shifts that move their natural sleep onset time significantly later, while school still starts early. It’s often compounded by other demands on their time, including homework, extracurricular activities, and the gravitational pull of social connections. Independent teenagers make their own decisions about how to manage their time and may feel sleep is optional, or manage their fatigue with naps and caffeine, both of which will further compromise the quality and efficiency of sleep.

Chronic sleep deprivation will present with difficulties with focus, attention, memory, and cognitive performance. Treatment of this problem with stimulants is likely to make the underlying poor sleep habits even worse. When your patient presents complaining of difficulty concentrating and worsening school performance, be sure to start with a thorough sleep history, and always provide guidance about the body’s need for sleep and healthy sleep habits.
 

Anxiety

Anxiety disorders are the most common psychiatric illnesses of youth, with estimates of as many as 30% of children and adolescents experiencing one. The true prevalence of ADHD is estimated to be about 4% of the population. Whether social phobia, generalized anxiety disorder, or even posttraumatic stress disorder, anxiety disorders interfere with attention as ruminative worry tends to distract those experiencing it. It can also affect attention and focus indirectly by interfering with restful sleep. Anxiety disorders can be difficult to identify, as the sufferers typically internalize their symptoms. But inquire about specific worries (such as speaking in front of others, meeting new people, or an illness or accident striking themselves or a loved one) and how much time they take up. Explore if worries fill their thoughts during quiet or downtime, and explore more about their worries. You may use a screening instrument such as the Pediatric Symptom Checklist or the SCARED, both of which will indicate a likely problem with anxiety. While it is possible to have comorbid ADHD with an anxiety disorder, the anxiety disorder will likely worsen with stimulants and should be treated first. These are usually curable illnesses and you may find that remission of anxiety symptoms resolves the attentional problems.

Depression

Mood disorders are less common than anxiety disorders in youth, but far more prevalent than ADHD. And depression is usually marked by serious difficulty concentrating across settings (including for things that were previously very interesting). A sullen teenager who is deeply self-critical about school performance would benefit from exploration of associated changes in mood, interests, energy, appetite, sleep, and for feelings of worthlessness, guilt, and suicidal thoughts. The PHQ9A is a simple, free screening instrument that is reasonable to use with every sick visit (and well-check) with your adolescent patients, given the risks of undetected and untreated depression. If your patient presents complaining of poor school performance, always screen for depression. As with anxiety disorders, comorbid ADHD is possible, but it is always recommended to treat the mood disorder first and then to assess for residual ADHD symptoms once the mood disorder is in remission.

Substance abuse

Adolescence is a time of exploration, and drug and alcohol use is common. While attentional impairment will happen with intoxication, occasional or rare use should not lead to consistent impairment in school. But when parents are more worried than their children about a significant change in school performance, it is important to screen for substance abuse. A child with a secret substance use disorder will often present with behavioral changes and deteriorating school performance and might deny any drug or alcohol use to parents. Indeed, stimulants have some street value and some patients may be seeking a stimulant prescription to sell or trade for other drugs. Regular marijuana use may present with only deteriorating school performance and no irritability or other noticeable behavioral changes. Marijuana is seen as safe and even healthy by many teenagers (and even many parents), and some youth may be using it recreationally or to manage difficulties with sleep, anxiety, or mood symptoms.

But there is compelling evidence that marijuana use causes cognitive impairment, including difficulty with sustaining attention, short-term memory, and processing speed, for as long as 24 hours after use. If a teenager is using marijuana daily after school, it is certainly going to interfere, in a dose-dependent manner, with attention and cognitive function. Sustained heavy use can lead to permanent cognitive deficits. It can also trigger or worsen anxiety or mood symptoms (contrary to much popular opinion).

Gathering a thorough substance use history is essential when assessing a teenager for difficulties with focus or attention, especially when these are accompanied by change in behavior and school performance. Remember, it is critical to interview these children without their parents present to invite them to be forthcoming with you.
 

History

While true ADHD should have been present throughout childhood, it is possible that the symptoms have become noticeable only in adolescence. For patients with very high intelligence and lower levels of impulsivity and hyperactivity, they might easily have “flown under the radar” during their elementary and even middle school years. Their difficulties with attention and focus might become apparent only when the volume and difficulty of schoolwork both are great enough that their intelligence is not enough to get good grades. That is, their problems with executive function, prioritizing, shifting sets, and completing tasks in a timely way make it impossible to keep up good grades when the work gets harder.

Your history should reveal a long history of dreaminess or distractibility, a tendency to lose and forget things, and the other symptoms of inattention. Did they often seem to not be listening when they were younger? Forget to hand in homework? Leave chores unfinished? Leave messes behind everywhere they went? These will not be definitive, but they do reassure that symptoms may have been present for a long time, even if school performance was considered fine until the workload got too large. If such problems were not present before puberty, consider whether a subtle learning disability could be impairing them as they face more challenging academic subjects.

If you have ruled out anxiety, mood, and substance use concerns, and helped them to address a sleep deficit, then you can proceed. It is worthwhile to get Vanderbilt Assessments as you would for a younger child. If they meet criteria, discuss the risks and benefits of medication, executive skills coaching, and environmental adjustments (extra time for tests, a less stimulating environment) that can help them explore academic challenges without the discouragement that ADHD can bring.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

Pediatricians are increasingly expert in the assessment and treatment of attention-deficit/hyperactivity disorder. But what do you do when adolescents present to your office saying they think they have ADHD? While ADHD is a common and treatable disorder of youth, it is important to take special care when assessing an adolescent. Difficulties with attention and concentration are common symptoms for many different challenges of adolescence, and for ADHD to be the underlying cause, those symptoms must have started prior to adolescence (according to DSM-5, prior to the age of 12). When your adolescent patients or their parents come to your office complaining of inattention, it is important to consider the full range of possible explanations.

Sleep

We have written in this column previously about the challenges that adolescents face in getting adequate sleep consistently. Teenagers, on average, need more than 9 hours of sleep nightly and American teenagers get fewer than 6. This mismatch is because of physiologic shifts that move their natural sleep onset time significantly later, while school still starts early. It’s often compounded by other demands on their time, including homework, extracurricular activities, and the gravitational pull of social connections. Independent teenagers make their own decisions about how to manage their time and may feel sleep is optional, or manage their fatigue with naps and caffeine, both of which will further compromise the quality and efficiency of sleep.

Chronic sleep deprivation will present with difficulties with focus, attention, memory, and cognitive performance. Treatment of this problem with stimulants is likely to make the underlying poor sleep habits even worse. When your patient presents complaining of difficulty concentrating and worsening school performance, be sure to start with a thorough sleep history, and always provide guidance about the body’s need for sleep and healthy sleep habits.
 

Anxiety

Anxiety disorders are the most common psychiatric illnesses of youth, with estimates of as many as 30% of children and adolescents experiencing one. The true prevalence of ADHD is estimated to be about 4% of the population. Whether social phobia, generalized anxiety disorder, or even posttraumatic stress disorder, anxiety disorders interfere with attention as ruminative worry tends to distract those experiencing it. It can also affect attention and focus indirectly by interfering with restful sleep. Anxiety disorders can be difficult to identify, as the sufferers typically internalize their symptoms. But inquire about specific worries (such as speaking in front of others, meeting new people, or an illness or accident striking themselves or a loved one) and how much time they take up. Explore if worries fill their thoughts during quiet or downtime, and explore more about their worries. You may use a screening instrument such as the Pediatric Symptom Checklist or the SCARED, both of which will indicate a likely problem with anxiety. While it is possible to have comorbid ADHD with an anxiety disorder, the anxiety disorder will likely worsen with stimulants and should be treated first. These are usually curable illnesses and you may find that remission of anxiety symptoms resolves the attentional problems.

Depression

Mood disorders are less common than anxiety disorders in youth, but far more prevalent than ADHD. And depression is usually marked by serious difficulty concentrating across settings (including for things that were previously very interesting). A sullen teenager who is deeply self-critical about school performance would benefit from exploration of associated changes in mood, interests, energy, appetite, sleep, and for feelings of worthlessness, guilt, and suicidal thoughts. The PHQ9A is a simple, free screening instrument that is reasonable to use with every sick visit (and well-check) with your adolescent patients, given the risks of undetected and untreated depression. If your patient presents complaining of poor school performance, always screen for depression. As with anxiety disorders, comorbid ADHD is possible, but it is always recommended to treat the mood disorder first and then to assess for residual ADHD symptoms once the mood disorder is in remission.

Substance abuse

Adolescence is a time of exploration, and drug and alcohol use is common. While attentional impairment will happen with intoxication, occasional or rare use should not lead to consistent impairment in school. But when parents are more worried than their children about a significant change in school performance, it is important to screen for substance abuse. A child with a secret substance use disorder will often present with behavioral changes and deteriorating school performance and might deny any drug or alcohol use to parents. Indeed, stimulants have some street value and some patients may be seeking a stimulant prescription to sell or trade for other drugs. Regular marijuana use may present with only deteriorating school performance and no irritability or other noticeable behavioral changes. Marijuana is seen as safe and even healthy by many teenagers (and even many parents), and some youth may be using it recreationally or to manage difficulties with sleep, anxiety, or mood symptoms.

But there is compelling evidence that marijuana use causes cognitive impairment, including difficulty with sustaining attention, short-term memory, and processing speed, for as long as 24 hours after use. If a teenager is using marijuana daily after school, it is certainly going to interfere, in a dose-dependent manner, with attention and cognitive function. Sustained heavy use can lead to permanent cognitive deficits. It can also trigger or worsen anxiety or mood symptoms (contrary to much popular opinion).

Gathering a thorough substance use history is essential when assessing a teenager for difficulties with focus or attention, especially when these are accompanied by change in behavior and school performance. Remember, it is critical to interview these children without their parents present to invite them to be forthcoming with you.
 

History

While true ADHD should have been present throughout childhood, it is possible that the symptoms have become noticeable only in adolescence. For patients with very high intelligence and lower levels of impulsivity and hyperactivity, they might easily have “flown under the radar” during their elementary and even middle school years. Their difficulties with attention and focus might become apparent only when the volume and difficulty of schoolwork both are great enough that their intelligence is not enough to get good grades. That is, their problems with executive function, prioritizing, shifting sets, and completing tasks in a timely way make it impossible to keep up good grades when the work gets harder.

Your history should reveal a long history of dreaminess or distractibility, a tendency to lose and forget things, and the other symptoms of inattention. Did they often seem to not be listening when they were younger? Forget to hand in homework? Leave chores unfinished? Leave messes behind everywhere they went? These will not be definitive, but they do reassure that symptoms may have been present for a long time, even if school performance was considered fine until the workload got too large. If such problems were not present before puberty, consider whether a subtle learning disability could be impairing them as they face more challenging academic subjects.

If you have ruled out anxiety, mood, and substance use concerns, and helped them to address a sleep deficit, then you can proceed. It is worthwhile to get Vanderbilt Assessments as you would for a younger child. If they meet criteria, discuss the risks and benefits of medication, executive skills coaching, and environmental adjustments (extra time for tests, a less stimulating environment) that can help them explore academic challenges without the discouragement that ADHD can bring.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

New studies show that chronic exposure to air pollution is associated with increased risk of autoimmune disease in adults and depression in adolescents.

Other analyses of data have found environmental air pollution from sources such as car exhaust and factory output can trigger an inflammatory response in the body. What’s new about a study published in RMD Open is that it explored an association between long-term exposure to pollution and risk of autoimmune diseases, wrote Giovanni Adami, MD, of the University of Verona (Italy) and colleagues.

“Environmental air pollution, according to the World Health Organization, is a major risk to health and 99% of the population worldwide is living in places where recommendations for air quality are not met,” said Dr. Adami in an interview. The limited data on the precise role of air pollution on rheumatic diseases in particular prompted the study, he said.

To explore the potential link between air pollution exposure and autoimmune disease, the researchers reviewed medical information from 81,363 adults via a national medical database in Italy; the data were submitted between June 2016 and November 2020.

The average age of the study population was 65 years, and 92% were women; 22% had at least one coexisting health condition. Each study participant was linked to local environmental monitoring via their residential postcode. 

The researchers obtained details about concentrations of particulate matter in the environment from the Italian Institute of Environmental Protection that included 617 monitoring stations in 110 Italian provinces. They focused on concentrations of 10 and 2.5 (PM10 and PM2.5).

Exposure thresholds of 30 mcg/m³ for PM10 and 20 mcg/m³ for PM2.5 are generally considered harmful to health, they noted. On average, the long-term exposure was 16 mcg/m³ for PM2.5 and 25 mcg/m³ for PM10 between 2013 and 2019.

Overall, 9,723 individuals (12%) were diagnosed with an autoimmune disease between 2016 and 2020.

Exposure to PM10 was associated with a 7% higher risk of diagnosis with any autoimmune disease for every 10 mcg/m³ increase in concentration, but no association appeared between PM2.5 exposure and increased risk of autoimmune diseases.

However, in an adjusted model, chronic exposure to PM10 above 30 mcg/m³ and to PM2.5 above 20 mcg/m³ were associated with a 12% and 13% higher risk, respectively, of any autoimmune disease. 

Chronic exposure to high levels of PM10 was specifically associated with a higher risk of rheumatoid arthritis, but no other autoimmune diseases. Chronic exposure to high levels of PM2.5 was associated with a higher risk of rheumatoid arthritis, connective tissue diseases, and inflammatory bowel diseases.

In their discussion, the researchers noted that the smaller diameter of PM2.5 molecules fluctuate less in response to rain and other weather, compared with PM10 molecules, which might make them a more accurate predictor of exposure to chronic air pollution.

The study findings were limited by several factors including the observational design, which prohibits the establishment of cause, and a lack of data on the start of symptoms and dates of diagnoses for autoimmune diseases, the researchers noted. Other limitations include the high percentage of older women in the study, which may limit generalizability, and the inability to account for additional personal exposure to pollutants outside of the environmental exposure, they said.

However, the results were strengthened by the large sample size and wide geographic distribution with variable pollution exposure, they said.

“Unfortunately, we were not surprised at all,” by the findings, Dr. Adami said in an interview.

“The biological rationale underpinning our findings is strong. Nevertheless, the magnitude of the effect was overwhelming. In addition, we saw an effect even at threshold of exposure that is widely considered as safe,” Dr. Adami noted.

Clinicians have been taught to consider cigarette smoking or other lifestyle behaviors as major risk factors for the development of several autoimmune diseases, said Dr. Adami. “In the future, we probably should include air pollution exposure as a risk factor as well. Interestingly, there is also accumulating evidence linking acute exposure to environmental air pollution with flares of chronic arthritis,” he said.

“Our study could have direct societal and political consequences,” and might help direct policy makers’ decisions on addressing strategies aimed to reduce fossil emissions, he said. As for additional research, “we certainly need multination studies to confirm our results on a larger scale,” Dr. Adami emphasized. “In addition, it is time to take action and start designing interventions aimed to reduce acute and chronic exposure to air pollution in patients suffering from RMDs.”

Consider the big picture of air quality

The Italian study is especially timely “given our evolving and emerging understanding of environmental risk factors for acute and chronic diseases, which we must first understand before we can address,” said Eileen Barrett, MD, of the University of New Mexico, Albuquerque, in an interview.

“I am largely surprised about the findings, as most physicians aren’t studying ambient air quality and risk for autoimmune disease,” said Dr. Barrett. “More often we think of air quality when we think of risk for respiratory diseases than autoimmune diseases, per se,” she said.

“There are several take-home messages from this study,” said Dr. Barrett. “The first is that we need more research to understand the consequences of air pollutants on health. Second, this study reminds us to think broadly about how air quality and our environment can affect health. And third, all clinicians should be committed to promoting science that can improve public health and reduce death and disability,” she emphasized.

The findings do not specifically reflect associations between pollution and other conditions such as chronic obstructive pulmonary disease and asthma although previous studies have shown an association between asthma and COPD exacerbations and air pollution, Dr. Barrett said.

“Further research will be needed to confirm the associations reported in this study,” Dr. Barrett said.

More research in other countries, including research related to other autoimmune diseases, and with other datasets on population and community level risks from poor air quality, would be helpful, and that information could be used to advise smart public policy, Dr. Barrett added.

Air pollution’s mental health impact

Air pollution’s effects extend beyond physical to the psychological, a new study of depression in teenagers showed. This study was published in Developmental Psychology.

Previous research on the environmental factors associated with depressive symptoms in teens has focused mainly on individual and family level contributors; the impact of the physical environment has not been well studied, the investigators, Erika M. Manczak, PhD, of the University of Denver and colleagues, wrote.

In their paper, the authors found a significant impact of neighborhood ozone exposure on the trajectory of depressive symptoms in teens over a 4-year period.

“Given that inhaling pollution activates biological pathways implicated in the development of depression, including immune, cardiovascular, and neurodevelopmental processes, exposure to ambient air pollution may influence the development and/or trajectory of depressive symptoms in youth,” they said.

The researchers recruited 213 adolescents in the San Francisco Bay area through local advertisements. The participants were aged 9-13 years at baseline, with an average age of 11 years. A total of 121 were female, 47% were white, 8.5% were African American, 12.3% were Asian, 10.4% were nonwhite Latin, and 21.7% were biracial or another ethnicity. The participants self-reported depressive symptoms and other psychopathology symptoms up to three times during the study period. Ozone exposure was calculated based on home addresses.

After controlling for other personal, family, and neighborhood variables, the researchers found that higher levels of ozone exposure were significantly associated with increased depressive symptoms over time, and the slope of trajectory of depressive symptoms became steeper as the ozone levels increased (P less than .001). Ozone did not significantly predict the trajectory of any other psychopathology symptoms.

“The results of this study provide preliminary support for the possibility that ozone is an overlooked contributor to the development or course of youth depressive symptoms,” the researchers wrote in their discussion.

“Interestingly, the association between ozone and symptom trajectories as measured by Anxious/Depressed subscale of the [Youth Self-Report] was not as strong as it was for the [Children’s Depression Inventory-Short Version] or Withdrawn/Depressed scales, suggesting that associations are more robust for behavioral withdrawal symptoms of depression than for other types of symptoms,” they noted.

The study findings were limited by the use of self-reports and by the inability of the study design to show causality, the researchers said. Other limitations include the use of average assessments of ozone that are less precise, lack of assessment of biological pathways for risk, lack of formal psychiatric diagnoses, and the small geographic region included in the study, they said.

However, the results provide preliminary evidence that ozone exposure is a potential contributing factor to depressive symptoms in youth, and serve as a jumping-off point for future research, they noted. Future studies should address changes in systemic inflammation, neurodevelopment, or stress reactivity, as well as concurrent psychosocial or biological factors, and temporal associations between air pollution and mental health symptoms, they concluded.

Environmental factors drive inflammatory responses

Peter L. Loper Jr., MD, considers the findings of the Developmental Psychology study to be unsurprising but important – because air pollution is simply getting worse.

“As the study authors cite, there is sufficient data correlating ozone to negative physical health outcomes in youth, but a paucity of data exploring the impact of poor air quality on mental health outcomes in this demographic,” noted Dr. Loper, of the University of South Carolina, Columbia, in an interview.

“As discussed by the study researchers, any environmental exposure that increases immune-mediated inflammation can result in negative health outcomes. In fact, there is already data to suggest that similar cytokines, or immune cell signalers, that get released by our immune system due to environmental exposures and that contribute to asthma, may also be implicated in depression and other mental health problems,” he noted.

“Just like downstream symptom indicators of physical illnesses such as asthma are secondary to immune-mediated pulmonary inflammation, downstream symptom indicators of mental illness, such as depression, are secondary to immune-mediated neuroinflammation,” Dr. Loper emphasized. “The most well-characterized upstream phenomenon perpetuating the downstream symptom indicators of depression involve neuroinflammatory states due to psychosocial and relational factors such as chronic stress, poor relationships, or substance use. However, any environmental factor that triggers an immune response and inflammation can promote neuroinflammation that manifests as symptoms of mental illness.”

The message for teens with depression and their families is that “we are a product of our environment,” Dr. Loper said. “When our environments are proinflammatory, or cause our immune system to become overactive, then we will develop illness; however, the most potent mediator of inflammation in the brain, and the downstream symptoms of depression, is our relationships with those we love most,” he said.

Dr. Loper suggested research aimed at identifying other sources of immune-mediated inflammation caused by physical environments and better understanding how environmental phenomenon like ozone may compound previously established risk factors for mental illness could be useful.

The RMD Open study received no outside funding, and its authors had no financial conflicts.

The Developmental Psychology study was supported by the National Institute of Mental Health and the Stanford University Precision Health and Integrated Diagnostics Center. The researchers for that report, and Dr. Loper and Dr. Barrett had no conflicts to disclose.

New studies show that chronic exposure to air pollution is associated with increased risk of autoimmune disease in adults and depression in adolescents.

Other analyses of data have found environmental air pollution from sources such as car exhaust and factory output can trigger an inflammatory response in the body. What’s new about a study published in RMD Open is that it explored an association between long-term exposure to pollution and risk of autoimmune diseases, wrote Giovanni Adami, MD, of the University of Verona (Italy) and colleagues.

“Environmental air pollution, according to the World Health Organization, is a major risk to health and 99% of the population worldwide is living in places where recommendations for air quality are not met,” said Dr. Adami in an interview. The limited data on the precise role of air pollution on rheumatic diseases in particular prompted the study, he said.

To explore the potential link between air pollution exposure and autoimmune disease, the researchers reviewed medical information from 81,363 adults via a national medical database in Italy; the data were submitted between June 2016 and November 2020.

The average age of the study population was 65 years, and 92% were women; 22% had at least one coexisting health condition. Each study participant was linked to local environmental monitoring via their residential postcode. 

The researchers obtained details about concentrations of particulate matter in the environment from the Italian Institute of Environmental Protection that included 617 monitoring stations in 110 Italian provinces. They focused on concentrations of 10 and 2.5 (PM10 and PM2.5).

Exposure thresholds of 30 mcg/m³ for PM10 and 20 mcg/m³ for PM2.5 are generally considered harmful to health, they noted. On average, the long-term exposure was 16 mcg/m³ for PM2.5 and 25 mcg/m³ for PM10 between 2013 and 2019.

Overall, 9,723 individuals (12%) were diagnosed with an autoimmune disease between 2016 and 2020.

Exposure to PM10 was associated with a 7% higher risk of diagnosis with any autoimmune disease for every 10 mcg/m³ increase in concentration, but no association appeared between PM2.5 exposure and increased risk of autoimmune diseases.

However, in an adjusted model, chronic exposure to PM10 above 30 mcg/m³ and to PM2.5 above 20 mcg/m³ were associated with a 12% and 13% higher risk, respectively, of any autoimmune disease. 

Chronic exposure to high levels of PM10 was specifically associated with a higher risk of rheumatoid arthritis, but no other autoimmune diseases. Chronic exposure to high levels of PM2.5 was associated with a higher risk of rheumatoid arthritis, connective tissue diseases, and inflammatory bowel diseases.

In their discussion, the researchers noted that the smaller diameter of PM2.5 molecules fluctuate less in response to rain and other weather, compared with PM10 molecules, which might make them a more accurate predictor of exposure to chronic air pollution.

The study findings were limited by several factors including the observational design, which prohibits the establishment of cause, and a lack of data on the start of symptoms and dates of diagnoses for autoimmune diseases, the researchers noted. Other limitations include the high percentage of older women in the study, which may limit generalizability, and the inability to account for additional personal exposure to pollutants outside of the environmental exposure, they said.

However, the results were strengthened by the large sample size and wide geographic distribution with variable pollution exposure, they said.

“Unfortunately, we were not surprised at all,” by the findings, Dr. Adami said in an interview.

“The biological rationale underpinning our findings is strong. Nevertheless, the magnitude of the effect was overwhelming. In addition, we saw an effect even at threshold of exposure that is widely considered as safe,” Dr. Adami noted.

Clinicians have been taught to consider cigarette smoking or other lifestyle behaviors as major risk factors for the development of several autoimmune diseases, said Dr. Adami. “In the future, we probably should include air pollution exposure as a risk factor as well. Interestingly, there is also accumulating evidence linking acute exposure to environmental air pollution with flares of chronic arthritis,” he said.

“Our study could have direct societal and political consequences,” and might help direct policy makers’ decisions on addressing strategies aimed to reduce fossil emissions, he said. As for additional research, “we certainly need multination studies to confirm our results on a larger scale,” Dr. Adami emphasized. “In addition, it is time to take action and start designing interventions aimed to reduce acute and chronic exposure to air pollution in patients suffering from RMDs.”

Consider the big picture of air quality

The Italian study is especially timely “given our evolving and emerging understanding of environmental risk factors for acute and chronic diseases, which we must first understand before we can address,” said Eileen Barrett, MD, of the University of New Mexico, Albuquerque, in an interview.

“I am largely surprised about the findings, as most physicians aren’t studying ambient air quality and risk for autoimmune disease,” said Dr. Barrett. “More often we think of air quality when we think of risk for respiratory diseases than autoimmune diseases, per se,” she said.

“There are several take-home messages from this study,” said Dr. Barrett. “The first is that we need more research to understand the consequences of air pollutants on health. Second, this study reminds us to think broadly about how air quality and our environment can affect health. And third, all clinicians should be committed to promoting science that can improve public health and reduce death and disability,” she emphasized.

The findings do not specifically reflect associations between pollution and other conditions such as chronic obstructive pulmonary disease and asthma although previous studies have shown an association between asthma and COPD exacerbations and air pollution, Dr. Barrett said.

“Further research will be needed to confirm the associations reported in this study,” Dr. Barrett said.

More research in other countries, including research related to other autoimmune diseases, and with other datasets on population and community level risks from poor air quality, would be helpful, and that information could be used to advise smart public policy, Dr. Barrett added.

Air pollution’s mental health impact

Air pollution’s effects extend beyond physical to the psychological, a new study of depression in teenagers showed. This study was published in Developmental Psychology.

Previous research on the environmental factors associated with depressive symptoms in teens has focused mainly on individual and family level contributors; the impact of the physical environment has not been well studied, the investigators, Erika M. Manczak, PhD, of the University of Denver and colleagues, wrote.

In their paper, the authors found a significant impact of neighborhood ozone exposure on the trajectory of depressive symptoms in teens over a 4-year period.

“Given that inhaling pollution activates biological pathways implicated in the development of depression, including immune, cardiovascular, and neurodevelopmental processes, exposure to ambient air pollution may influence the development and/or trajectory of depressive symptoms in youth,” they said.

The researchers recruited 213 adolescents in the San Francisco Bay area through local advertisements. The participants were aged 9-13 years at baseline, with an average age of 11 years. A total of 121 were female, 47% were white, 8.5% were African American, 12.3% were Asian, 10.4% were nonwhite Latin, and 21.7% were biracial or another ethnicity. The participants self-reported depressive symptoms and other psychopathology symptoms up to three times during the study period. Ozone exposure was calculated based on home addresses.

After controlling for other personal, family, and neighborhood variables, the researchers found that higher levels of ozone exposure were significantly associated with increased depressive symptoms over time, and the slope of trajectory of depressive symptoms became steeper as the ozone levels increased (P less than .001). Ozone did not significantly predict the trajectory of any other psychopathology symptoms.

“The results of this study provide preliminary support for the possibility that ozone is an overlooked contributor to the development or course of youth depressive symptoms,” the researchers wrote in their discussion.

“Interestingly, the association between ozone and symptom trajectories as measured by Anxious/Depressed subscale of the [Youth Self-Report] was not as strong as it was for the [Children’s Depression Inventory-Short Version] or Withdrawn/Depressed scales, suggesting that associations are more robust for behavioral withdrawal symptoms of depression than for other types of symptoms,” they noted.

The study findings were limited by the use of self-reports and by the inability of the study design to show causality, the researchers said. Other limitations include the use of average assessments of ozone that are less precise, lack of assessment of biological pathways for risk, lack of formal psychiatric diagnoses, and the small geographic region included in the study, they said.

However, the results provide preliminary evidence that ozone exposure is a potential contributing factor to depressive symptoms in youth, and serve as a jumping-off point for future research, they noted. Future studies should address changes in systemic inflammation, neurodevelopment, or stress reactivity, as well as concurrent psychosocial or biological factors, and temporal associations between air pollution and mental health symptoms, they concluded.

Environmental factors drive inflammatory responses

Peter L. Loper Jr., MD, considers the findings of the Developmental Psychology study to be unsurprising but important – because air pollution is simply getting worse.

“As the study authors cite, there is sufficient data correlating ozone to negative physical health outcomes in youth, but a paucity of data exploring the impact of poor air quality on mental health outcomes in this demographic,” noted Dr. Loper, of the University of South Carolina, Columbia, in an interview.

“As discussed by the study researchers, any environmental exposure that increases immune-mediated inflammation can result in negative health outcomes. In fact, there is already data to suggest that similar cytokines, or immune cell signalers, that get released by our immune system due to environmental exposures and that contribute to asthma, may also be implicated in depression and other mental health problems,” he noted.

“Just like downstream symptom indicators of physical illnesses such as asthma are secondary to immune-mediated pulmonary inflammation, downstream symptom indicators of mental illness, such as depression, are secondary to immune-mediated neuroinflammation,” Dr. Loper emphasized. “The most well-characterized upstream phenomenon perpetuating the downstream symptom indicators of depression involve neuroinflammatory states due to psychosocial and relational factors such as chronic stress, poor relationships, or substance use. However, any environmental factor that triggers an immune response and inflammation can promote neuroinflammation that manifests as symptoms of mental illness.”

The message for teens with depression and their families is that “we are a product of our environment,” Dr. Loper said. “When our environments are proinflammatory, or cause our immune system to become overactive, then we will develop illness; however, the most potent mediator of inflammation in the brain, and the downstream symptoms of depression, is our relationships with those we love most,” he said.

Dr. Loper suggested research aimed at identifying other sources of immune-mediated inflammation caused by physical environments and better understanding how environmental phenomenon like ozone may compound previously established risk factors for mental illness could be useful.

The RMD Open study received no outside funding, and its authors had no financial conflicts.

The Developmental Psychology study was supported by the National Institute of Mental Health and the Stanford University Precision Health and Integrated Diagnostics Center. The researchers for that report, and Dr. Loper and Dr. Barrett had no conflicts to disclose.

New studies show that chronic exposure to air pollution is associated with increased risk of autoimmune disease in adults and depression in adolescents.

Other analyses of data have found environmental air pollution from sources such as car exhaust and factory output can trigger an inflammatory response in the body. What’s new about a study published in RMD Open is that it explored an association between long-term exposure to pollution and risk of autoimmune diseases, wrote Giovanni Adami, MD, of the University of Verona (Italy) and colleagues.

“Environmental air pollution, according to the World Health Organization, is a major risk to health and 99% of the population worldwide is living in places where recommendations for air quality are not met,” said Dr. Adami in an interview. The limited data on the precise role of air pollution on rheumatic diseases in particular prompted the study, he said.

To explore the potential link between air pollution exposure and autoimmune disease, the researchers reviewed medical information from 81,363 adults via a national medical database in Italy; the data were submitted between June 2016 and November 2020.

The average age of the study population was 65 years, and 92% were women; 22% had at least one coexisting health condition. Each study participant was linked to local environmental monitoring via their residential postcode. 

The researchers obtained details about concentrations of particulate matter in the environment from the Italian Institute of Environmental Protection that included 617 monitoring stations in 110 Italian provinces. They focused on concentrations of 10 and 2.5 (PM10 and PM2.5).

Exposure thresholds of 30 mcg/m³ for PM10 and 20 mcg/m³ for PM2.5 are generally considered harmful to health, they noted. On average, the long-term exposure was 16 mcg/m³ for PM2.5 and 25 mcg/m³ for PM10 between 2013 and 2019.

Overall, 9,723 individuals (12%) were diagnosed with an autoimmune disease between 2016 and 2020.

Exposure to PM10 was associated with a 7% higher risk of diagnosis with any autoimmune disease for every 10 mcg/m³ increase in concentration, but no association appeared between PM2.5 exposure and increased risk of autoimmune diseases.

However, in an adjusted model, chronic exposure to PM10 above 30 mcg/m³ and to PM2.5 above 20 mcg/m³ were associated with a 12% and 13% higher risk, respectively, of any autoimmune disease. 

Chronic exposure to high levels of PM10 was specifically associated with a higher risk of rheumatoid arthritis, but no other autoimmune diseases. Chronic exposure to high levels of PM2.5 was associated with a higher risk of rheumatoid arthritis, connective tissue diseases, and inflammatory bowel diseases.

In their discussion, the researchers noted that the smaller diameter of PM2.5 molecules fluctuate less in response to rain and other weather, compared with PM10 molecules, which might make them a more accurate predictor of exposure to chronic air pollution.

The study findings were limited by several factors including the observational design, which prohibits the establishment of cause, and a lack of data on the start of symptoms and dates of diagnoses for autoimmune diseases, the researchers noted. Other limitations include the high percentage of older women in the study, which may limit generalizability, and the inability to account for additional personal exposure to pollutants outside of the environmental exposure, they said.

However, the results were strengthened by the large sample size and wide geographic distribution with variable pollution exposure, they said.

“Unfortunately, we were not surprised at all,” by the findings, Dr. Adami said in an interview.

“The biological rationale underpinning our findings is strong. Nevertheless, the magnitude of the effect was overwhelming. In addition, we saw an effect even at threshold of exposure that is widely considered as safe,” Dr. Adami noted.

Clinicians have been taught to consider cigarette smoking or other lifestyle behaviors as major risk factors for the development of several autoimmune diseases, said Dr. Adami. “In the future, we probably should include air pollution exposure as a risk factor as well. Interestingly, there is also accumulating evidence linking acute exposure to environmental air pollution with flares of chronic arthritis,” he said.

“Our study could have direct societal and political consequences,” and might help direct policy makers’ decisions on addressing strategies aimed to reduce fossil emissions, he said. As for additional research, “we certainly need multination studies to confirm our results on a larger scale,” Dr. Adami emphasized. “In addition, it is time to take action and start designing interventions aimed to reduce acute and chronic exposure to air pollution in patients suffering from RMDs.”

Consider the big picture of air quality

The Italian study is especially timely “given our evolving and emerging understanding of environmental risk factors for acute and chronic diseases, which we must first understand before we can address,” said Eileen Barrett, MD, of the University of New Mexico, Albuquerque, in an interview.

“I am largely surprised about the findings, as most physicians aren’t studying ambient air quality and risk for autoimmune disease,” said Dr. Barrett. “More often we think of air quality when we think of risk for respiratory diseases than autoimmune diseases, per se,” she said.

“There are several take-home messages from this study,” said Dr. Barrett. “The first is that we need more research to understand the consequences of air pollutants on health. Second, this study reminds us to think broadly about how air quality and our environment can affect health. And third, all clinicians should be committed to promoting science that can improve public health and reduce death and disability,” she emphasized.

The findings do not specifically reflect associations between pollution and other conditions such as chronic obstructive pulmonary disease and asthma although previous studies have shown an association between asthma and COPD exacerbations and air pollution, Dr. Barrett said.

“Further research will be needed to confirm the associations reported in this study,” Dr. Barrett said.

More research in other countries, including research related to other autoimmune diseases, and with other datasets on population and community level risks from poor air quality, would be helpful, and that information could be used to advise smart public policy, Dr. Barrett added.

Air pollution’s mental health impact

Air pollution’s effects extend beyond physical to the psychological, a new study of depression in teenagers showed. This study was published in Developmental Psychology.

Previous research on the environmental factors associated with depressive symptoms in teens has focused mainly on individual and family level contributors; the impact of the physical environment has not been well studied, the investigators, Erika M. Manczak, PhD, of the University of Denver and colleagues, wrote.

In their paper, the authors found a significant impact of neighborhood ozone exposure on the trajectory of depressive symptoms in teens over a 4-year period.

“Given that inhaling pollution activates biological pathways implicated in the development of depression, including immune, cardiovascular, and neurodevelopmental processes, exposure to ambient air pollution may influence the development and/or trajectory of depressive symptoms in youth,” they said.

The researchers recruited 213 adolescents in the San Francisco Bay area through local advertisements. The participants were aged 9-13 years at baseline, with an average age of 11 years. A total of 121 were female, 47% were white, 8.5% were African American, 12.3% were Asian, 10.4% were nonwhite Latin, and 21.7% were biracial or another ethnicity. The participants self-reported depressive symptoms and other psychopathology symptoms up to three times during the study period. Ozone exposure was calculated based on home addresses.

After controlling for other personal, family, and neighborhood variables, the researchers found that higher levels of ozone exposure were significantly associated with increased depressive symptoms over time, and the slope of trajectory of depressive symptoms became steeper as the ozone levels increased (P less than .001). Ozone did not significantly predict the trajectory of any other psychopathology symptoms.

“The results of this study provide preliminary support for the possibility that ozone is an overlooked contributor to the development or course of youth depressive symptoms,” the researchers wrote in their discussion.

“Interestingly, the association between ozone and symptom trajectories as measured by Anxious/Depressed subscale of the [Youth Self-Report] was not as strong as it was for the [Children’s Depression Inventory-Short Version] or Withdrawn/Depressed scales, suggesting that associations are more robust for behavioral withdrawal symptoms of depression than for other types of symptoms,” they noted.

The study findings were limited by the use of self-reports and by the inability of the study design to show causality, the researchers said. Other limitations include the use of average assessments of ozone that are less precise, lack of assessment of biological pathways for risk, lack of formal psychiatric diagnoses, and the small geographic region included in the study, they said.

However, the results provide preliminary evidence that ozone exposure is a potential contributing factor to depressive symptoms in youth, and serve as a jumping-off point for future research, they noted. Future studies should address changes in systemic inflammation, neurodevelopment, or stress reactivity, as well as concurrent psychosocial or biological factors, and temporal associations between air pollution and mental health symptoms, they concluded.

Environmental factors drive inflammatory responses

Peter L. Loper Jr., MD, considers the findings of the Developmental Psychology study to be unsurprising but important – because air pollution is simply getting worse.

“As the study authors cite, there is sufficient data correlating ozone to negative physical health outcomes in youth, but a paucity of data exploring the impact of poor air quality on mental health outcomes in this demographic,” noted Dr. Loper, of the University of South Carolina, Columbia, in an interview.

“As discussed by the study researchers, any environmental exposure that increases immune-mediated inflammation can result in negative health outcomes. In fact, there is already data to suggest that similar cytokines, or immune cell signalers, that get released by our immune system due to environmental exposures and that contribute to asthma, may also be implicated in depression and other mental health problems,” he noted.

“Just like downstream symptom indicators of physical illnesses such as asthma are secondary to immune-mediated pulmonary inflammation, downstream symptom indicators of mental illness, such as depression, are secondary to immune-mediated neuroinflammation,” Dr. Loper emphasized. “The most well-characterized upstream phenomenon perpetuating the downstream symptom indicators of depression involve neuroinflammatory states due to psychosocial and relational factors such as chronic stress, poor relationships, or substance use. However, any environmental factor that triggers an immune response and inflammation can promote neuroinflammation that manifests as symptoms of mental illness.”

The message for teens with depression and their families is that “we are a product of our environment,” Dr. Loper said. “When our environments are proinflammatory, or cause our immune system to become overactive, then we will develop illness; however, the most potent mediator of inflammation in the brain, and the downstream symptoms of depression, is our relationships with those we love most,” he said.

Dr. Loper suggested research aimed at identifying other sources of immune-mediated inflammation caused by physical environments and better understanding how environmental phenomenon like ozone may compound previously established risk factors for mental illness could be useful.

The RMD Open study received no outside funding, and its authors had no financial conflicts.

The Developmental Psychology study was supported by the National Institute of Mental Health and the Stanford University Precision Health and Integrated Diagnostics Center. The researchers for that report, and Dr. Loper and Dr. Barrett had no conflicts to disclose.