MDedge Neurology

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.

Frexalimab (Sanofi), a novel, investigational second-generation inhibitor of the CD40 ligand, significantly reduced disease activity in relapsing multiple sclerosis (MS) and was well tolerated in a phase 2 study.

At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.

The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.

The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
 

‘Unambiguous Benefit’

Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.

“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.

The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.

Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).

All but four patients completed the 12-week double-blind period and entered the open-label period.

The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.

At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.

The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.

On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.

The effects were sustained over time across both active treatment groups.

Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
 

Phase 3 Trials Underway

The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.

There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.

No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.

Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.

Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
 

‘A High Bar for Any New Treatment’

In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”

If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”

Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”

“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”

“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.

While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.

The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
 

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

Frexalimab (Sanofi), a novel, investigational second-generation inhibitor of the CD40 ligand, significantly reduced disease activity in relapsing multiple sclerosis (MS) and was well tolerated in a phase 2 study.

At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.

The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.

The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
 

‘Unambiguous Benefit’

Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.

“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.

The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.

Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).

All but four patients completed the 12-week double-blind period and entered the open-label period.

The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.

At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.

The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.

On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.

The effects were sustained over time across both active treatment groups.

Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
 

Phase 3 Trials Underway

The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.

There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.

No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.

Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.

Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
 

‘A High Bar for Any New Treatment’

In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”

If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”

Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”

“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”

“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.

While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.

The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
 

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

Frexalimab (Sanofi), a novel, investigational second-generation inhibitor of the CD40 ligand, significantly reduced disease activity in relapsing multiple sclerosis (MS) and was well tolerated in a phase 2 study.

At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.

The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.

The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
 

‘Unambiguous Benefit’

Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.

“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.

The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.

Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).

All but four patients completed the 12-week double-blind period and entered the open-label period.

The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.

At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.

The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.

On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.

The effects were sustained over time across both active treatment groups.

Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
 

Phase 3 Trials Underway

The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.

There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.

No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.

Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.

Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
 

‘A High Bar for Any New Treatment’

In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”

If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”

Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”

“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”

“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.

While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.

The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
 

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

WEST PALM BEACH, FLORIDA — There is growing confidence that remyelinating agents will be a viable option in the treatment of multiple sclerosis (MS) in the not-too-distant future, according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.

Ted Bosworth/MDedge News

“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.

“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”

The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
 

Remyelinating Effect Documented at Multiple Sites

The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.

The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.

Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.

Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.

“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.

One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.

“We might need to provide drugs with a remyelinating effect very early in the process,” he said.

The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
 

Late-breaker: Two Remyelinating Drugs with Promise

Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).

Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.

The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.

“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.

He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.

Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — There is growing confidence that remyelinating agents will be a viable option in the treatment of multiple sclerosis (MS) in the not-too-distant future, according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.

Ted Bosworth/MDedge News

“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.

“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”

The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
 

Remyelinating Effect Documented at Multiple Sites

The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.

The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.

Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.

Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.

“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.

One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.

“We might need to provide drugs with a remyelinating effect very early in the process,” he said.

The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
 

Late-breaker: Two Remyelinating Drugs with Promise

Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).

Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.

The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.

“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.

He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.

Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — There is growing confidence that remyelinating agents will be a viable option in the treatment of multiple sclerosis (MS) in the not-too-distant future, according to a summary of the science as well as a late-breaker study presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

In an outline of barriers to remyelinating drugs, including the challenge of delivering well-tolerated therapies into the central nervous system (CNS), Ari J. Green, MD, Chief of the Division of Neuroimmunology and Glial Biology, University of California, San Francisco, spoke specifically about recent progress in drug development.

Ted Bosworth/MDedge News

“The important thing is that once we understand the biology, we can turn barriers into opportunities,” he said as he outlined advances over the 6 years since he led the ReBUILD trial.

“We are thinking of remyelination therapies as something off in the horizon,” said Dr. Green, but “the horizon might be closer than we might imagine.”

The double-blind ReBUILD trial provided the first evidence of activity from a remyelinating drug. In this study, 50 patients with chronic demyelinating optic neuropathy and relapsing-remitting MS were randomized to twice daily doses (5-36 mg) of clemastine fumarate for 90 days followed by placebo for 60 days or to placebo for 60 days followed by active drug for 90 days.
 

Remyelinating Effect Documented at Multiple Sites

The improvement on the primary endpoint of visual evoked potentials was interpreted as evidence that the therapy had a positive remyelinating effect, and Dr. Green said that the result has been reproduced by more than a dozen other centers.

The theoretical benefit is from a favorable effect on myelin-producing stem cells, but Dr. Green emphasized that theoretical benefits are not enough for moving the field forward. Negative trials with a theoretical potential to generate remyelination both preceded and followed ReBUILD. Examples include the RENEW study with the anti-lingo monoclonal antibody opicinumab and the CCMR One study with the non-selective retinoid X receptor agonist bexarotene.

Whether there is benefit or failure, “we need to be able to tell what is going on,” Dr. Green said. The reason is that a negative result is not necessarily due to the absence of a meaningful remyelination. Rather, other variables, such as an insufficient number of axons to remyelinate, might explain a lack of effect.

Citing evidence that remyelination and demyelination are often concurrent events, Dr. Green said that there is an urgent need for tools to objectively quantify myelination in order to document that drugs purported to favorably influence myelin repair are doing so. Surrogate markers are potentially unreliable.

“There is an unfortunate tendency in our field to overinterpret atrophy and neurodegeneration and to use those terms too loosely,” Dr. Green said. He said these terms are not interchangeable.

One basis for excitement is the growing support for the theory that oligodendrocyte progenitor cell (OPC) recruitment is critical to the remyelination process. By activating these cells or blocking inhibitors of their activity, experimental evidence suggests new myelin formation can occur. However, a clinically meaningful benefit might still be dependent on multiple additional factors, including the timing of OPC recruitment, Dr. Green explained.

“We might need to provide drugs with a remyelinating effect very early in the process,” he said.

The progress in understanding the interacting factors that define the biology of remyelination is the basis for new enthusiasm about this field, agreed Véronique Miron, PhD, Chair of the Multiple Sclerosis Research, Barlo MS Center, Toronto. Dr. Miron, professor in the Department of Immunology at the University of Toronto, identified the session on remyelination in which Dr. Green spoke as one of the highlights of this year’s ACTRIMS conference.
 

Late-breaker: Two Remyelinating Drugs with Promise

Consistent with this progress, a late-breaker presentation on two drugs that promote oligodendrocyte formation and remyelination in the experimental setting reinforced the growing array of potential therapeutic targets to generate remyelination. The two drugs, CVL-1001 and CVL-2001, act by inhibiting the cholesterol biosynthesis enzymes sterol 14-demethylase (CYP51) and an emopamil binding protein (EBP).

Multiple studies have suggested that CYP51 and EBP are “key therapeutic targets to promote oligodendrocyte formation,” thereby promoting remyelination, reported Brad T. Lang, PhD, vice president of research for Convelo Therapeutics, Cleveland.

The drugs performed as predicted in animal models, where remyelination was documented, and in promoting human oligodendrocyte formation in human brain organoids. The development of these agents has been accompanied by strategy to measure their activity.

“We established a mechanistic biomarker to assess target engagement in the CNS and periphery to guide the next steps in preclinical and clinical development,” Dr. Lang said.

He called these drugs “first-in-class potential therapies in the field of remyelination.” While he acknowledged that no clinical studies have yet been performed, his late-breaker presentation indicated that many of the criteria identified by Dr. Green, including an ability to penetrate the CNS and a plausible, measurable mechanism of action have been fulfilled.

Dr. Green reported financial relationships with Biogen, Mylan, and Novartis. Dr. Miron reported no potential conflicts of interest.

While severe COVID-19 is associated with a significantly higher risk for psychiatric and neurologic disorders a year after infection, mild does not carry the same risk, a new study shows.

Hospitalized patients with COVID-19 had twice the risk for psychiatric or neurologic diagnoses during the 12 months after acute infection, compared with individuals who never tested positive for SARS-CoV-2. However, less severe COVID-19 was not linked to a higher incidence of psychiatric diagnoses and was associated with only a slightly higher risk for neurologic disorders.

The new research challenges previous findings of long-term risk for psychiatric and neurologic disorders associated with SARS-CoV-2 in patients who had not been hospitalized for the condition.

“Our study does not support previous findings of substantial post-acute neurologic and psychiatric morbidities among the general population of SARS-CoV-2-infected individuals but does corroborate an elevated risk among the most severe cases with COVID-19,” the authors wrote.

The study was published online on February 21 in Neurology.

‘Alarming’ Findings

Previous studies have reported nervous system symptoms in patients who have experienced COVID-19, which may persist for several weeks or months after the acute phase, even in milder cases.

But these findings haven’t been consistent across all studies, and few studies have addressed the potential effect of different viral variants and vaccination status on post-acute psychiatric and neurologic morbidities.

“Our study was partly motivated by our strong research interest in the associations between infectious disease and later chronic disease and partly by international studies, such as those conducted in the US Veterans Health databases, that have suggested substantial risks of psychiatric and neurological conditions associated with infection,” senior author Anders Hviid, MSc, DrMedSci, head of the department and professor of pharmacoepidemiology, Statens Serum Institut, Copenhagen, Denmark, told this news organization.

Investigators drew on data from the Danish National Patient Registry to compare the risk for neurologic and psychiatric disorders during the 12 months after acute COVID-19 infection to risk among people who never tested positive.

They examined data on all recorded hospital contacts between January 2005 and January 2023 for a discharge diagnosis of at least one of 11 psychiatric illnesses or at least one of 30 neurologic disorders.

The researchers compared the incidence of each disorder within 1-12 months after infection with those of COVID-naive individuals and stratified analyses according to time since infection, vaccination status, variant period, age, sex, and infection severity.

The final study cohort included 1.8 million individuals who tested positive during the study period and 1.5 who didn’t. Three quarters of those who tested positive were infected primarily with the Omicron variant.

Hospitalized vs Nonhospitalized

Overall, individuals who tested positive had a 24% lower risk for psychiatric disorders during the post-acute period (incident rate ratio [IRR], 0.76; 95% CI, 0.74-0.78) compared with the control group, but a 5% higher risk for any neurologic disorder (IRR, 1.05; 95% CI, 1.04-1.07).

Age, sex, and variant had less influence on risk than infection severity, where the differences between hospitalized and nonhospitalized patients were significant.

Compared with COVID-negative individuals, the risk for any psychiatric disorder was double for hospitalized patients (IRR, 2.05; 95% CI, 1.78-2.37) but was 25% lower among nonhospitalized patients (IRR, 0.75; 95% CI, 0.73-0.77).

For neurologic disorders, the IRR for hospitalized patients was 2.44 (95% CI, 2.29-2.60) compared with COVID-negative individuals vs an IRR of only 1.02 (95% CI, 1.01-1.04) among nonhospitalized patients.

“In a general population, there was little support for clinically relevant post-acute risk increases of psychiatric and neurologic disorders associated with SARS-CoV-2 infection without hospitalization. This was particularly true for vaccinated individuals and for the more recent variants,” the authors wrote, adding that the only exception was for change in sense and smell.

‘Flaws’ in Previous Studies?

The findings in hospitalized patients were in line with previous findings, but those in nonhospitalized patients stand out, they added.

Previous studies were done predominantly in older males with comorbidities and those who were more socioeconomically disadvantaged, which could lead to a bias, Dr. Hviid said.

Those other studies “had a number of fundamental flaws that we do not believe our study has,” Dr. Hviid said. “Our study was conducted in the general population, with free and universal testing and healthcare.”

Researchers stress that sequelae after infection are predominantly associated with severe illness.

“Today, a healthy vaccinated adult having an asymptomatic or mild bout of COVID-19 with the current variants shouldn’t fear developing serious psychiatric or neurologic disorders in the months or years after infection.”

One limitation is that only hospital contacts were included, omitting possible diagnoses given outside hospital settings.

‘Extreme Caution’ Required

The link between COVID-19 and brain health is “complex,” and the new findings should be viewed cautiously, said Maxime Taquet, MRCPsych, PhD, National Institute for Health and Care Research clinical lecturer and specialty registrar in Psychiatry, Oxford Health NHS Foundation Trust, England, who commented on the findings.

Previous research by Dr. Taquet, who was not involved in the current study, found an increased risk for neurologic and psychiatric diagnoses during the first 6 months after COVID-19 diagnosis.

The current study “contributes to better understanding this link by providing data from another country with a different organization of healthcare provision than the US, where most of the existing data come from,” Dr. Taquet said.

However, “some observations — for example, that COVID-19 is associated with a 50% reduction in the risk of autism, a condition present from very early in life — call for extreme caution in the interpretation of the findings, as they suggest that residual bias has not been accounted for,” Dr. Taquet continued.

Authors of an accompanying editorial, Eric Chow, MD, MS, MPH, of the Division of Allergy and Infectious Diseases, University of Washington, School of Public Health, and Anita Chopra, MD, of the post-COVID Clinic, University of Washington, Seattle, called the study a “critical contribution to the published literature.”

The association of neurologic and psychiatric diagnoses with severe disease “is a reminder of the importance of risk reduction by combining vaccinations with improved indoor ventilation and masking,” they concluded.

The study was supported by a grant from the Independent Research Fund Denmark. Dr. Hviid and coauthors, Dr. Chopra, and Dr. Taquet reported no relevant financial relationships. Dr. Chow received a travel award from the Infectious Diseases Society of America to attend ID Week 2022.
 

A version of this article appeared on Medscape.com.

While severe COVID-19 is associated with a significantly higher risk for psychiatric and neurologic disorders a year after infection, mild does not carry the same risk, a new study shows.

Hospitalized patients with COVID-19 had twice the risk for psychiatric or neurologic diagnoses during the 12 months after acute infection, compared with individuals who never tested positive for SARS-CoV-2. However, less severe COVID-19 was not linked to a higher incidence of psychiatric diagnoses and was associated with only a slightly higher risk for neurologic disorders.

The new research challenges previous findings of long-term risk for psychiatric and neurologic disorders associated with SARS-CoV-2 in patients who had not been hospitalized for the condition.

“Our study does not support previous findings of substantial post-acute neurologic and psychiatric morbidities among the general population of SARS-CoV-2-infected individuals but does corroborate an elevated risk among the most severe cases with COVID-19,” the authors wrote.

The study was published online on February 21 in Neurology.

‘Alarming’ Findings

Previous studies have reported nervous system symptoms in patients who have experienced COVID-19, which may persist for several weeks or months after the acute phase, even in milder cases.

But these findings haven’t been consistent across all studies, and few studies have addressed the potential effect of different viral variants and vaccination status on post-acute psychiatric and neurologic morbidities.

“Our study was partly motivated by our strong research interest in the associations between infectious disease and later chronic disease and partly by international studies, such as those conducted in the US Veterans Health databases, that have suggested substantial risks of psychiatric and neurological conditions associated with infection,” senior author Anders Hviid, MSc, DrMedSci, head of the department and professor of pharmacoepidemiology, Statens Serum Institut, Copenhagen, Denmark, told this news organization.

Investigators drew on data from the Danish National Patient Registry to compare the risk for neurologic and psychiatric disorders during the 12 months after acute COVID-19 infection to risk among people who never tested positive.

They examined data on all recorded hospital contacts between January 2005 and January 2023 for a discharge diagnosis of at least one of 11 psychiatric illnesses or at least one of 30 neurologic disorders.

The researchers compared the incidence of each disorder within 1-12 months after infection with those of COVID-naive individuals and stratified analyses according to time since infection, vaccination status, variant period, age, sex, and infection severity.

The final study cohort included 1.8 million individuals who tested positive during the study period and 1.5 who didn’t. Three quarters of those who tested positive were infected primarily with the Omicron variant.

Hospitalized vs Nonhospitalized

Overall, individuals who tested positive had a 24% lower risk for psychiatric disorders during the post-acute period (incident rate ratio [IRR], 0.76; 95% CI, 0.74-0.78) compared with the control group, but a 5% higher risk for any neurologic disorder (IRR, 1.05; 95% CI, 1.04-1.07).

Age, sex, and variant had less influence on risk than infection severity, where the differences between hospitalized and nonhospitalized patients were significant.

Compared with COVID-negative individuals, the risk for any psychiatric disorder was double for hospitalized patients (IRR, 2.05; 95% CI, 1.78-2.37) but was 25% lower among nonhospitalized patients (IRR, 0.75; 95% CI, 0.73-0.77).

For neurologic disorders, the IRR for hospitalized patients was 2.44 (95% CI, 2.29-2.60) compared with COVID-negative individuals vs an IRR of only 1.02 (95% CI, 1.01-1.04) among nonhospitalized patients.

“In a general population, there was little support for clinically relevant post-acute risk increases of psychiatric and neurologic disorders associated with SARS-CoV-2 infection without hospitalization. This was particularly true for vaccinated individuals and for the more recent variants,” the authors wrote, adding that the only exception was for change in sense and smell.

‘Flaws’ in Previous Studies?

The findings in hospitalized patients were in line with previous findings, but those in nonhospitalized patients stand out, they added.

Previous studies were done predominantly in older males with comorbidities and those who were more socioeconomically disadvantaged, which could lead to a bias, Dr. Hviid said.

Those other studies “had a number of fundamental flaws that we do not believe our study has,” Dr. Hviid said. “Our study was conducted in the general population, with free and universal testing and healthcare.”

Researchers stress that sequelae after infection are predominantly associated with severe illness.

“Today, a healthy vaccinated adult having an asymptomatic or mild bout of COVID-19 with the current variants shouldn’t fear developing serious psychiatric or neurologic disorders in the months or years after infection.”

One limitation is that only hospital contacts were included, omitting possible diagnoses given outside hospital settings.

‘Extreme Caution’ Required

The link between COVID-19 and brain health is “complex,” and the new findings should be viewed cautiously, said Maxime Taquet, MRCPsych, PhD, National Institute for Health and Care Research clinical lecturer and specialty registrar in Psychiatry, Oxford Health NHS Foundation Trust, England, who commented on the findings.

Previous research by Dr. Taquet, who was not involved in the current study, found an increased risk for neurologic and psychiatric diagnoses during the first 6 months after COVID-19 diagnosis.

The current study “contributes to better understanding this link by providing data from another country with a different organization of healthcare provision than the US, where most of the existing data come from,” Dr. Taquet said.

However, “some observations — for example, that COVID-19 is associated with a 50% reduction in the risk of autism, a condition present from very early in life — call for extreme caution in the interpretation of the findings, as they suggest that residual bias has not been accounted for,” Dr. Taquet continued.

Authors of an accompanying editorial, Eric Chow, MD, MS, MPH, of the Division of Allergy and Infectious Diseases, University of Washington, School of Public Health, and Anita Chopra, MD, of the post-COVID Clinic, University of Washington, Seattle, called the study a “critical contribution to the published literature.”

The association of neurologic and psychiatric diagnoses with severe disease “is a reminder of the importance of risk reduction by combining vaccinations with improved indoor ventilation and masking,” they concluded.

The study was supported by a grant from the Independent Research Fund Denmark. Dr. Hviid and coauthors, Dr. Chopra, and Dr. Taquet reported no relevant financial relationships. Dr. Chow received a travel award from the Infectious Diseases Society of America to attend ID Week 2022.
 

A version of this article appeared on Medscape.com.

While severe COVID-19 is associated with a significantly higher risk for psychiatric and neurologic disorders a year after infection, mild does not carry the same risk, a new study shows.

Hospitalized patients with COVID-19 had twice the risk for psychiatric or neurologic diagnoses during the 12 months after acute infection, compared with individuals who never tested positive for SARS-CoV-2. However, less severe COVID-19 was not linked to a higher incidence of psychiatric diagnoses and was associated with only a slightly higher risk for neurologic disorders.

The new research challenges previous findings of long-term risk for psychiatric and neurologic disorders associated with SARS-CoV-2 in patients who had not been hospitalized for the condition.

“Our study does not support previous findings of substantial post-acute neurologic and psychiatric morbidities among the general population of SARS-CoV-2-infected individuals but does corroborate an elevated risk among the most severe cases with COVID-19,” the authors wrote.

The study was published online on February 21 in Neurology.

‘Alarming’ Findings

Previous studies have reported nervous system symptoms in patients who have experienced COVID-19, which may persist for several weeks or months after the acute phase, even in milder cases.

But these findings haven’t been consistent across all studies, and few studies have addressed the potential effect of different viral variants and vaccination status on post-acute psychiatric and neurologic morbidities.

“Our study was partly motivated by our strong research interest in the associations between infectious disease and later chronic disease and partly by international studies, such as those conducted in the US Veterans Health databases, that have suggested substantial risks of psychiatric and neurological conditions associated with infection,” senior author Anders Hviid, MSc, DrMedSci, head of the department and professor of pharmacoepidemiology, Statens Serum Institut, Copenhagen, Denmark, told this news organization.

Investigators drew on data from the Danish National Patient Registry to compare the risk for neurologic and psychiatric disorders during the 12 months after acute COVID-19 infection to risk among people who never tested positive.

They examined data on all recorded hospital contacts between January 2005 and January 2023 for a discharge diagnosis of at least one of 11 psychiatric illnesses or at least one of 30 neurologic disorders.

The researchers compared the incidence of each disorder within 1-12 months after infection with those of COVID-naive individuals and stratified analyses according to time since infection, vaccination status, variant period, age, sex, and infection severity.

The final study cohort included 1.8 million individuals who tested positive during the study period and 1.5 who didn’t. Three quarters of those who tested positive were infected primarily with the Omicron variant.

Hospitalized vs Nonhospitalized

Overall, individuals who tested positive had a 24% lower risk for psychiatric disorders during the post-acute period (incident rate ratio [IRR], 0.76; 95% CI, 0.74-0.78) compared with the control group, but a 5% higher risk for any neurologic disorder (IRR, 1.05; 95% CI, 1.04-1.07).

Age, sex, and variant had less influence on risk than infection severity, where the differences between hospitalized and nonhospitalized patients were significant.

Compared with COVID-negative individuals, the risk for any psychiatric disorder was double for hospitalized patients (IRR, 2.05; 95% CI, 1.78-2.37) but was 25% lower among nonhospitalized patients (IRR, 0.75; 95% CI, 0.73-0.77).

For neurologic disorders, the IRR for hospitalized patients was 2.44 (95% CI, 2.29-2.60) compared with COVID-negative individuals vs an IRR of only 1.02 (95% CI, 1.01-1.04) among nonhospitalized patients.

“In a general population, there was little support for clinically relevant post-acute risk increases of psychiatric and neurologic disorders associated with SARS-CoV-2 infection without hospitalization. This was particularly true for vaccinated individuals and for the more recent variants,” the authors wrote, adding that the only exception was for change in sense and smell.

‘Flaws’ in Previous Studies?

The findings in hospitalized patients were in line with previous findings, but those in nonhospitalized patients stand out, they added.

Previous studies were done predominantly in older males with comorbidities and those who were more socioeconomically disadvantaged, which could lead to a bias, Dr. Hviid said.

Those other studies “had a number of fundamental flaws that we do not believe our study has,” Dr. Hviid said. “Our study was conducted in the general population, with free and universal testing and healthcare.”

Researchers stress that sequelae after infection are predominantly associated with severe illness.

“Today, a healthy vaccinated adult having an asymptomatic or mild bout of COVID-19 with the current variants shouldn’t fear developing serious psychiatric or neurologic disorders in the months or years after infection.”

One limitation is that only hospital contacts were included, omitting possible diagnoses given outside hospital settings.

‘Extreme Caution’ Required

The link between COVID-19 and brain health is “complex,” and the new findings should be viewed cautiously, said Maxime Taquet, MRCPsych, PhD, National Institute for Health and Care Research clinical lecturer and specialty registrar in Psychiatry, Oxford Health NHS Foundation Trust, England, who commented on the findings.

Previous research by Dr. Taquet, who was not involved in the current study, found an increased risk for neurologic and psychiatric diagnoses during the first 6 months after COVID-19 diagnosis.

The current study “contributes to better understanding this link by providing data from another country with a different organization of healthcare provision than the US, where most of the existing data come from,” Dr. Taquet said.

However, “some observations — for example, that COVID-19 is associated with a 50% reduction in the risk of autism, a condition present from very early in life — call for extreme caution in the interpretation of the findings, as they suggest that residual bias has not been accounted for,” Dr. Taquet continued.

Authors of an accompanying editorial, Eric Chow, MD, MS, MPH, of the Division of Allergy and Infectious Diseases, University of Washington, School of Public Health, and Anita Chopra, MD, of the post-COVID Clinic, University of Washington, Seattle, called the study a “critical contribution to the published literature.”

The association of neurologic and psychiatric diagnoses with severe disease “is a reminder of the importance of risk reduction by combining vaccinations with improved indoor ventilation and masking,” they concluded.

The study was supported by a grant from the Independent Research Fund Denmark. Dr. Hviid and coauthors, Dr. Chopra, and Dr. Taquet reported no relevant financial relationships. Dr. Chow received a travel award from the Infectious Diseases Society of America to attend ID Week 2022.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Exposure to more traffic-related air pollution is associated with greater levels of amyloid plaques in the brain, with exposure in the 3 years before death having the greatest risk, a new postmortem study showed.

METHODOLOGY:

• Investigators examined the brain tissue of 224 people living in the Atlanta area who agreed to donate their brains after death (average age of death, 76 years) for the presence of amyloid plaques and tau tangles.
• They also studied the amount of fine particulate matter < 2.5 microns (PM2.5) from traffic-related air pollution at participants’ home addresses at 1, 3, and 5 years before death.
• The presence of the APOE e4 gene was examined for evidence of any effect on the relationship between air pollution and evidence of Alzheimer’s disease (AD).

TAKEAWAY: 

The average level of exposure in the year before death was 1.32 µg/m³ and 1.35 µg/m³ in the 3 years before death.

People with 1 µg/m³ higher PM2.5 exposure in the year before death were nearly twice as likely to have higher levels of plaques (odds ratio [OR], 1.92; 95% CI, 1.12-3.30), while those with higher exposure in the 3 years before death were 87% more likely to have higher levels of plaques (OR, 1.87; 95% CI, 1.01-3.17).

A little more than half (56%) of the sample were positive for the APOE e4 genotype, but the strongest association between pollution and neuropathology markers was for noncarriers of the genotype, although this relationship did not reach statistical significance.

IN PRACTICE:

“More research is needed to establish causality for the association between PM2.5 and AD, including epidemiologic and mechanistic studies. Future studies should also investigate the association between PM2.5 and other dementia-related pathologies, including cerebrovascular pathology,” the study authors wrote. 

SOURCE:

Anke Hüls, PhD, of Emory University in Atlanta, led the study, which was published online on February 21, 2024, in Neurology.

LIMITATIONS:

The sample was not population-based but a convenience sample composed mostly of highly educated White participants.

DISCLOSURES:

The study was funded by the National Institute of Environmental Health Sciences, the Goizueta Alzheimer’s Disease Research Center, the National Institute on Aging, and the National Institutes of Health. There were no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

TOPLINE:

Exposure to more traffic-related air pollution is associated with greater levels of amyloid plaques in the brain, with exposure in the 3 years before death having the greatest risk, a new postmortem study showed.

METHODOLOGY:

• Investigators examined the brain tissue of 224 people living in the Atlanta area who agreed to donate their brains after death (average age of death, 76 years) for the presence of amyloid plaques and tau tangles.
• They also studied the amount of fine particulate matter < 2.5 microns (PM2.5) from traffic-related air pollution at participants’ home addresses at 1, 3, and 5 years before death.
• The presence of the APOE e4 gene was examined for evidence of any effect on the relationship between air pollution and evidence of Alzheimer’s disease (AD).

TAKEAWAY: 

The average level of exposure in the year before death was 1.32 µg/m³ and 1.35 µg/m³ in the 3 years before death.

People with 1 µg/m³ higher PM2.5 exposure in the year before death were nearly twice as likely to have higher levels of plaques (odds ratio [OR], 1.92; 95% CI, 1.12-3.30), while those with higher exposure in the 3 years before death were 87% more likely to have higher levels of plaques (OR, 1.87; 95% CI, 1.01-3.17).

A little more than half (56%) of the sample were positive for the APOE e4 genotype, but the strongest association between pollution and neuropathology markers was for noncarriers of the genotype, although this relationship did not reach statistical significance.

IN PRACTICE:

“More research is needed to establish causality for the association between PM2.5 and AD, including epidemiologic and mechanistic studies. Future studies should also investigate the association between PM2.5 and other dementia-related pathologies, including cerebrovascular pathology,” the study authors wrote. 

SOURCE:

Anke Hüls, PhD, of Emory University in Atlanta, led the study, which was published online on February 21, 2024, in Neurology.

LIMITATIONS:

The sample was not population-based but a convenience sample composed mostly of highly educated White participants.

DISCLOSURES:

The study was funded by the National Institute of Environmental Health Sciences, the Goizueta Alzheimer’s Disease Research Center, the National Institute on Aging, and the National Institutes of Health. There were no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

TOPLINE:

Exposure to more traffic-related air pollution is associated with greater levels of amyloid plaques in the brain, with exposure in the 3 years before death having the greatest risk, a new postmortem study showed.

METHODOLOGY:

• Investigators examined the brain tissue of 224 people living in the Atlanta area who agreed to donate their brains after death (average age of death, 76 years) for the presence of amyloid plaques and tau tangles.
• They also studied the amount of fine particulate matter < 2.5 microns (PM2.5) from traffic-related air pollution at participants’ home addresses at 1, 3, and 5 years before death.
• The presence of the APOE e4 gene was examined for evidence of any effect on the relationship between air pollution and evidence of Alzheimer’s disease (AD).

TAKEAWAY: 

The average level of exposure in the year before death was 1.32 µg/m³ and 1.35 µg/m³ in the 3 years before death.

People with 1 µg/m³ higher PM2.5 exposure in the year before death were nearly twice as likely to have higher levels of plaques (odds ratio [OR], 1.92; 95% CI, 1.12-3.30), while those with higher exposure in the 3 years before death were 87% more likely to have higher levels of plaques (OR, 1.87; 95% CI, 1.01-3.17).

A little more than half (56%) of the sample were positive for the APOE e4 genotype, but the strongest association between pollution and neuropathology markers was for noncarriers of the genotype, although this relationship did not reach statistical significance.

IN PRACTICE:

“More research is needed to establish causality for the association between PM2.5 and AD, including epidemiologic and mechanistic studies. Future studies should also investigate the association between PM2.5 and other dementia-related pathologies, including cerebrovascular pathology,” the study authors wrote. 

SOURCE:

Anke Hüls, PhD, of Emory University in Atlanta, led the study, which was published online on February 21, 2024, in Neurology.

LIMITATIONS:

The sample was not population-based but a convenience sample composed mostly of highly educated White participants.

DISCLOSURES:

The study was funded by the National Institute of Environmental Health Sciences, the Goizueta Alzheimer’s Disease Research Center, the National Institute on Aging, and the National Institutes of Health. There were no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

TOPLINE:

The odds of having cognitive impairment may be increased among children with atopic dermatitis, primarily among those with neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder (ADHD) or a learning disability.

METHODOLOGY:

It remains unknown whether subpopulations of children with atopic dermatitis face a greater risk for cognitive impairment or not.

To determine the association, researchers drew from a weighted sample of 69,732,807 children with atopic dermatitis in the 2021 US National Health Interview Survey.

Main outcomes of interest were difficulty in learning or memory (cognitive impairment symptoms) as reported by the child’s caregiver.

The researchers performed logistic regression to compare the odds of learning or memory difficulties between 60,509,794 children without atopic dermatitis and 9,223,013 children with atopic dermatitis.

TAKEAWAY:

Children with versus without atopic dermatitis were more likely to experience difficulties with learning (10.8% [95% CI, 7.8%-15.8%] vs 5.9% [95% CI, 5.1%-6.9%]; P < .001) and difficulties with memory (11.1% [95% CI, 8.0%-15.9%] vs 5.8% [95% CI, 4.9%-6.9%]; P < .001).

On multivariable logistic regression adjusted for sociodemographic factors, asthma, food allergies, and seasonal allergies or hay fever, researchers found that having atopic dermatitis was associated with increased odds of difficulties in learning (adjusted odds ratio [aOR], 1.77; 95% CI, 1.28-2.45) and memory (aOR, 1.69; 95% CI, 1.19-2.41). 

When stratified by neurodevelopmental comorbidities, having atopic dermatitis was associated with a 2- to 3-fold greater odds of memory difficulties among children with any neurodevelopmental disorder (aOR, 2.26; 95% CI, 1.43-3.57), which included ADHD (aOR, 2.90; 95% CI, 1.60-5.24) or learning disabilities (aOR, 2.04; 95% CI, 1.04-4.00).

Having atopic dermatitis was not associated with learning or memory difficulties among children without neurodevelopmental conditions. 

IN PRACTICE:

“These findings may improve the risk stratification of children with atopic dermatitis for cognitive impairment and suggest that evaluation for cognitive impairment should be prioritized among children with atopic dermatitis and comorbid ADHD or learning disability,” the authors wrote.

SOURCE:

Corresponding author Joy Wan, MD, of the department of dermatology at Johns Hopkins University School of Medicine, Baltimore, and colleagues conducted the research, which was published on March 6, 2024, in JAMA Dermatology.

LIMITATIONS:

The study’s limitations were its cross-sectional design, reliance on caregiver reports, and the fact that National Health Interview Survey data do not include information on factors such as atopic dermatitis severity, age at atopic dermatitis diagnosis, and sleep. 

DISCLOSURES:

The study was supported by a grant from the National Institutes of Health. Dr. Wan reported receiving a grant from Pfizer and personal fees from Sun Pharmaceutical Industries and Janssen Pharmaceuticals outside the submitted work. No other study authors had disclosures to report. 

A version of this article appeared on Medscape.com.

TOPLINE:

The odds of having cognitive impairment may be increased among children with atopic dermatitis, primarily among those with neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder (ADHD) or a learning disability.

METHODOLOGY:

It remains unknown whether subpopulations of children with atopic dermatitis face a greater risk for cognitive impairment or not.

To determine the association, researchers drew from a weighted sample of 69,732,807 children with atopic dermatitis in the 2021 US National Health Interview Survey.

Main outcomes of interest were difficulty in learning or memory (cognitive impairment symptoms) as reported by the child’s caregiver.

The researchers performed logistic regression to compare the odds of learning or memory difficulties between 60,509,794 children without atopic dermatitis and 9,223,013 children with atopic dermatitis.

TAKEAWAY:

Children with versus without atopic dermatitis were more likely to experience difficulties with learning (10.8% [95% CI, 7.8%-15.8%] vs 5.9% [95% CI, 5.1%-6.9%]; P < .001) and difficulties with memory (11.1% [95% CI, 8.0%-15.9%] vs 5.8% [95% CI, 4.9%-6.9%]; P < .001).

On multivariable logistic regression adjusted for sociodemographic factors, asthma, food allergies, and seasonal allergies or hay fever, researchers found that having atopic dermatitis was associated with increased odds of difficulties in learning (adjusted odds ratio [aOR], 1.77; 95% CI, 1.28-2.45) and memory (aOR, 1.69; 95% CI, 1.19-2.41). 

When stratified by neurodevelopmental comorbidities, having atopic dermatitis was associated with a 2- to 3-fold greater odds of memory difficulties among children with any neurodevelopmental disorder (aOR, 2.26; 95% CI, 1.43-3.57), which included ADHD (aOR, 2.90; 95% CI, 1.60-5.24) or learning disabilities (aOR, 2.04; 95% CI, 1.04-4.00).

Having atopic dermatitis was not associated with learning or memory difficulties among children without neurodevelopmental conditions. 

IN PRACTICE:

“These findings may improve the risk stratification of children with atopic dermatitis for cognitive impairment and suggest that evaluation for cognitive impairment should be prioritized among children with atopic dermatitis and comorbid ADHD or learning disability,” the authors wrote.

SOURCE:

Corresponding author Joy Wan, MD, of the department of dermatology at Johns Hopkins University School of Medicine, Baltimore, and colleagues conducted the research, which was published on March 6, 2024, in JAMA Dermatology.

LIMITATIONS:

The study’s limitations were its cross-sectional design, reliance on caregiver reports, and the fact that National Health Interview Survey data do not include information on factors such as atopic dermatitis severity, age at atopic dermatitis diagnosis, and sleep. 

DISCLOSURES:

The study was supported by a grant from the National Institutes of Health. Dr. Wan reported receiving a grant from Pfizer and personal fees from Sun Pharmaceutical Industries and Janssen Pharmaceuticals outside the submitted work. No other study authors had disclosures to report. 

A version of this article appeared on Medscape.com.

TOPLINE:

The odds of having cognitive impairment may be increased among children with atopic dermatitis, primarily among those with neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder (ADHD) or a learning disability.

METHODOLOGY:

It remains unknown whether subpopulations of children with atopic dermatitis face a greater risk for cognitive impairment or not.

To determine the association, researchers drew from a weighted sample of 69,732,807 children with atopic dermatitis in the 2021 US National Health Interview Survey.

Main outcomes of interest were difficulty in learning or memory (cognitive impairment symptoms) as reported by the child’s caregiver.

The researchers performed logistic regression to compare the odds of learning or memory difficulties between 60,509,794 children without atopic dermatitis and 9,223,013 children with atopic dermatitis.

TAKEAWAY:

Children with versus without atopic dermatitis were more likely to experience difficulties with learning (10.8% [95% CI, 7.8%-15.8%] vs 5.9% [95% CI, 5.1%-6.9%]; P < .001) and difficulties with memory (11.1% [95% CI, 8.0%-15.9%] vs 5.8% [95% CI, 4.9%-6.9%]; P < .001).

On multivariable logistic regression adjusted for sociodemographic factors, asthma, food allergies, and seasonal allergies or hay fever, researchers found that having atopic dermatitis was associated with increased odds of difficulties in learning (adjusted odds ratio [aOR], 1.77; 95% CI, 1.28-2.45) and memory (aOR, 1.69; 95% CI, 1.19-2.41). 

When stratified by neurodevelopmental comorbidities, having atopic dermatitis was associated with a 2- to 3-fold greater odds of memory difficulties among children with any neurodevelopmental disorder (aOR, 2.26; 95% CI, 1.43-3.57), which included ADHD (aOR, 2.90; 95% CI, 1.60-5.24) or learning disabilities (aOR, 2.04; 95% CI, 1.04-4.00).

Having atopic dermatitis was not associated with learning or memory difficulties among children without neurodevelopmental conditions. 

IN PRACTICE:

“These findings may improve the risk stratification of children with atopic dermatitis for cognitive impairment and suggest that evaluation for cognitive impairment should be prioritized among children with atopic dermatitis and comorbid ADHD or learning disability,” the authors wrote.

SOURCE:

Corresponding author Joy Wan, MD, of the department of dermatology at Johns Hopkins University School of Medicine, Baltimore, and colleagues conducted the research, which was published on March 6, 2024, in JAMA Dermatology.

LIMITATIONS:

The study’s limitations were its cross-sectional design, reliance on caregiver reports, and the fact that National Health Interview Survey data do not include information on factors such as atopic dermatitis severity, age at atopic dermatitis diagnosis, and sleep. 

DISCLOSURES:

The study was supported by a grant from the National Institutes of Health. Dr. Wan reported receiving a grant from Pfizer and personal fees from Sun Pharmaceutical Industries and Janssen Pharmaceuticals outside the submitted work. No other study authors had disclosures to report. 

A version of this article appeared on Medscape.com.

Lawmakers have added a provision to raise Medicare payments to clinicians to a $460 billion bipartisan package of federal spending bills that passed in the House on March 6 and is expected to be passed in the Senate and signed by President Biden before then end of March 8, but industry groups have criticized it as paltry.

Lawmakers often tweak Medicare policy by adding provisions to other kinds of legislation, including the spending bills Congress must pass to keep the federal government running.

Physicians’ groups and some lawmakers have long pressed Congress to change Medicare payment rules with little success, even as inflation has caused physicians’ expenses to rise. Doctors now face a 3.4% cut to Medicare reimbursements in 2024, which would be only partly mitigated by the recently announced provision.

The Medical Group Management Association (MGMA) said the proposed increase would total 1.68%. The increase, part of a bipartisan package of bills released by the House and Senate Appropriations committees on March 3, would apply to the budget for fiscal 2024, which began on October 1, 2023.

“We are deeply disappointed with Congress’ half-hearted attempt to remedy the devastating blow physician practices were dealt by the 2024 Medicare Physician Fee Schedule,” Anders Gilberg, senior vice president of MGMA, said in a statement. “Anything less than a full reversal of the 3.4% cut is appallingly inadequate.”

The American Medical Association said it was “extremely disappointed” that the boost only eased, but did not fully reverse, a deeper planned cut.

The American Academy of Family Physicians (AAFP) also expressed disappointment with the proposed increase.

“The AAFP has repeatedly told Congress that the 3.4% Medicare payment reduction that went into effect on January 1 is untenable for family physicians and threatens patients’ access to primary care,” the group said in a statement.

“While we appreciate the partial relief, family physicians continue to face an annual threat of payment cuts that are detrimental to practices and patients,” AAFP said.

A version of this article appeared on Medscape.com.

Lawmakers have added a provision to raise Medicare payments to clinicians to a $460 billion bipartisan package of federal spending bills that passed in the House on March 6 and is expected to be passed in the Senate and signed by President Biden before then end of March 8, but industry groups have criticized it as paltry.

Lawmakers often tweak Medicare policy by adding provisions to other kinds of legislation, including the spending bills Congress must pass to keep the federal government running.

Physicians’ groups and some lawmakers have long pressed Congress to change Medicare payment rules with little success, even as inflation has caused physicians’ expenses to rise. Doctors now face a 3.4% cut to Medicare reimbursements in 2024, which would be only partly mitigated by the recently announced provision.

The Medical Group Management Association (MGMA) said the proposed increase would total 1.68%. The increase, part of a bipartisan package of bills released by the House and Senate Appropriations committees on March 3, would apply to the budget for fiscal 2024, which began on October 1, 2023.

“We are deeply disappointed with Congress’ half-hearted attempt to remedy the devastating blow physician practices were dealt by the 2024 Medicare Physician Fee Schedule,” Anders Gilberg, senior vice president of MGMA, said in a statement. “Anything less than a full reversal of the 3.4% cut is appallingly inadequate.”

The American Medical Association said it was “extremely disappointed” that the boost only eased, but did not fully reverse, a deeper planned cut.

The American Academy of Family Physicians (AAFP) also expressed disappointment with the proposed increase.

“The AAFP has repeatedly told Congress that the 3.4% Medicare payment reduction that went into effect on January 1 is untenable for family physicians and threatens patients’ access to primary care,” the group said in a statement.

“While we appreciate the partial relief, family physicians continue to face an annual threat of payment cuts that are detrimental to practices and patients,” AAFP said.

A version of this article appeared on Medscape.com.

Lawmakers have added a provision to raise Medicare payments to clinicians to a $460 billion bipartisan package of federal spending bills that passed in the House on March 6 and is expected to be passed in the Senate and signed by President Biden before then end of March 8, but industry groups have criticized it as paltry.

Lawmakers often tweak Medicare policy by adding provisions to other kinds of legislation, including the spending bills Congress must pass to keep the federal government running.

Physicians’ groups and some lawmakers have long pressed Congress to change Medicare payment rules with little success, even as inflation has caused physicians’ expenses to rise. Doctors now face a 3.4% cut to Medicare reimbursements in 2024, which would be only partly mitigated by the recently announced provision.

The Medical Group Management Association (MGMA) said the proposed increase would total 1.68%. The increase, part of a bipartisan package of bills released by the House and Senate Appropriations committees on March 3, would apply to the budget for fiscal 2024, which began on October 1, 2023.

“We are deeply disappointed with Congress’ half-hearted attempt to remedy the devastating blow physician practices were dealt by the 2024 Medicare Physician Fee Schedule,” Anders Gilberg, senior vice president of MGMA, said in a statement. “Anything less than a full reversal of the 3.4% cut is appallingly inadequate.”

The American Medical Association said it was “extremely disappointed” that the boost only eased, but did not fully reverse, a deeper planned cut.

The American Academy of Family Physicians (AAFP) also expressed disappointment with the proposed increase.

“The AAFP has repeatedly told Congress that the 3.4% Medicare payment reduction that went into effect on January 1 is untenable for family physicians and threatens patients’ access to primary care,” the group said in a statement.

“While we appreciate the partial relief, family physicians continue to face an annual threat of payment cuts that are detrimental to practices and patients,” AAFP said.

A version of this article appeared on Medscape.com.

Do I deserve to be here? Am I doing what I’m supposed to be doing? Is anyone going to tell me if I’m terrible?

Kerri Palamara McGrath, MD, remembered worrying over these questions as chief resident at Massachusetts General Hospital, Boston, Massachusetts, in 2009. Having graduated from New York Medical College, she felt out of step with her peers from Ivy League medical schools and considered herself lucky to be there. In order to measure up, she felt she had to work twice as hard as everybody else.

But as Dr. McGrath moved through residency and spoke with other trainees, she had a realization. Her constant fears, the nagging voice in her head saying she wasn’t good enough, these issues weren’t exclusive to her; they were pervasive.

Today, Dr. McGrath is the director of the Center for Physician Well-Being at Massachusetts General Hospital. The facility aims to address physician stress and equip doctors with the tools to navigate personal and professional issues. Dr. McGrath is also a physician coach, a growing nonclinical field, helping doctors identify their own stressors, values, and measures of success. This type of internal work, Dr. McGrath feels, can help alleviate imposter syndrome, that inner refrain saying: I’ll never be good enough.

What Is Imposter Syndrome?

While not a formal medical diagnosis, imposter syndrome has been defined as «an internal experience of intellectual phoniness.» It›s considered an inability to internalize success and a tendency to attribute gains to external factors — for example, being in the right place at the right time.

“Many people describe imposter phenomena in medicine as fearing that others are going to realize that they don’t belong somewhere or question why they’re there,” said Dr. McGrath.

It’s a “fear of being found out,” added Jessi Gold, MD, a psychiatrist who treats physicians. “In many ways, imposter syndrome shows up as a conflict between the outer self — the metaphorical mask you’re ‘putting on’ [in order] to achieve, and the inner self — how you feel like you’re not measuring up.”

Dr. McGrath said she experienced imposter syndrome before her medical career even began. She applied to 26 medical schools. Only one accepted her. “The whole time, I was like, ‘This is the only school you got into, so you’re obviously not good enough,’” she recalled. Later, having been chosen by a “coveted” institution like Mass General, “you assume that, at some point, someone will realize that the gig is up, that everybody’s better than you.”

Where Does Imposter Syndrome Come From?

Dr. McGrath felt that in medicine, high expectations are often coupled with low self-compassion. “We are so hard on ourselves, and when we set our expectations so high, we’re constantly disappointed in ourselves,” she said. External markers of success — papers published, promotions, or even social media — can further fuel this.

It can feel like “striving for excellence in a sea of excellence,” Dr. McGrath added, and this can invite comparison.

Ravi Parikh, MD, a medical oncologist and physician-scientist at the University of Pennsylvania, Philadelphia, Pennsylvania, remembered struggling with imposter syndrome early in his career. As a new doctor, he had a ton of questions, and yet those above him seemed able to make weighty decisions on their own. The comparison shook his confidence. “I remember thinking that when I became an attending, I would just magically not have to run decisions by people,” said Dr. Parikh. But even then, the “magical” self-assurance didn’t materialize.

Research found that imposter syndrome is more likely to affect women and groups that are underrepresented in medicine. But overall, the incidence is remarkably high.

A 2023 survey published in the Journal of the American College of Surgeons found that 90% of female surgeons and more than two-thirds of male ones experienced imposter syndrome. In a 2023 study on medical students in JAMA, it was nearly universal; 97% reported feelings of imposter syndrome with women 1.7 times more likely to report it than men and underrepresented groups often three times more likely.

‘I’m Clearly in the Minority Here’

The term “imposter” also suggests a lack of belonging. If medicine doesn’t “look like you,” this can create feelings of pressure, like you’re “representing a whole group with your mere existence,” said Dr. Gold, “and you have to keep proving yourself.”

Chloe Slocum, MD, MPH, an assistant professor of physical medicine and rehabilitation at Harvard Medical School, Boston, Massachusetts, remembered that feeling of conspicuous “otherness.” As a resident, Dr. Slocum began presenting at national meetings and later pursued physician leadership training. Many of her counterparts at these events were older males. “At some programs early on, I’d wonder, ‘I’m clearly in the minority here; did they really make the right decision including me in this?’”

Reactions from those around you can also have an impact. Dr. McGrath — who is 5’ 2” and describes herself as looking “very young” — noted that when she started out, neither patients nor other providers thought she was a doctor.

“I have tried everything in the book to be seen, in somebody else’s eyes, as more consistent with a doctor,” she said. “I’ve dressed down. I’ve dressed up. I’ve worn heels. I’ve worn flats. I’ve worn glasses. I’ve done all the things. When you’re constantly being told you don’t look like a doctor, you start questioning yourself.”

The Emotional Toll

If that sounds mentally exhausting, it is. Research found that imposter syndrome is often linked with burnout, depression, and anxiety.

The need to prove yourself and prevent being “found out” can push some doctors toward traditional measurements of success — promotions or published work, said Dr. Gold. But “if you’re trying to achieve in ways that you don’t value,” she warned, “you’re going to burn out.”

On the other hand, intense self-doubt can also limit advancement. After all, if you don’t think you’re good enough, you may not apply for job opportunities or leadership positions.

This mental burden can persist over years and even decades. A 2020 review of studies on imposter syndrome noted that “it would be reassuring to believe that imposter symptoms decline with age.” Unfortunately, several studies indicated that they do not.

How to Manage Imposter Syndrome

While it can be difficult to overcome imposter syndrome, there are ways to work through it and make it less pervasive or intense. Here are some tips from our experts:

• Prioritize your mental health. This can be difficult for some physicians, but don’t ignore symptoms of depression, anxiety, or burnout. Untreated mental health conditions cloud the ability to reflect on some of the existential questions that will help you navigate imposter syndrome, said Dr. Gold.
• Assess how often you need validation and why. Try to identify what you›re feeling, what needs aren›t being met, and how you can meet those needs. You can then consider where to get that validation either internally or by connecting with a colleague. Dr. McGrath encourages physicians to ask, “What does success look like for me?” and can you make success more personal and meaningful. It might sound shocking, but rather than an unattainable ideal, success should be something that feels good.
• Know the power of teamwork. As Dr. Parikh eventually realized, collaborative care is a common and beneficial part of medicine — not something that makes you a less-than physician. “There’s a lot of opportunity to crowdsource the medical decision-making process in ways that increase your own confidence as a doctor,” he said.
• Practice self-compassion. Critical voices in your head add to an already hard and stressful world. This is where self-compassion comes in. “We don’t have much control over medicine, but we have control over how medicine makes us feel,” Dr. Gold said. Imagine treating yourself how you would treat a friend.
• Consider a physician coach.  suggests that physician coaches can help lower rates of burnout and improve well-being, resilience, professional fulfillment, and self-worth. “Coaching looks into the future to help you envision what things would look like if you were feeling differently. It helps you explore what’s in your control and how you want to shape that,” said Dr. McGrath.
• Amplify the good. Apps and web-based tools can remind you to celebrate your own achievements. The “” exercise created by J. Bryan Sexton, PhD, at the Duke Center for Healthcare Safety & Quality for example, was documented in a . When healthcare workers reflected on three good things that happened each day for 2 weeks, they reported significant improvements in depression, burnout, and work-life balance.
• Do a values check. Dr. Gold often suggested that physicians with imposter syndrome ask themselves what they value, what medicine values, and how the two line up. Pausing to consider this can guide you toward useful strategies. If you value family life but feel like medicine doesn’t, for example, you might talk with a colleague who has navigated this conflict.

Dr. Gold added that reminding yourself of the range of options can be freeing. “There’s no ‘one career’ in medicine,” she said. “There are multiple ways to be happy in medicine; there are multiple ways to be happy outside of medicine. And you’re not a failure for the path you choose.”

A version of this article appeared on Medscape.com.

Do I deserve to be here? Am I doing what I’m supposed to be doing? Is anyone going to tell me if I’m terrible?

Kerri Palamara McGrath, MD, remembered worrying over these questions as chief resident at Massachusetts General Hospital, Boston, Massachusetts, in 2009. Having graduated from New York Medical College, she felt out of step with her peers from Ivy League medical schools and considered herself lucky to be there. In order to measure up, she felt she had to work twice as hard as everybody else.

But as Dr. McGrath moved through residency and spoke with other trainees, she had a realization. Her constant fears, the nagging voice in her head saying she wasn’t good enough, these issues weren’t exclusive to her; they were pervasive.

Today, Dr. McGrath is the director of the Center for Physician Well-Being at Massachusetts General Hospital. The facility aims to address physician stress and equip doctors with the tools to navigate personal and professional issues. Dr. McGrath is also a physician coach, a growing nonclinical field, helping doctors identify their own stressors, values, and measures of success. This type of internal work, Dr. McGrath feels, can help alleviate imposter syndrome, that inner refrain saying: I’ll never be good enough.

What Is Imposter Syndrome?

While not a formal medical diagnosis, imposter syndrome has been defined as «an internal experience of intellectual phoniness.» It›s considered an inability to internalize success and a tendency to attribute gains to external factors — for example, being in the right place at the right time.

“Many people describe imposter phenomena in medicine as fearing that others are going to realize that they don’t belong somewhere or question why they’re there,” said Dr. McGrath.

It’s a “fear of being found out,” added Jessi Gold, MD, a psychiatrist who treats physicians. “In many ways, imposter syndrome shows up as a conflict between the outer self — the metaphorical mask you’re ‘putting on’ [in order] to achieve, and the inner self — how you feel like you’re not measuring up.”

Dr. McGrath said she experienced imposter syndrome before her medical career even began. She applied to 26 medical schools. Only one accepted her. “The whole time, I was like, ‘This is the only school you got into, so you’re obviously not good enough,’” she recalled. Later, having been chosen by a “coveted” institution like Mass General, “you assume that, at some point, someone will realize that the gig is up, that everybody’s better than you.”

Where Does Imposter Syndrome Come From?

Dr. McGrath felt that in medicine, high expectations are often coupled with low self-compassion. “We are so hard on ourselves, and when we set our expectations so high, we’re constantly disappointed in ourselves,” she said. External markers of success — papers published, promotions, or even social media — can further fuel this.

It can feel like “striving for excellence in a sea of excellence,” Dr. McGrath added, and this can invite comparison.

Ravi Parikh, MD, a medical oncologist and physician-scientist at the University of Pennsylvania, Philadelphia, Pennsylvania, remembered struggling with imposter syndrome early in his career. As a new doctor, he had a ton of questions, and yet those above him seemed able to make weighty decisions on their own. The comparison shook his confidence. “I remember thinking that when I became an attending, I would just magically not have to run decisions by people,” said Dr. Parikh. But even then, the “magical” self-assurance didn’t materialize.

Research found that imposter syndrome is more likely to affect women and groups that are underrepresented in medicine. But overall, the incidence is remarkably high.

A 2023 survey published in the Journal of the American College of Surgeons found that 90% of female surgeons and more than two-thirds of male ones experienced imposter syndrome. In a 2023 study on medical students in JAMA, it was nearly universal; 97% reported feelings of imposter syndrome with women 1.7 times more likely to report it than men and underrepresented groups often three times more likely.

‘I’m Clearly in the Minority Here’

The term “imposter” also suggests a lack of belonging. If medicine doesn’t “look like you,” this can create feelings of pressure, like you’re “representing a whole group with your mere existence,” said Dr. Gold, “and you have to keep proving yourself.”

Chloe Slocum, MD, MPH, an assistant professor of physical medicine and rehabilitation at Harvard Medical School, Boston, Massachusetts, remembered that feeling of conspicuous “otherness.” As a resident, Dr. Slocum began presenting at national meetings and later pursued physician leadership training. Many of her counterparts at these events were older males. “At some programs early on, I’d wonder, ‘I’m clearly in the minority here; did they really make the right decision including me in this?’”

Reactions from those around you can also have an impact. Dr. McGrath — who is 5’ 2” and describes herself as looking “very young” — noted that when she started out, neither patients nor other providers thought she was a doctor.

“I have tried everything in the book to be seen, in somebody else’s eyes, as more consistent with a doctor,” she said. “I’ve dressed down. I’ve dressed up. I’ve worn heels. I’ve worn flats. I’ve worn glasses. I’ve done all the things. When you’re constantly being told you don’t look like a doctor, you start questioning yourself.”

The Emotional Toll

If that sounds mentally exhausting, it is. Research found that imposter syndrome is often linked with burnout, depression, and anxiety.

The need to prove yourself and prevent being “found out” can push some doctors toward traditional measurements of success — promotions or published work, said Dr. Gold. But “if you’re trying to achieve in ways that you don’t value,” she warned, “you’re going to burn out.”

On the other hand, intense self-doubt can also limit advancement. After all, if you don’t think you’re good enough, you may not apply for job opportunities or leadership positions.

This mental burden can persist over years and even decades. A 2020 review of studies on imposter syndrome noted that “it would be reassuring to believe that imposter symptoms decline with age.” Unfortunately, several studies indicated that they do not.

How to Manage Imposter Syndrome

While it can be difficult to overcome imposter syndrome, there are ways to work through it and make it less pervasive or intense. Here are some tips from our experts:

• Prioritize your mental health. This can be difficult for some physicians, but don’t ignore symptoms of depression, anxiety, or burnout. Untreated mental health conditions cloud the ability to reflect on some of the existential questions that will help you navigate imposter syndrome, said Dr. Gold.
• Assess how often you need validation and why. Try to identify what you›re feeling, what needs aren›t being met, and how you can meet those needs. You can then consider where to get that validation either internally or by connecting with a colleague. Dr. McGrath encourages physicians to ask, “What does success look like for me?” and can you make success more personal and meaningful. It might sound shocking, but rather than an unattainable ideal, success should be something that feels good.
• Know the power of teamwork. As Dr. Parikh eventually realized, collaborative care is a common and beneficial part of medicine — not something that makes you a less-than physician. “There’s a lot of opportunity to crowdsource the medical decision-making process in ways that increase your own confidence as a doctor,” he said.
• Practice self-compassion. Critical voices in your head add to an already hard and stressful world. This is where self-compassion comes in. “We don’t have much control over medicine, but we have control over how medicine makes us feel,” Dr. Gold said. Imagine treating yourself how you would treat a friend.
• Consider a physician coach.  suggests that physician coaches can help lower rates of burnout and improve well-being, resilience, professional fulfillment, and self-worth. “Coaching looks into the future to help you envision what things would look like if you were feeling differently. It helps you explore what’s in your control and how you want to shape that,” said Dr. McGrath.
• Amplify the good. Apps and web-based tools can remind you to celebrate your own achievements. The “” exercise created by J. Bryan Sexton, PhD, at the Duke Center for Healthcare Safety & Quality for example, was documented in a . When healthcare workers reflected on three good things that happened each day for 2 weeks, they reported significant improvements in depression, burnout, and work-life balance.
• Do a values check. Dr. Gold often suggested that physicians with imposter syndrome ask themselves what they value, what medicine values, and how the two line up. Pausing to consider this can guide you toward useful strategies. If you value family life but feel like medicine doesn’t, for example, you might talk with a colleague who has navigated this conflict.

Dr. Gold added that reminding yourself of the range of options can be freeing. “There’s no ‘one career’ in medicine,” she said. “There are multiple ways to be happy in medicine; there are multiple ways to be happy outside of medicine. And you’re not a failure for the path you choose.”

A version of this article appeared on Medscape.com.

Do I deserve to be here? Am I doing what I’m supposed to be doing? Is anyone going to tell me if I’m terrible?

Kerri Palamara McGrath, MD, remembered worrying over these questions as chief resident at Massachusetts General Hospital, Boston, Massachusetts, in 2009. Having graduated from New York Medical College, she felt out of step with her peers from Ivy League medical schools and considered herself lucky to be there. In order to measure up, she felt she had to work twice as hard as everybody else.

But as Dr. McGrath moved through residency and spoke with other trainees, she had a realization. Her constant fears, the nagging voice in her head saying she wasn’t good enough, these issues weren’t exclusive to her; they were pervasive.

Today, Dr. McGrath is the director of the Center for Physician Well-Being at Massachusetts General Hospital. The facility aims to address physician stress and equip doctors with the tools to navigate personal and professional issues. Dr. McGrath is also a physician coach, a growing nonclinical field, helping doctors identify their own stressors, values, and measures of success. This type of internal work, Dr. McGrath feels, can help alleviate imposter syndrome, that inner refrain saying: I’ll never be good enough.

What Is Imposter Syndrome?

While not a formal medical diagnosis, imposter syndrome has been defined as «an internal experience of intellectual phoniness.» It›s considered an inability to internalize success and a tendency to attribute gains to external factors — for example, being in the right place at the right time.

“Many people describe imposter phenomena in medicine as fearing that others are going to realize that they don’t belong somewhere or question why they’re there,” said Dr. McGrath.

It’s a “fear of being found out,” added Jessi Gold, MD, a psychiatrist who treats physicians. “In many ways, imposter syndrome shows up as a conflict between the outer self — the metaphorical mask you’re ‘putting on’ [in order] to achieve, and the inner self — how you feel like you’re not measuring up.”

Dr. McGrath said she experienced imposter syndrome before her medical career even began. She applied to 26 medical schools. Only one accepted her. “The whole time, I was like, ‘This is the only school you got into, so you’re obviously not good enough,’” she recalled. Later, having been chosen by a “coveted” institution like Mass General, “you assume that, at some point, someone will realize that the gig is up, that everybody’s better than you.”

Where Does Imposter Syndrome Come From?

Dr. McGrath felt that in medicine, high expectations are often coupled with low self-compassion. “We are so hard on ourselves, and when we set our expectations so high, we’re constantly disappointed in ourselves,” she said. External markers of success — papers published, promotions, or even social media — can further fuel this.

It can feel like “striving for excellence in a sea of excellence,” Dr. McGrath added, and this can invite comparison.

Ravi Parikh, MD, a medical oncologist and physician-scientist at the University of Pennsylvania, Philadelphia, Pennsylvania, remembered struggling with imposter syndrome early in his career. As a new doctor, he had a ton of questions, and yet those above him seemed able to make weighty decisions on their own. The comparison shook his confidence. “I remember thinking that when I became an attending, I would just magically not have to run decisions by people,” said Dr. Parikh. But even then, the “magical” self-assurance didn’t materialize.

Research found that imposter syndrome is more likely to affect women and groups that are underrepresented in medicine. But overall, the incidence is remarkably high.

A 2023 survey published in the Journal of the American College of Surgeons found that 90% of female surgeons and more than two-thirds of male ones experienced imposter syndrome. In a 2023 study on medical students in JAMA, it was nearly universal; 97% reported feelings of imposter syndrome with women 1.7 times more likely to report it than men and underrepresented groups often three times more likely.

‘I’m Clearly in the Minority Here’

The term “imposter” also suggests a lack of belonging. If medicine doesn’t “look like you,” this can create feelings of pressure, like you’re “representing a whole group with your mere existence,” said Dr. Gold, “and you have to keep proving yourself.”

Chloe Slocum, MD, MPH, an assistant professor of physical medicine and rehabilitation at Harvard Medical School, Boston, Massachusetts, remembered that feeling of conspicuous “otherness.” As a resident, Dr. Slocum began presenting at national meetings and later pursued physician leadership training. Many of her counterparts at these events were older males. “At some programs early on, I’d wonder, ‘I’m clearly in the minority here; did they really make the right decision including me in this?’”

Reactions from those around you can also have an impact. Dr. McGrath — who is 5’ 2” and describes herself as looking “very young” — noted that when she started out, neither patients nor other providers thought she was a doctor.

“I have tried everything in the book to be seen, in somebody else’s eyes, as more consistent with a doctor,” she said. “I’ve dressed down. I’ve dressed up. I’ve worn heels. I’ve worn flats. I’ve worn glasses. I’ve done all the things. When you’re constantly being told you don’t look like a doctor, you start questioning yourself.”

The Emotional Toll

If that sounds mentally exhausting, it is. Research found that imposter syndrome is often linked with burnout, depression, and anxiety.

The need to prove yourself and prevent being “found out” can push some doctors toward traditional measurements of success — promotions or published work, said Dr. Gold. But “if you’re trying to achieve in ways that you don’t value,” she warned, “you’re going to burn out.”

On the other hand, intense self-doubt can also limit advancement. After all, if you don’t think you’re good enough, you may not apply for job opportunities or leadership positions.

This mental burden can persist over years and even decades. A 2020 review of studies on imposter syndrome noted that “it would be reassuring to believe that imposter symptoms decline with age.” Unfortunately, several studies indicated that they do not.

How to Manage Imposter Syndrome

While it can be difficult to overcome imposter syndrome, there are ways to work through it and make it less pervasive or intense. Here are some tips from our experts:

• Prioritize your mental health. This can be difficult for some physicians, but don’t ignore symptoms of depression, anxiety, or burnout. Untreated mental health conditions cloud the ability to reflect on some of the existential questions that will help you navigate imposter syndrome, said Dr. Gold.
• Assess how often you need validation and why. Try to identify what you›re feeling, what needs aren›t being met, and how you can meet those needs. You can then consider where to get that validation either internally or by connecting with a colleague. Dr. McGrath encourages physicians to ask, “What does success look like for me?” and can you make success more personal and meaningful. It might sound shocking, but rather than an unattainable ideal, success should be something that feels good.
• Know the power of teamwork. As Dr. Parikh eventually realized, collaborative care is a common and beneficial part of medicine — not something that makes you a less-than physician. “There’s a lot of opportunity to crowdsource the medical decision-making process in ways that increase your own confidence as a doctor,” he said.
• Practice self-compassion. Critical voices in your head add to an already hard and stressful world. This is where self-compassion comes in. “We don’t have much control over medicine, but we have control over how medicine makes us feel,” Dr. Gold said. Imagine treating yourself how you would treat a friend.
• Consider a physician coach.  suggests that physician coaches can help lower rates of burnout and improve well-being, resilience, professional fulfillment, and self-worth. “Coaching looks into the future to help you envision what things would look like if you were feeling differently. It helps you explore what’s in your control and how you want to shape that,” said Dr. McGrath.
• Amplify the good. Apps and web-based tools can remind you to celebrate your own achievements. The “” exercise created by J. Bryan Sexton, PhD, at the Duke Center for Healthcare Safety & Quality for example, was documented in a . When healthcare workers reflected on three good things that happened each day for 2 weeks, they reported significant improvements in depression, burnout, and work-life balance.
• Do a values check. Dr. Gold often suggested that physicians with imposter syndrome ask themselves what they value, what medicine values, and how the two line up. Pausing to consider this can guide you toward useful strategies. If you value family life but feel like medicine doesn’t, for example, you might talk with a colleague who has navigated this conflict.

Dr. Gold added that reminding yourself of the range of options can be freeing. “There’s no ‘one career’ in medicine,” she said. “There are multiple ways to be happy in medicine; there are multiple ways to be happy outside of medicine. And you’re not a failure for the path you choose.”

A version of this article appeared on Medscape.com.

Myasthenia gravis (MG) is a rare autoimmune neurologic disorder that occurs when the transmission between nerves and muscles is disrupted. It is caused by autoantibodies against acetylcholine receptors (AChRs), which results in muscle weakness that is often fatigable and affects various muscles in the body, including those that move the eyes, eyelids, and limbs. Ocular MG affects only the muscles that move the eyes and eyelids, whereas generalized MG (gMG) affects muscles throughout the body. When MG occurs with a thymoma, it is called thymoma-associated MG and is considered a paraneoplastic disease. In severe cases of MG, patients can experience a myasthenic crisis (MC), during which respiratory muscles weaken and necessitate mechanical ventilation. Diagnosis of MG is based on clinical examination, and laboratory tests are used to confirm the diagnosis. Treatment options include cholinesterase enzyme inhibitors and immunosuppressive agents, which aim to either reduce symptoms or cause nonspecific immunosuppression, respectively, but do not target the pathogenetic autoantibodies that characterize the disease.

1. The most common age at onset of gMG is the second and third decades in women and the seventh and eighth decades in men.

MG has an annual incidence of approximately  four to 30 new cases per million population. Prevalence rates range from 150 to 200 cases per million population, and they have steadily increased over the past 50 years. This increase in prevalence is probably the result of better disease recognition, aging of the population, and an increased life span in patients.

MG can occur at any age; however, onset is more common in females in the second and third decades and is more common in males in the seventh to eighth decades. Before age 40 years, the female-to-male ratio is 3:1, and after age 50 years, the female-to-male ratio is 3:2.

2. gMG commonly weakens muscles responsible for eye movement, facial expressions, and functions such as chewing, swallowing, and speaking.

gMG typically manifests as muscle weakness that worsens with repeated use. Patients often report that their function is best in the morning, with more pronounced weakness at the end of the day. Permanent muscle damage is rare, however, and maximal muscle strength is often good.

Extraocular muscles are more commonly affected, as twitch fibers in these muscles develop tension faster, have a higher frequency of synaptic firing than limb muscles, and have fewer AChRs, making them more susceptible to fatigue. Patients present asymmetrically; intermittent drooping of the upper eyelid (ptosis) and double vision (diplopia) are the most common symptoms.

Muscles innervated by the cranial nerves (bulbar muscles) are involved in 60% of patients with gMG and can lead to fatigable chewing, reduced facial expression, speech difficulties (dysarthria), and weakness of swallowing (dysphagia). Up to 15% of patients initially present with bulbar muscle involvement, including dysarthria and painless dysphagia.

3. Emotional stress can trigger an MC.

MC is a complication of MG characterized by worsening muscle weakness that results in respiratory failure and necessitates mechanical ventilation.

MC is often the result of respiratory muscle weakness but can also be due to bulbar weakness with upper airway collapse. MC can occur in 15%-20% of patients within the first 2-3 years of the disease; however, it can also be the first presentation of MG in 18%-28% of cases.

MC can be triggered by multiple causes, including emotional or physical stress. The most common precipitant is infection; other precipitants include surgery, pregnancy, perimenstrual state, certain medications, tapering of immune-modulating medications, exposure to temperature extremes, pain, and sleep deprivation. Approximately one third to one half of patients with MC may have no obvious cause.

4. High levels of anti-AChR antibodies strongly indicate MG, but normal levels do not rule it out.

All patients with a clinical history suggestive of MG should be tested for antibodies for confirmation. Most patients have anti-AChR antibodies (~85%), and those without have anti–muscle-specific kinase (MuSK antibodies) (6%) and anti–lipoprotein receptor-related protein 4 (LRP4) antibodies (2%).

The sensitivity of anti-AChR antibodies varies depending on whether the antibody is binding, modulating, or blocking the AChR. Binding antibody is the most common, and when combined with blocking antibodies, has a high sensitivity (99.6%) and is typically tested first. Higher AChR antibody titers are more specific for the diagnosis of MG than are low titers, but they do not correlate with disease severity.

For patients who do not have anti-AChR antibodies but do have clinical features of MG, anti-MuSK antibodies and anti-LRP4 antibodies are measured to increase diagnostic sensitivity. For symptomatic patients who do not have any autoantibodies (seronegative), electrodiagnostic testing that shows evidence of impaired signal transmission at the neuromuscular junction is used to confirm the diagnosis of MG.

5. Studies suggest that over 75% of seropositive MG patients show distinct thymus abnormalities.

More than 75% of patients with AChR antibody–positive MG have abnormalities in their thymus, and up to 40% of patients with a thymoma have MG. Among those with thymic pathology, thymic hyperplasia is the most common type (85%), but other thymic tumors (mainly thymoma) can be present in up to 15% of cases. Thymomas are typically noninvasive and cortical, but in some rare cases, invasive thymic carcinoma can occur.

Given this overlap in presentation, it is recommended that patients with seronegative and seropositive MG undergo chest CT or MRI for evaluation of their anterior mediastinal anatomy and to detect the presence of a thymoma. For patients with MG and a thymoma, as well as selected (nonthymomatous) patients with seropositive or seronegative MG, therapeutic thymectomy is recommended.

Myasthenia gravis (MG) is a rare autoimmune neurologic disorder that occurs when the transmission between nerves and muscles is disrupted. It is caused by autoantibodies against acetylcholine receptors (AChRs), which results in muscle weakness that is often fatigable and affects various muscles in the body, including those that move the eyes, eyelids, and limbs. Ocular MG affects only the muscles that move the eyes and eyelids, whereas generalized MG (gMG) affects muscles throughout the body. When MG occurs with a thymoma, it is called thymoma-associated MG and is considered a paraneoplastic disease. In severe cases of MG, patients can experience a myasthenic crisis (MC), during which respiratory muscles weaken and necessitate mechanical ventilation. Diagnosis of MG is based on clinical examination, and laboratory tests are used to confirm the diagnosis. Treatment options include cholinesterase enzyme inhibitors and immunosuppressive agents, which aim to either reduce symptoms or cause nonspecific immunosuppression, respectively, but do not target the pathogenetic autoantibodies that characterize the disease.

1. The most common age at onset of gMG is the second and third decades in women and the seventh and eighth decades in men.

MG has an annual incidence of approximately  four to 30 new cases per million population. Prevalence rates range from 150 to 200 cases per million population, and they have steadily increased over the past 50 years. This increase in prevalence is probably the result of better disease recognition, aging of the population, and an increased life span in patients.

MG can occur at any age; however, onset is more common in females in the second and third decades and is more common in males in the seventh to eighth decades. Before age 40 years, the female-to-male ratio is 3:1, and after age 50 years, the female-to-male ratio is 3:2.

2. gMG commonly weakens muscles responsible for eye movement, facial expressions, and functions such as chewing, swallowing, and speaking.

gMG typically manifests as muscle weakness that worsens with repeated use. Patients often report that their function is best in the morning, with more pronounced weakness at the end of the day. Permanent muscle damage is rare, however, and maximal muscle strength is often good.

Extraocular muscles are more commonly affected, as twitch fibers in these muscles develop tension faster, have a higher frequency of synaptic firing than limb muscles, and have fewer AChRs, making them more susceptible to fatigue. Patients present asymmetrically; intermittent drooping of the upper eyelid (ptosis) and double vision (diplopia) are the most common symptoms.

Muscles innervated by the cranial nerves (bulbar muscles) are involved in 60% of patients with gMG and can lead to fatigable chewing, reduced facial expression, speech difficulties (dysarthria), and weakness of swallowing (dysphagia). Up to 15% of patients initially present with bulbar muscle involvement, including dysarthria and painless dysphagia.

3. Emotional stress can trigger an MC.

MC is a complication of MG characterized by worsening muscle weakness that results in respiratory failure and necessitates mechanical ventilation.

MC is often the result of respiratory muscle weakness but can also be due to bulbar weakness with upper airway collapse. MC can occur in 15%-20% of patients within the first 2-3 years of the disease; however, it can also be the first presentation of MG in 18%-28% of cases.

MC can be triggered by multiple causes, including emotional or physical stress. The most common precipitant is infection; other precipitants include surgery, pregnancy, perimenstrual state, certain medications, tapering of immune-modulating medications, exposure to temperature extremes, pain, and sleep deprivation. Approximately one third to one half of patients with MC may have no obvious cause.

4. High levels of anti-AChR antibodies strongly indicate MG, but normal levels do not rule it out.

All patients with a clinical history suggestive of MG should be tested for antibodies for confirmation. Most patients have anti-AChR antibodies (~85%), and those without have anti–muscle-specific kinase (MuSK antibodies) (6%) and anti–lipoprotein receptor-related protein 4 (LRP4) antibodies (2%).

The sensitivity of anti-AChR antibodies varies depending on whether the antibody is binding, modulating, or blocking the AChR. Binding antibody is the most common, and when combined with blocking antibodies, has a high sensitivity (99.6%) and is typically tested first. Higher AChR antibody titers are more specific for the diagnosis of MG than are low titers, but they do not correlate with disease severity.

For patients who do not have anti-AChR antibodies but do have clinical features of MG, anti-MuSK antibodies and anti-LRP4 antibodies are measured to increase diagnostic sensitivity. For symptomatic patients who do not have any autoantibodies (seronegative), electrodiagnostic testing that shows evidence of impaired signal transmission at the neuromuscular junction is used to confirm the diagnosis of MG.

5. Studies suggest that over 75% of seropositive MG patients show distinct thymus abnormalities.

More than 75% of patients with AChR antibody–positive MG have abnormalities in their thymus, and up to 40% of patients with a thymoma have MG. Among those with thymic pathology, thymic hyperplasia is the most common type (85%), but other thymic tumors (mainly thymoma) can be present in up to 15% of cases. Thymomas are typically noninvasive and cortical, but in some rare cases, invasive thymic carcinoma can occur.

Given this overlap in presentation, it is recommended that patients with seronegative and seropositive MG undergo chest CT or MRI for evaluation of their anterior mediastinal anatomy and to detect the presence of a thymoma. For patients with MG and a thymoma, as well as selected (nonthymomatous) patients with seropositive or seronegative MG, therapeutic thymectomy is recommended.

Myasthenia gravis (MG) is a rare autoimmune neurologic disorder that occurs when the transmission between nerves and muscles is disrupted. It is caused by autoantibodies against acetylcholine receptors (AChRs), which results in muscle weakness that is often fatigable and affects various muscles in the body, including those that move the eyes, eyelids, and limbs. Ocular MG affects only the muscles that move the eyes and eyelids, whereas generalized MG (gMG) affects muscles throughout the body. When MG occurs with a thymoma, it is called thymoma-associated MG and is considered a paraneoplastic disease. In severe cases of MG, patients can experience a myasthenic crisis (MC), during which respiratory muscles weaken and necessitate mechanical ventilation. Diagnosis of MG is based on clinical examination, and laboratory tests are used to confirm the diagnosis. Treatment options include cholinesterase enzyme inhibitors and immunosuppressive agents, which aim to either reduce symptoms or cause nonspecific immunosuppression, respectively, but do not target the pathogenetic autoantibodies that characterize the disease.

1. The most common age at onset of gMG is the second and third decades in women and the seventh and eighth decades in men.

MG has an annual incidence of approximately  four to 30 new cases per million population. Prevalence rates range from 150 to 200 cases per million population, and they have steadily increased over the past 50 years. This increase in prevalence is probably the result of better disease recognition, aging of the population, and an increased life span in patients.

MG can occur at any age; however, onset is more common in females in the second and third decades and is more common in males in the seventh to eighth decades. Before age 40 years, the female-to-male ratio is 3:1, and after age 50 years, the female-to-male ratio is 3:2.

2. gMG commonly weakens muscles responsible for eye movement, facial expressions, and functions such as chewing, swallowing, and speaking.

gMG typically manifests as muscle weakness that worsens with repeated use. Patients often report that their function is best in the morning, with more pronounced weakness at the end of the day. Permanent muscle damage is rare, however, and maximal muscle strength is often good.

Extraocular muscles are more commonly affected, as twitch fibers in these muscles develop tension faster, have a higher frequency of synaptic firing than limb muscles, and have fewer AChRs, making them more susceptible to fatigue. Patients present asymmetrically; intermittent drooping of the upper eyelid (ptosis) and double vision (diplopia) are the most common symptoms.

Muscles innervated by the cranial nerves (bulbar muscles) are involved in 60% of patients with gMG and can lead to fatigable chewing, reduced facial expression, speech difficulties (dysarthria), and weakness of swallowing (dysphagia). Up to 15% of patients initially present with bulbar muscle involvement, including dysarthria and painless dysphagia.

3. Emotional stress can trigger an MC.

MC is a complication of MG characterized by worsening muscle weakness that results in respiratory failure and necessitates mechanical ventilation.

MC is often the result of respiratory muscle weakness but can also be due to bulbar weakness with upper airway collapse. MC can occur in 15%-20% of patients within the first 2-3 years of the disease; however, it can also be the first presentation of MG in 18%-28% of cases.

MC can be triggered by multiple causes, including emotional or physical stress. The most common precipitant is infection; other precipitants include surgery, pregnancy, perimenstrual state, certain medications, tapering of immune-modulating medications, exposure to temperature extremes, pain, and sleep deprivation. Approximately one third to one half of patients with MC may have no obvious cause.

4. High levels of anti-AChR antibodies strongly indicate MG, but normal levels do not rule it out.

All patients with a clinical history suggestive of MG should be tested for antibodies for confirmation. Most patients have anti-AChR antibodies (~85%), and those without have anti–muscle-specific kinase (MuSK antibodies) (6%) and anti–lipoprotein receptor-related protein 4 (LRP4) antibodies (2%).

The sensitivity of anti-AChR antibodies varies depending on whether the antibody is binding, modulating, or blocking the AChR. Binding antibody is the most common, and when combined with blocking antibodies, has a high sensitivity (99.6%) and is typically tested first. Higher AChR antibody titers are more specific for the diagnosis of MG than are low titers, but they do not correlate with disease severity.

For patients who do not have anti-AChR antibodies but do have clinical features of MG, anti-MuSK antibodies and anti-LRP4 antibodies are measured to increase diagnostic sensitivity. For symptomatic patients who do not have any autoantibodies (seronegative), electrodiagnostic testing that shows evidence of impaired signal transmission at the neuromuscular junction is used to confirm the diagnosis of MG.

5. Studies suggest that over 75% of seropositive MG patients show distinct thymus abnormalities.

More than 75% of patients with AChR antibody–positive MG have abnormalities in their thymus, and up to 40% of patients with a thymoma have MG. Among those with thymic pathology, thymic hyperplasia is the most common type (85%), but other thymic tumors (mainly thymoma) can be present in up to 15% of cases. Thymomas are typically noninvasive and cortical, but in some rare cases, invasive thymic carcinoma can occur.

Given this overlap in presentation, it is recommended that patients with seronegative and seropositive MG undergo chest CT or MRI for evaluation of their anterior mediastinal anatomy and to detect the presence of a thymoma. For patients with MG and a thymoma, as well as selected (nonthymomatous) patients with seropositive or seronegative MG, therapeutic thymectomy is recommended.

WEST PALM BEACH, FLORIDA — Migraine, a common comorbidity in multiple sclerosis (MS), is not part of the MS prodrome, new research suggested. Investigators found that patients with MS were more likely than controls to develop migraine shortly before disease diagnosis, suggesting the headache type is not a forerunner of MS.

“The risk [of migraine] was concentrated in the year of their first [MS] symptom, or the year prior, instead of many years before,” said lead investigator Vinicius A. Schoeps, MD, MPH, postdoctoral fellow at the University of California San Francisco.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Is MS a Migraine Trigger?

Worldwide up to 43% of patients with MS report migraine. Recent data point to a 3- to 5-year clinically symptomatic prodromal phase of MS and suggest migraine may be one of its potential constituents. However, the relationship between the two disorders remains unclear.

The investigators wanted to determine whether migraine is part of the MS prodrome because if this is the case, it could provide a potential opportunity for early intervention to delay or prevent the disease.

The team analyzed incidence cases of MS and matched controls in the Kaiser Permanente Southern California health system from 2011 to 2014. Participants took part in structured in-person interviews that included questions about migraine.

The 591 MS cases had an average age of onset at 36 years, with a similar index date for controls. Among the cases, 71% were women, 42% were White, 32% Hispanic, and 21% Black. Almost 40% of cases had obesity. These demographic data were similar in the control group.

In those with MS, 13% had a history of mononucleosis compared with 6% of controls. Epstein-Barr virus, which causes conditions such as mononucleosis, was considered a likely cause of MS.

Migraine was diagnosed before MS onset in 27% of cases and before the index date in 21% of controls (adjusted odds ratio [aOR], 1.36; P = .03). Migraine onset occurred later in cases versus controls (mean, 21 years vs 17 years; P = .008).

Migraine was also more likely to occur at the same time or 1 year prior to MS symptoms or the index date in cases versus controls (4.3% vs 1.3%; aOR, 3.54; P = .002).

“These findings suggest that migraine can be triggered by MS rather than part of the constellation of nonspecific symptoms that constitute the 3- to 5-year-long MS prodrome,” the investigators reported.

“The inflammatory setting of the first MS relapse might be actually triggering the migraine,” Dr. Shoeps said. He added that patients with MS developed migraines later in life.

“There could be a different pathological process in people who have traditional migraine at the most common age where people get their diagnosis of migraine — and have them throughout their lifetime — versus having a migraine at older age and a diagnosis of MS close to that period of time,” he said. However, he noted, the study design does not allow for this type of analysis.

Commenting on the findings, Anibal Chertcoff, MD, PhD, an assistant professor in the Multiple Sclerosis Research Centre at the University of Manitoba, Winnipeg, Manitoba, Canada, noted the study’s large population and well-balanced case and control groups are strengths of the study.

However, Dr. Chertcoff, who was not involved in the research, cautioned that the study is cross-sectional noting that he is “not convinced this is the best type of study design to provide insights into cause-and-effect relationships.”

Dr. Chertcoff added the findings are limited by their reliance on data from a single health system.

Disclosures were not provided. A grant from the National Institute of Neurologic Disorders and Stroke to an author helped support the study. Dr. Chertcoff received funding from MS Canada and the Michael Smith Foundation for Health Research and support from Novartis to attend a scientific meeting.

A version of this article appeared on Medscape.com.

WEST PALM BEACH, FLORIDA — Migraine, a common comorbidity in multiple sclerosis (MS), is not part of the MS prodrome, new research suggested. Investigators found that patients with MS were more likely than controls to develop migraine shortly before disease diagnosis, suggesting the headache type is not a forerunner of MS.

“The risk [of migraine] was concentrated in the year of their first [MS] symptom, or the year prior, instead of many years before,” said lead investigator Vinicius A. Schoeps, MD, MPH, postdoctoral fellow at the University of California San Francisco.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Is MS a Migraine Trigger?

Worldwide up to 43% of patients with MS report migraine. Recent data point to a 3- to 5-year clinically symptomatic prodromal phase of MS and suggest migraine may be one of its potential constituents. However, the relationship between the two disorders remains unclear.

The investigators wanted to determine whether migraine is part of the MS prodrome because if this is the case, it could provide a potential opportunity for early intervention to delay or prevent the disease.

The team analyzed incidence cases of MS and matched controls in the Kaiser Permanente Southern California health system from 2011 to 2014. Participants took part in structured in-person interviews that included questions about migraine.

The 591 MS cases had an average age of onset at 36 years, with a similar index date for controls. Among the cases, 71% were women, 42% were White, 32% Hispanic, and 21% Black. Almost 40% of cases had obesity. These demographic data were similar in the control group.

In those with MS, 13% had a history of mononucleosis compared with 6% of controls. Epstein-Barr virus, which causes conditions such as mononucleosis, was considered a likely cause of MS.

Migraine was diagnosed before MS onset in 27% of cases and before the index date in 21% of controls (adjusted odds ratio [aOR], 1.36; P = .03). Migraine onset occurred later in cases versus controls (mean, 21 years vs 17 years; P = .008).

Migraine was also more likely to occur at the same time or 1 year prior to MS symptoms or the index date in cases versus controls (4.3% vs 1.3%; aOR, 3.54; P = .002).

“These findings suggest that migraine can be triggered by MS rather than part of the constellation of nonspecific symptoms that constitute the 3- to 5-year-long MS prodrome,” the investigators reported.

“The inflammatory setting of the first MS relapse might be actually triggering the migraine,” Dr. Shoeps said. He added that patients with MS developed migraines later in life.

“There could be a different pathological process in people who have traditional migraine at the most common age where people get their diagnosis of migraine — and have them throughout their lifetime — versus having a migraine at older age and a diagnosis of MS close to that period of time,” he said. However, he noted, the study design does not allow for this type of analysis.

Commenting on the findings, Anibal Chertcoff, MD, PhD, an assistant professor in the Multiple Sclerosis Research Centre at the University of Manitoba, Winnipeg, Manitoba, Canada, noted the study’s large population and well-balanced case and control groups are strengths of the study.

However, Dr. Chertcoff, who was not involved in the research, cautioned that the study is cross-sectional noting that he is “not convinced this is the best type of study design to provide insights into cause-and-effect relationships.”

Dr. Chertcoff added the findings are limited by their reliance on data from a single health system.

Disclosures were not provided. A grant from the National Institute of Neurologic Disorders and Stroke to an author helped support the study. Dr. Chertcoff received funding from MS Canada and the Michael Smith Foundation for Health Research and support from Novartis to attend a scientific meeting.

A version of this article appeared on Medscape.com.

WEST PALM BEACH, FLORIDA — Migraine, a common comorbidity in multiple sclerosis (MS), is not part of the MS prodrome, new research suggested. Investigators found that patients with MS were more likely than controls to develop migraine shortly before disease diagnosis, suggesting the headache type is not a forerunner of MS.

“The risk [of migraine] was concentrated in the year of their first [MS] symptom, or the year prior, instead of many years before,” said lead investigator Vinicius A. Schoeps, MD, MPH, postdoctoral fellow at the University of California San Francisco.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Is MS a Migraine Trigger?

Worldwide up to 43% of patients with MS report migraine. Recent data point to a 3- to 5-year clinically symptomatic prodromal phase of MS and suggest migraine may be one of its potential constituents. However, the relationship between the two disorders remains unclear.

The investigators wanted to determine whether migraine is part of the MS prodrome because if this is the case, it could provide a potential opportunity for early intervention to delay or prevent the disease.

The team analyzed incidence cases of MS and matched controls in the Kaiser Permanente Southern California health system from 2011 to 2014. Participants took part in structured in-person interviews that included questions about migraine.

The 591 MS cases had an average age of onset at 36 years, with a similar index date for controls. Among the cases, 71% were women, 42% were White, 32% Hispanic, and 21% Black. Almost 40% of cases had obesity. These demographic data were similar in the control group.

In those with MS, 13% had a history of mononucleosis compared with 6% of controls. Epstein-Barr virus, which causes conditions such as mononucleosis, was considered a likely cause of MS.

Migraine was diagnosed before MS onset in 27% of cases and before the index date in 21% of controls (adjusted odds ratio [aOR], 1.36; P = .03). Migraine onset occurred later in cases versus controls (mean, 21 years vs 17 years; P = .008).

Migraine was also more likely to occur at the same time or 1 year prior to MS symptoms or the index date in cases versus controls (4.3% vs 1.3%; aOR, 3.54; P = .002).

“These findings suggest that migraine can be triggered by MS rather than part of the constellation of nonspecific symptoms that constitute the 3- to 5-year-long MS prodrome,” the investigators reported.

“The inflammatory setting of the first MS relapse might be actually triggering the migraine,” Dr. Shoeps said. He added that patients with MS developed migraines later in life.

“There could be a different pathological process in people who have traditional migraine at the most common age where people get their diagnosis of migraine — and have them throughout their lifetime — versus having a migraine at older age and a diagnosis of MS close to that period of time,” he said. However, he noted, the study design does not allow for this type of analysis.

Commenting on the findings, Anibal Chertcoff, MD, PhD, an assistant professor in the Multiple Sclerosis Research Centre at the University of Manitoba, Winnipeg, Manitoba, Canada, noted the study’s large population and well-balanced case and control groups are strengths of the study.

However, Dr. Chertcoff, who was not involved in the research, cautioned that the study is cross-sectional noting that he is “not convinced this is the best type of study design to provide insights into cause-and-effect relationships.”

Dr. Chertcoff added the findings are limited by their reliance on data from a single health system.

Disclosures were not provided. A grant from the National Institute of Neurologic Disorders and Stroke to an author helped support the study. Dr. Chertcoff received funding from MS Canada and the Michael Smith Foundation for Health Research and support from Novartis to attend a scientific meeting.

A version of this article appeared on Medscape.com.