Neurology

For patients with primary progressive multiple sclerosis (MS), longer exposure to disease-modifying therapy (DMT) may delay the time at which a patient is restricted to a wheelchair. Reducing the delay to treatment initiation, as well as treating younger patients, might improve long-term disability outcomes, according to a new study. 

“To optimize treatment decision-making in primary progressive MS, further profiling of the best candidates for treatment is needed,” said the researchers. The study was presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Ocrelizumab remains the only treatment available for patients with primary progressive MS. In clinical trials, other drugs have failed to reduce disability progression in this population. Mattia Fonderico, a doctoral student and research assistant at the University of Florence (Italy), and colleagues reviewed data from the Italian MS Registry to examine whether DMT affects the attainment of given disability outcomes.

Patients with longer exposure were younger at baseline

Patients eligible for inclusion in the study had primary progressive MS, at least three evaluations using the Expanded Disability Status Scale (EDSS), and 3 years’ follow-up. The investigators defined the baseline for untreated patients as the first EDSS evaluation. For treated patients, the baseline was the date of DMT initiation.

Using multivariable Cox regression models, Ms. Fonderico and colleagues examined the effect of DMT on the risk of reaching EDSS scores of 6 (i.e., requirement for intermittent or unilateral constant walking assistance) and 7 (i.e., restriction to a wheelchair) as a dichotomous variable and as a time-dependent covariate. The researchers adjusted the data for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, and annualized relapse rate. They compared outcomes with an as-treated analysis and chose cohorts with similar baseline characteristics using propensity-score matching. In addition, Ms. Fonderico and colleagues also analyzed quartiles of DMT exposure.

The investigators included 1,214 patients (671 women) in their analysis. The population’s mean age at baseline was 48.7 years, and its mean EDSS score was 4.1. A total of 626 patients (52%) received DMT during follow-up. Approximately 57% of DMTs were platform therapies, and 43% were high-efficacy therapies.

Mean follow-up duration was 11.6 years. By the end of follow-up, 994 patients (82%) reached an EDSS score of 6, and 539 (44%) reached an EDSS score of 7. Multivariable Cox regression models indicated that DMT, analyzed as a dichotomous variable, did not affect the risk of reaching EDSS 6 (adjusted hazard ratio, 1.1) or EDSS 7 (aHR, 0.93). Longer DMT exposure, however, significantly reduced the risk of reaching EDSS 7 (aHR, 0.73).

Compared with patients with shorter exposure to DMT, patients in the highest quartile of DMT exposure were younger at baseline (mean age, 44.1 years) and initiated DMT closer to disease onset (mean time to DMT initiation was 6.8 years). The propensity score matching analysis confirmed these findings.

The investigators did not consider MRI variables, which Ms. Fonderico acknowledged was a weakness of the study. In addition, they did not analyze the effect of superimposed relapses.

 

A new perspective on primary progressive MS?

These results suggest that primary progressive MS behaves like relapsing-remitting MS, said Gavin Giovannoni, MD, PhD, chair of neurology at Queen Mary University of London. That is, they suggest that primary progressive MS “is modifiable by a DMT and that the earlier you treat, the better the outcome.” The results also indicate that neurologists commonly prescribe DMT off label in Italy, he added.

A weakness of the study is that it was not randomized. Furthermore, “EDSS [evaluations] tend not be done properly in routine clinical practice,” said Dr. Giovannoni. Still, the study raises an important question for future research. “Why have we missed the treatment effect in previous trials?” asked Dr. Giovannoni. Whether previous trials were too short or underpowered could be investigated, he added.

Study funding was not reported. Ms. Fonderico had no relevant disclosures. Dr. Giovannoni had no relevant disclosures.

[email protected]

For patients with primary progressive multiple sclerosis (MS), longer exposure to disease-modifying therapy (DMT) may delay the time at which a patient is restricted to a wheelchair. Reducing the delay to treatment initiation, as well as treating younger patients, might improve long-term disability outcomes, according to a new study. 

“To optimize treatment decision-making in primary progressive MS, further profiling of the best candidates for treatment is needed,” said the researchers. The study was presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Ocrelizumab remains the only treatment available for patients with primary progressive MS. In clinical trials, other drugs have failed to reduce disability progression in this population. Mattia Fonderico, a doctoral student and research assistant at the University of Florence (Italy), and colleagues reviewed data from the Italian MS Registry to examine whether DMT affects the attainment of given disability outcomes.

Patients with longer exposure were younger at baseline

Patients eligible for inclusion in the study had primary progressive MS, at least three evaluations using the Expanded Disability Status Scale (EDSS), and 3 years’ follow-up. The investigators defined the baseline for untreated patients as the first EDSS evaluation. For treated patients, the baseline was the date of DMT initiation.

Using multivariable Cox regression models, Ms. Fonderico and colleagues examined the effect of DMT on the risk of reaching EDSS scores of 6 (i.e., requirement for intermittent or unilateral constant walking assistance) and 7 (i.e., restriction to a wheelchair) as a dichotomous variable and as a time-dependent covariate. The researchers adjusted the data for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, and annualized relapse rate. They compared outcomes with an as-treated analysis and chose cohorts with similar baseline characteristics using propensity-score matching. In addition, Ms. Fonderico and colleagues also analyzed quartiles of DMT exposure.

The investigators included 1,214 patients (671 women) in their analysis. The population’s mean age at baseline was 48.7 years, and its mean EDSS score was 4.1. A total of 626 patients (52%) received DMT during follow-up. Approximately 57% of DMTs were platform therapies, and 43% were high-efficacy therapies.

Mean follow-up duration was 11.6 years. By the end of follow-up, 994 patients (82%) reached an EDSS score of 6, and 539 (44%) reached an EDSS score of 7. Multivariable Cox regression models indicated that DMT, analyzed as a dichotomous variable, did not affect the risk of reaching EDSS 6 (adjusted hazard ratio, 1.1) or EDSS 7 (aHR, 0.93). Longer DMT exposure, however, significantly reduced the risk of reaching EDSS 7 (aHR, 0.73).

Compared with patients with shorter exposure to DMT, patients in the highest quartile of DMT exposure were younger at baseline (mean age, 44.1 years) and initiated DMT closer to disease onset (mean time to DMT initiation was 6.8 years). The propensity score matching analysis confirmed these findings.

The investigators did not consider MRI variables, which Ms. Fonderico acknowledged was a weakness of the study. In addition, they did not analyze the effect of superimposed relapses.

 

A new perspective on primary progressive MS?

These results suggest that primary progressive MS behaves like relapsing-remitting MS, said Gavin Giovannoni, MD, PhD, chair of neurology at Queen Mary University of London. That is, they suggest that primary progressive MS “is modifiable by a DMT and that the earlier you treat, the better the outcome.” The results also indicate that neurologists commonly prescribe DMT off label in Italy, he added.

A weakness of the study is that it was not randomized. Furthermore, “EDSS [evaluations] tend not be done properly in routine clinical practice,” said Dr. Giovannoni. Still, the study raises an important question for future research. “Why have we missed the treatment effect in previous trials?” asked Dr. Giovannoni. Whether previous trials were too short or underpowered could be investigated, he added.

Study funding was not reported. Ms. Fonderico had no relevant disclosures. Dr. Giovannoni had no relevant disclosures.

[email protected]

For patients with primary progressive multiple sclerosis (MS), longer exposure to disease-modifying therapy (DMT) may delay the time at which a patient is restricted to a wheelchair. Reducing the delay to treatment initiation, as well as treating younger patients, might improve long-term disability outcomes, according to a new study. 

“To optimize treatment decision-making in primary progressive MS, further profiling of the best candidates for treatment is needed,” said the researchers. The study was presented at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS–ACTRIMS) 2020, this year known as MSVirtual2020.

Ocrelizumab remains the only treatment available for patients with primary progressive MS. In clinical trials, other drugs have failed to reduce disability progression in this population. Mattia Fonderico, a doctoral student and research assistant at the University of Florence (Italy), and colleagues reviewed data from the Italian MS Registry to examine whether DMT affects the attainment of given disability outcomes.

Patients with longer exposure were younger at baseline

Patients eligible for inclusion in the study had primary progressive MS, at least three evaluations using the Expanded Disability Status Scale (EDSS), and 3 years’ follow-up. The investigators defined the baseline for untreated patients as the first EDSS evaluation. For treated patients, the baseline was the date of DMT initiation.

Using multivariable Cox regression models, Ms. Fonderico and colleagues examined the effect of DMT on the risk of reaching EDSS scores of 6 (i.e., requirement for intermittent or unilateral constant walking assistance) and 7 (i.e., restriction to a wheelchair) as a dichotomous variable and as a time-dependent covariate. The researchers adjusted the data for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, and annualized relapse rate. They compared outcomes with an as-treated analysis and chose cohorts with similar baseline characteristics using propensity-score matching. In addition, Ms. Fonderico and colleagues also analyzed quartiles of DMT exposure.

The investigators included 1,214 patients (671 women) in their analysis. The population’s mean age at baseline was 48.7 years, and its mean EDSS score was 4.1. A total of 626 patients (52%) received DMT during follow-up. Approximately 57% of DMTs were platform therapies, and 43% were high-efficacy therapies.

Mean follow-up duration was 11.6 years. By the end of follow-up, 994 patients (82%) reached an EDSS score of 6, and 539 (44%) reached an EDSS score of 7. Multivariable Cox regression models indicated that DMT, analyzed as a dichotomous variable, did not affect the risk of reaching EDSS 6 (adjusted hazard ratio, 1.1) or EDSS 7 (aHR, 0.93). Longer DMT exposure, however, significantly reduced the risk of reaching EDSS 7 (aHR, 0.73).

Compared with patients with shorter exposure to DMT, patients in the highest quartile of DMT exposure were younger at baseline (mean age, 44.1 years) and initiated DMT closer to disease onset (mean time to DMT initiation was 6.8 years). The propensity score matching analysis confirmed these findings.

The investigators did not consider MRI variables, which Ms. Fonderico acknowledged was a weakness of the study. In addition, they did not analyze the effect of superimposed relapses.

 

A new perspective on primary progressive MS?

These results suggest that primary progressive MS behaves like relapsing-remitting MS, said Gavin Giovannoni, MD, PhD, chair of neurology at Queen Mary University of London. That is, they suggest that primary progressive MS “is modifiable by a DMT and that the earlier you treat, the better the outcome.” The results also indicate that neurologists commonly prescribe DMT off label in Italy, he added.

A weakness of the study is that it was not randomized. Furthermore, “EDSS [evaluations] tend not be done properly in routine clinical practice,” said Dr. Giovannoni. Still, the study raises an important question for future research. “Why have we missed the treatment effect in previous trials?” asked Dr. Giovannoni. Whether previous trials were too short or underpowered could be investigated, he added.

Study funding was not reported. Ms. Fonderico had no relevant disclosures. Dr. Giovannoni had no relevant disclosures.

[email protected]

In contrast to findings of previous research, low levels of von Willebrand Factor (VWF) and blood group O were not associated with a first-ever intracerebral hemorrhage (ICH), according to a study published in Thrombosis Research.

The researchers compared 176 cases of ICH with 349 age- and sex-matched controls. The mean patient age was 57 years, and 50% were women. The median time from baseline blood sampling to the first ICH was 5.6 years, according to the study reported by Kristina Johansson of Umeå (Sweden) University and her colleagues.
 

Complicated picture

The level of VWF differed significantly among blood groups: In individuals with blood group O, the mean VWF level was 1.29 kIU/L; for blood group A, it was 1.52 kIU/L; for blood group AB, 1.59 kIU/L; and in blood group B, 1.76 kIU/L. However, there was no difference in VWF concentration between cases and controls.

The researchers found no association between blood group O and the risk of ICH, a finding previously seen in other studies. They did, however, find that, in the limited number of patients with blood group B there was an association with a lower risk of ICH, compared with blood group A (odds ratio, 0.47; 95% confidence interval, 0.23-0.95).

“To our knowledge this is the largest prospective study investigating the association between VWF, ABO blood group and ICH. We found no association between VWF or blood group O and risk of future ICH,” the researchers concluded.

The study was funded by public institutions in Sweden. The authors declared that they had no conflicts.
 

[email protected]

SOURCE: Johansson K et al. Thromb Res. 2020 Jul 5;195:77-80.

In contrast to findings of previous research, low levels of von Willebrand Factor (VWF) and blood group O were not associated with a first-ever intracerebral hemorrhage (ICH), according to a study published in Thrombosis Research.

The researchers compared 176 cases of ICH with 349 age- and sex-matched controls. The mean patient age was 57 years, and 50% were women. The median time from baseline blood sampling to the first ICH was 5.6 years, according to the study reported by Kristina Johansson of Umeå (Sweden) University and her colleagues.
 

Complicated picture

The level of VWF differed significantly among blood groups: In individuals with blood group O, the mean VWF level was 1.29 kIU/L; for blood group A, it was 1.52 kIU/L; for blood group AB, 1.59 kIU/L; and in blood group B, 1.76 kIU/L. However, there was no difference in VWF concentration between cases and controls.

The researchers found no association between blood group O and the risk of ICH, a finding previously seen in other studies. They did, however, find that, in the limited number of patients with blood group B there was an association with a lower risk of ICH, compared with blood group A (odds ratio, 0.47; 95% confidence interval, 0.23-0.95).

“To our knowledge this is the largest prospective study investigating the association between VWF, ABO blood group and ICH. We found no association between VWF or blood group O and risk of future ICH,” the researchers concluded.

The study was funded by public institutions in Sweden. The authors declared that they had no conflicts.
 

[email protected]

SOURCE: Johansson K et al. Thromb Res. 2020 Jul 5;195:77-80.

In contrast to findings of previous research, low levels of von Willebrand Factor (VWF) and blood group O were not associated with a first-ever intracerebral hemorrhage (ICH), according to a study published in Thrombosis Research.

The researchers compared 176 cases of ICH with 349 age- and sex-matched controls. The mean patient age was 57 years, and 50% were women. The median time from baseline blood sampling to the first ICH was 5.6 years, according to the study reported by Kristina Johansson of Umeå (Sweden) University and her colleagues.
 

Complicated picture

The level of VWF differed significantly among blood groups: In individuals with blood group O, the mean VWF level was 1.29 kIU/L; for blood group A, it was 1.52 kIU/L; for blood group AB, 1.59 kIU/L; and in blood group B, 1.76 kIU/L. However, there was no difference in VWF concentration between cases and controls.

The researchers found no association between blood group O and the risk of ICH, a finding previously seen in other studies. They did, however, find that, in the limited number of patients with blood group B there was an association with a lower risk of ICH, compared with blood group A (odds ratio, 0.47; 95% confidence interval, 0.23-0.95).

“To our knowledge this is the largest prospective study investigating the association between VWF, ABO blood group and ICH. We found no association between VWF or blood group O and risk of future ICH,” the researchers concluded.

The study was funded by public institutions in Sweden. The authors declared that they had no conflicts.
 

[email protected]

SOURCE: Johansson K et al. Thromb Res. 2020 Jul 5;195:77-80.

A novel biomarker could help identify progression in Parkinson’s disease, distinguish it from other neurodegenerative disorders, and monitor response to treatments. Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.

Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.

That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
 

A potential biomarker?

To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.

The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.

In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.

Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).

Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
 

More specific markers needed

The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”

The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”

The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.

SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.

A novel biomarker could help identify progression in Parkinson’s disease, distinguish it from other neurodegenerative disorders, and monitor response to treatments. Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.

Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.

That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
 

A potential biomarker?

To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.

The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.

In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.

Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).

Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
 

More specific markers needed

The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”

The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”

The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.

SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.

A novel biomarker could help identify progression in Parkinson’s disease, distinguish it from other neurodegenerative disorders, and monitor response to treatments. Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.

Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.

That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
 

A potential biomarker?

To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.

The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.

In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.

Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).

Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
 

More specific markers needed

The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”

The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”

The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.

SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.

Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.

“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.

Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.

Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).

Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).

P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.

Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).

A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.

Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.

Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”

Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?

“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.

“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”

The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.
 

Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.

“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.

Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.

Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).

Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).

P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.

Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).

A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.

Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.

Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”

Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?

“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.

“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”

The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.
 

Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.

“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.

Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.

Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).

Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).

P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.

Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).

A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.

Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.

Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”

Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?

“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.

“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”

The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.
 

Treatment with a fixed-dose combination of sodium phenylbutyrate and taurursodiol (AMX0035, Amylyx Pharmaceuticals) slows the rate of decline in physical function in patients with amyotrophic lateral sclerosis (ALS), according to results of the phase 2/3 CENTAUR study.

Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.

“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.

The study was published online Sept. 3 in the New England Journal of Medicine.

In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”

“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.

The CENTAUR trial

Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.

The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.

In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).

“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.

Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.

The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.

Open-label extension ongoing

AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.

More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.

The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.

Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
 

A cause for hope

“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.

“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.

They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.

“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.

They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”

Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.” 

The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.

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

Treatment with a fixed-dose combination of sodium phenylbutyrate and taurursodiol (AMX0035, Amylyx Pharmaceuticals) slows the rate of decline in physical function in patients with amyotrophic lateral sclerosis (ALS), according to results of the phase 2/3 CENTAUR study.

Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.

“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.

The study was published online Sept. 3 in the New England Journal of Medicine.

In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”

“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.

The CENTAUR trial

Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.

The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.

In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).

“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.

Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.

The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.

Open-label extension ongoing

AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.

More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.

The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.

Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
 

A cause for hope

“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.

“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.

They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.

“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.

They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”

Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.” 

The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.

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

Treatment with a fixed-dose combination of sodium phenylbutyrate and taurursodiol (AMX0035, Amylyx Pharmaceuticals) slows the rate of decline in physical function in patients with amyotrophic lateral sclerosis (ALS), according to results of the phase 2/3 CENTAUR study.

Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.

“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.

The study was published online Sept. 3 in the New England Journal of Medicine.

In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”

“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.

The CENTAUR trial

Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.

The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.

In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).

“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.

Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.

The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.

Open-label extension ongoing

AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.

More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.

The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.

Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
 

A cause for hope

“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.

“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.

They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.

“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.

They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”

Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.” 

The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.

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

“Nomophobia” – the fear of being without a mobile phone or out of mobile phone contact – is extremely prevalent among college students and is associated with poor sleep habits and fatigue. In a study of more than 300 college students, nearly 9 in 10 (89%) were classified as having moderate to severe nomophobia. Greater levels of nomophobia were significantly linked to daytime sleepiness and more behaviors associated with poor sleep hygiene.

“My undergraduate research team came up with the idea for this study,” said study investigator Jennifer Peszka, PhD, professor of psychology at Hendrix College, Conway, Ark. She explained that her students had been looking at the impact of technology use in the 2 hours before bed, and hypothesized that ‘cell phone addiction’ might play a role in sleep problems.

Incidentally, “that group of students were all pretty high on nomophobia themselves so they were really interested in the outcome,” Dr. Peszka said.

The study findings were presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

A likely suspect

The study involved 327 undergraduates (mean age, 19.7 years) recruited from introductory psychology courses and campus newsletters. They completed several questionnaires, including the Nomophobia Questionnaire, the Epworth Sleepiness Scale, and the Sleep Hygiene Index.

Nomophobia was prevalent, with mild, moderate, and severe nomophobia reported by 10%, 83%, and 7% of students, respectively. Only one student reported no nomophobia at all. Dr. Peszka said the fact that 89% of students had moderate or severe nomophobia is “concerning,” given a 2012 study suggesting that 77% of 18- to 24-year-olds had nomophobia. This phobia “very well may be on a rapid rise,” she lamented.

Greater severity of nomophobia was significantly correlated with greater sleepiness measured by both the Epworth Sleepiness Scale (P < .05) and the Associated Features of Poor Sleep Hygiene daytime sleepiness item (P < .05). More severe nomophobia was also related to decreased motivation (a commonly reported symptom of insufficient sleep) and with more maladaptive sleep hygiene behaviors (including using technology during sleep time, long daytime naps, inconsistent wake and bed times, using bed for nonsleep purposes, uncomfortable bed, and bedtime cognitive rumination).

Prior research has shown that smartphones may lead to compulsive “checking” habits, compulsive usage, increased distress, and potentially addictive behaviors. Active phone use at bedtime has also been implicated in disrupted sleep. Nomophobia is likely to be an important consideration when treating sleep disorders and/or making any sleep hygiene recommendations, Dr. Peszka said.
 

Proliferation of ‘night owls’

Reached for comment, Rajkumar (Raj) Dasgupta, MD, University of Southern California, Los Angeles, said this is a “very timely study with COVID-19. Right now, more than ever, technology is a double-edged sword. I’m a father of three kids and, for now, technology is the only way some kids are going to be socializing and learning.”

Yet a foundation of good sleep hygiene is keeping a nightly sleep routine, said Dr. Dasgupta, who was not involved in the study. “Right now, it seems like all my sleep patients are becoming night owls and sleep time is becoming more and more delayed because there is so much news to keep up with. Also, you may be stressed at night and you may not have the motivation to wake up early in the morning.”

He said it is important to counsel patients to “put technology away at night. That goes for kids and adults.”

Support for the study was provided by Hendrix College Charles Brewer Fund for Psychology. Dr. Peszka and Dr. Dasgupta disclosed no relevant financial relationships.

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

“Nomophobia” – the fear of being without a mobile phone or out of mobile phone contact – is extremely prevalent among college students and is associated with poor sleep habits and fatigue. In a study of more than 300 college students, nearly 9 in 10 (89%) were classified as having moderate to severe nomophobia. Greater levels of nomophobia were significantly linked to daytime sleepiness and more behaviors associated with poor sleep hygiene.

“My undergraduate research team came up with the idea for this study,” said study investigator Jennifer Peszka, PhD, professor of psychology at Hendrix College, Conway, Ark. She explained that her students had been looking at the impact of technology use in the 2 hours before bed, and hypothesized that ‘cell phone addiction’ might play a role in sleep problems.

Incidentally, “that group of students were all pretty high on nomophobia themselves so they were really interested in the outcome,” Dr. Peszka said.

The study findings were presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

A likely suspect

The study involved 327 undergraduates (mean age, 19.7 years) recruited from introductory psychology courses and campus newsletters. They completed several questionnaires, including the Nomophobia Questionnaire, the Epworth Sleepiness Scale, and the Sleep Hygiene Index.

Nomophobia was prevalent, with mild, moderate, and severe nomophobia reported by 10%, 83%, and 7% of students, respectively. Only one student reported no nomophobia at all. Dr. Peszka said the fact that 89% of students had moderate or severe nomophobia is “concerning,” given a 2012 study suggesting that 77% of 18- to 24-year-olds had nomophobia. This phobia “very well may be on a rapid rise,” she lamented.

Greater severity of nomophobia was significantly correlated with greater sleepiness measured by both the Epworth Sleepiness Scale (P < .05) and the Associated Features of Poor Sleep Hygiene daytime sleepiness item (P < .05). More severe nomophobia was also related to decreased motivation (a commonly reported symptom of insufficient sleep) and with more maladaptive sleep hygiene behaviors (including using technology during sleep time, long daytime naps, inconsistent wake and bed times, using bed for nonsleep purposes, uncomfortable bed, and bedtime cognitive rumination).

Prior research has shown that smartphones may lead to compulsive “checking” habits, compulsive usage, increased distress, and potentially addictive behaviors. Active phone use at bedtime has also been implicated in disrupted sleep. Nomophobia is likely to be an important consideration when treating sleep disorders and/or making any sleep hygiene recommendations, Dr. Peszka said.
 

Proliferation of ‘night owls’

Reached for comment, Rajkumar (Raj) Dasgupta, MD, University of Southern California, Los Angeles, said this is a “very timely study with COVID-19. Right now, more than ever, technology is a double-edged sword. I’m a father of three kids and, for now, technology is the only way some kids are going to be socializing and learning.”

Yet a foundation of good sleep hygiene is keeping a nightly sleep routine, said Dr. Dasgupta, who was not involved in the study. “Right now, it seems like all my sleep patients are becoming night owls and sleep time is becoming more and more delayed because there is so much news to keep up with. Also, you may be stressed at night and you may not have the motivation to wake up early in the morning.”

He said it is important to counsel patients to “put technology away at night. That goes for kids and adults.”

Support for the study was provided by Hendrix College Charles Brewer Fund for Psychology. Dr. Peszka and Dr. Dasgupta disclosed no relevant financial relationships.

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

“Nomophobia” – the fear of being without a mobile phone or out of mobile phone contact – is extremely prevalent among college students and is associated with poor sleep habits and fatigue. In a study of more than 300 college students, nearly 9 in 10 (89%) were classified as having moderate to severe nomophobia. Greater levels of nomophobia were significantly linked to daytime sleepiness and more behaviors associated with poor sleep hygiene.

“My undergraduate research team came up with the idea for this study,” said study investigator Jennifer Peszka, PhD, professor of psychology at Hendrix College, Conway, Ark. She explained that her students had been looking at the impact of technology use in the 2 hours before bed, and hypothesized that ‘cell phone addiction’ might play a role in sleep problems.

Incidentally, “that group of students were all pretty high on nomophobia themselves so they were really interested in the outcome,” Dr. Peszka said.

The study findings were presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

A likely suspect

The study involved 327 undergraduates (mean age, 19.7 years) recruited from introductory psychology courses and campus newsletters. They completed several questionnaires, including the Nomophobia Questionnaire, the Epworth Sleepiness Scale, and the Sleep Hygiene Index.

Nomophobia was prevalent, with mild, moderate, and severe nomophobia reported by 10%, 83%, and 7% of students, respectively. Only one student reported no nomophobia at all. Dr. Peszka said the fact that 89% of students had moderate or severe nomophobia is “concerning,” given a 2012 study suggesting that 77% of 18- to 24-year-olds had nomophobia. This phobia “very well may be on a rapid rise,” she lamented.

Greater severity of nomophobia was significantly correlated with greater sleepiness measured by both the Epworth Sleepiness Scale (P < .05) and the Associated Features of Poor Sleep Hygiene daytime sleepiness item (P < .05). More severe nomophobia was also related to decreased motivation (a commonly reported symptom of insufficient sleep) and with more maladaptive sleep hygiene behaviors (including using technology during sleep time, long daytime naps, inconsistent wake and bed times, using bed for nonsleep purposes, uncomfortable bed, and bedtime cognitive rumination).

Prior research has shown that smartphones may lead to compulsive “checking” habits, compulsive usage, increased distress, and potentially addictive behaviors. Active phone use at bedtime has also been implicated in disrupted sleep. Nomophobia is likely to be an important consideration when treating sleep disorders and/or making any sleep hygiene recommendations, Dr. Peszka said.
 

Proliferation of ‘night owls’

Reached for comment, Rajkumar (Raj) Dasgupta, MD, University of Southern California, Los Angeles, said this is a “very timely study with COVID-19. Right now, more than ever, technology is a double-edged sword. I’m a father of three kids and, for now, technology is the only way some kids are going to be socializing and learning.”

Yet a foundation of good sleep hygiene is keeping a nightly sleep routine, said Dr. Dasgupta, who was not involved in the study. “Right now, it seems like all my sleep patients are becoming night owls and sleep time is becoming more and more delayed because there is so much news to keep up with. Also, you may be stressed at night and you may not have the motivation to wake up early in the morning.”

He said it is important to counsel patients to “put technology away at night. That goes for kids and adults.”

Support for the study was provided by Hendrix College Charles Brewer Fund for Psychology. Dr. Peszka and Dr. Dasgupta disclosed no relevant financial relationships.

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

In the interest of public health and safety, the American Academy of Sleep Medicine (AASM) is calling for the elimination of daylight saving time in favor of permanent year-round standard time – a recommendation that has garnered strong support from multiple medical and other high-profile organizations.

“Permanent, year-round standard time is the best choice to most closely match our circadian sleep-wake cycle,” M. Adeel Rishi, MD, lead author of the AASM position statement, said in a news release. “Daylight saving time results in more darkness in the morning and more light in the evening, disrupting the body’s natural rhythm,” said Dr. Rishi, of the department of pulmonology, critical care, and sleep medicine, Mayo Clinic, Eau Claire, Wis., and vice chair of the AASM Public Safety Committee.

The position statement was published Aug. 26 in the Journal of Clinical Sleep Medicine to coincide with the virtual annual meeting of the Associated Professional Sleep Societies .
 

Significant health risks

In the United States, the annual “spring forward” to daylight saving time and “fall back” to standard time is required by law, although under the statute some exceptions are permitted.

There has been intense debate over the last several years about transitioning between standard and daylight saving time. The AASM says there is “an abundance of evidence” to indicate that quick transition from standard time to daylight saving time incurs significant public health and safety risks, including increased risk of heart attack, stroke, mood disorders, and car crashes.

“Although chronic effects of remaining in daylight saving time year-round have not been well-studied, daylight saving time is less aligned with human circadian biology – which, because of the impacts of the delayed natural light/dark cycle on human activity, could result in circadian misalignment, which has been associated in some studies with increased cardiovascular disease risk, metabolic syndrome and other health risks,” the authors wrote.

A recent study also showed an increase in medical errors in the week after switching to daylight saving time.

“Because the adoption of permanent standard time would be beneficial for public health and safety, the AASM will be advocating at the federal level for this legislative change,” said AASM President Kannan Ramar, MBBS, MD, with the Mayo Clinic in Rochester, Minn.

It seems that many Americans are in favor of the change. In July, an AASM survey of roughly 2,000 U.S. adults showed that two-thirds support doing away with the seasonal time change. Only 11% opposed it. In addition, the academy’s 2019 survey showed more than half of adults feel extremely, or somewhat, tired after the springing ahead to daylight saving time.

Strong support

The position statement has been endorsed by 19 organizations, including the American Academy of Cardiovascular Sleep Medicine, American College of Chest Physicians (CHEST), American College of Occupational and Environmental Medicine, National PTA, National Safety Council, Society of Anesthesia and Sleep Medicine, and the Society of Behavioral Sleep Medicine.

Weighing in on the issue, Saul Rothenberg, PhD, from the Sleep Center at Greenwich Hospital, Conn., said the literature on daylight saving time has grown over the past 20 years. He said he was ”humbled” by the research that shows that a “relatively small” misalignment of biological and social clocks has a measurable impact on human health and behavior.

“Because misalignment is associated with negative health and performance outcomes, keeping one set of hours year-round is promoted to minimize misalignment and associated consequences,” he added.

In light of this research, the recommendation to dispense with daylight saving time seems “quite reasonable” from a public health perspective. “I am left with a strengthened view on the importance of regular adequate sleep as a way to enhance health, performance, and quality of life,” he added.

This research had no commercial funding. Dr. Rishi and Dr. Rothenberg have disclosed no relevant financial relationships.

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

In the interest of public health and safety, the American Academy of Sleep Medicine (AASM) is calling for the elimination of daylight saving time in favor of permanent year-round standard time – a recommendation that has garnered strong support from multiple medical and other high-profile organizations.

“Permanent, year-round standard time is the best choice to most closely match our circadian sleep-wake cycle,” M. Adeel Rishi, MD, lead author of the AASM position statement, said in a news release. “Daylight saving time results in more darkness in the morning and more light in the evening, disrupting the body’s natural rhythm,” said Dr. Rishi, of the department of pulmonology, critical care, and sleep medicine, Mayo Clinic, Eau Claire, Wis., and vice chair of the AASM Public Safety Committee.

The position statement was published Aug. 26 in the Journal of Clinical Sleep Medicine to coincide with the virtual annual meeting of the Associated Professional Sleep Societies .
 

Significant health risks

In the United States, the annual “spring forward” to daylight saving time and “fall back” to standard time is required by law, although under the statute some exceptions are permitted.

There has been intense debate over the last several years about transitioning between standard and daylight saving time. The AASM says there is “an abundance of evidence” to indicate that quick transition from standard time to daylight saving time incurs significant public health and safety risks, including increased risk of heart attack, stroke, mood disorders, and car crashes.

“Although chronic effects of remaining in daylight saving time year-round have not been well-studied, daylight saving time is less aligned with human circadian biology – which, because of the impacts of the delayed natural light/dark cycle on human activity, could result in circadian misalignment, which has been associated in some studies with increased cardiovascular disease risk, metabolic syndrome and other health risks,” the authors wrote.

A recent study also showed an increase in medical errors in the week after switching to daylight saving time.

“Because the adoption of permanent standard time would be beneficial for public health and safety, the AASM will be advocating at the federal level for this legislative change,” said AASM President Kannan Ramar, MBBS, MD, with the Mayo Clinic in Rochester, Minn.

It seems that many Americans are in favor of the change. In July, an AASM survey of roughly 2,000 U.S. adults showed that two-thirds support doing away with the seasonal time change. Only 11% opposed it. In addition, the academy’s 2019 survey showed more than half of adults feel extremely, or somewhat, tired after the springing ahead to daylight saving time.

Strong support

The position statement has been endorsed by 19 organizations, including the American Academy of Cardiovascular Sleep Medicine, American College of Chest Physicians (CHEST), American College of Occupational and Environmental Medicine, National PTA, National Safety Council, Society of Anesthesia and Sleep Medicine, and the Society of Behavioral Sleep Medicine.

Weighing in on the issue, Saul Rothenberg, PhD, from the Sleep Center at Greenwich Hospital, Conn., said the literature on daylight saving time has grown over the past 20 years. He said he was ”humbled” by the research that shows that a “relatively small” misalignment of biological and social clocks has a measurable impact on human health and behavior.

“Because misalignment is associated with negative health and performance outcomes, keeping one set of hours year-round is promoted to minimize misalignment and associated consequences,” he added.

In light of this research, the recommendation to dispense with daylight saving time seems “quite reasonable” from a public health perspective. “I am left with a strengthened view on the importance of regular adequate sleep as a way to enhance health, performance, and quality of life,” he added.

This research had no commercial funding. Dr. Rishi and Dr. Rothenberg have disclosed no relevant financial relationships.

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

In the interest of public health and safety, the American Academy of Sleep Medicine (AASM) is calling for the elimination of daylight saving time in favor of permanent year-round standard time – a recommendation that has garnered strong support from multiple medical and other high-profile organizations.

“Permanent, year-round standard time is the best choice to most closely match our circadian sleep-wake cycle,” M. Adeel Rishi, MD, lead author of the AASM position statement, said in a news release. “Daylight saving time results in more darkness in the morning and more light in the evening, disrupting the body’s natural rhythm,” said Dr. Rishi, of the department of pulmonology, critical care, and sleep medicine, Mayo Clinic, Eau Claire, Wis., and vice chair of the AASM Public Safety Committee.

The position statement was published Aug. 26 in the Journal of Clinical Sleep Medicine to coincide with the virtual annual meeting of the Associated Professional Sleep Societies .
 

Significant health risks

In the United States, the annual “spring forward” to daylight saving time and “fall back” to standard time is required by law, although under the statute some exceptions are permitted.

There has been intense debate over the last several years about transitioning between standard and daylight saving time. The AASM says there is “an abundance of evidence” to indicate that quick transition from standard time to daylight saving time incurs significant public health and safety risks, including increased risk of heart attack, stroke, mood disorders, and car crashes.

“Although chronic effects of remaining in daylight saving time year-round have not been well-studied, daylight saving time is less aligned with human circadian biology – which, because of the impacts of the delayed natural light/dark cycle on human activity, could result in circadian misalignment, which has been associated in some studies with increased cardiovascular disease risk, metabolic syndrome and other health risks,” the authors wrote.

A recent study also showed an increase in medical errors in the week after switching to daylight saving time.

“Because the adoption of permanent standard time would be beneficial for public health and safety, the AASM will be advocating at the federal level for this legislative change,” said AASM President Kannan Ramar, MBBS, MD, with the Mayo Clinic in Rochester, Minn.

It seems that many Americans are in favor of the change. In July, an AASM survey of roughly 2,000 U.S. adults showed that two-thirds support doing away with the seasonal time change. Only 11% opposed it. In addition, the academy’s 2019 survey showed more than half of adults feel extremely, or somewhat, tired after the springing ahead to daylight saving time.

Strong support

The position statement has been endorsed by 19 organizations, including the American Academy of Cardiovascular Sleep Medicine, American College of Chest Physicians (CHEST), American College of Occupational and Environmental Medicine, National PTA, National Safety Council, Society of Anesthesia and Sleep Medicine, and the Society of Behavioral Sleep Medicine.

Weighing in on the issue, Saul Rothenberg, PhD, from the Sleep Center at Greenwich Hospital, Conn., said the literature on daylight saving time has grown over the past 20 years. He said he was ”humbled” by the research that shows that a “relatively small” misalignment of biological and social clocks has a measurable impact on human health and behavior.

“Because misalignment is associated with negative health and performance outcomes, keeping one set of hours year-round is promoted to minimize misalignment and associated consequences,” he added.

In light of this research, the recommendation to dispense with daylight saving time seems “quite reasonable” from a public health perspective. “I am left with a strengthened view on the importance of regular adequate sleep as a way to enhance health, performance, and quality of life,” he added.

This research had no commercial funding. Dr. Rishi and Dr. Rothenberg have disclosed no relevant financial relationships.

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

Two plasma biomarkers were notably associated with when athletes return to action after concussions, according to a new study of collegiate athletes and recovery time. “Although preliminary, the current results highlight the potential role of biomarkers in tracking neuronal recovery, which may be associated with duration of [return to sport],” wrote Cassandra L. Pattinson, PhD, of the University of Queensland, Brisbane, Australia, and the National Institutes of Health, Bethesda, Md., along with coauthors. The study was published in JAMA Network Open.

To determine if three specific blood biomarkers – total tau protein, glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL) – can help predict when athletes should return from sports-related concussions, a multicenter, prospective diagnostic study was launched and led by the Advanced Research Core (ARC) of the Concussion Assessment, Research, and Education (CARE) Consortium. The consortium is a joint effort of the National Collegiate Athletics Association (NCAA) and the U.S. Department of Defense.

From among the CARE ARC database, researchers evaluated 127 eligible student athletes who had experienced a sports-related concussion, underwent clinical testing and blood collection before and after their injuries, and returned to their sports. Their average age was 18.9 years old, 76% were men, and 65% were White. Biomarker levels were measured from nonfasting blood samples via ultrasensitive single molecule array technology. As current NCAA guidelines indicate that most athletes will be asymptomatic roughly 2 weeks after a concussion, the study used 14 days as a cutoff period.

Among the 127 athletes, the median return-to-sport time was 14 days; 65 returned to their sports in less than 14 days while 62 returned to their sports in 14 days or more. According to the study’s linear mixed models, athletes with a return-to-sport time of 14 days or longer had significantly higher total tau levels at 24-48 hours post injury (mean difference –0.51 pg/mL, 95% confidence interval, –0.88 to –0.14; P  = .008) and when symptoms had resolved (mean difference –0.71 pg/mL, 95% CI, –1.09 to –0.34; P < .001) compared with athletes with a return-to-sport time of less than 14 days. Athletes who returned in 14 days or more also had comparatively lower levels of GFAP postinjury than did those who returned in under 14 days (4.39 pg/mL versus 4.72 pg/mL; P = .04).
 

Preliminary steps toward an appropriate point-of-care test

“This particular study is one of several emerging studies on what these biomarkers look like,” Brian W. Hainline, MD, chief medical officer of the NCAA, said in an interview. “It’s all still very preliminary – you couldn’t make policy changes based on what we have – but the data is accumulating. Ultimately, we should be able to perform a multivariate analysis of all the different objective biomarkers, looking at repetitive head impact exposure, looking at imaging, looking at these blood-based biomarkers. Then you can say, ‘OK, what can we do? Can we actually predict recovery, who is likely or less likely to do well?’ ”

“It’s not realistic to be taking blood samples all the time,” said Dr. Hainline, who was not involved in the study. “Another goal, once we know which biomarkers are valuable, is to convert to a point-of-care test. You get a finger prick or even a salivary test and we get the result immediately; that’s the direction that all of this is heading. But first, we have to lay out the groundwork. We envision a day, in the not too distant future, where we can get this information much more quickly.”

The authors acknowledged their study’s limitations, including an inability to standardize the time of biomarker collection and the fact that they analyzed a “relatively small number of athletes” who met their specific criteria. That said, they emphasized that their work is based on “the largest prospective sample of sports-related concussions in athletes to date” and that they “anticipate that we will be able to continue to gather a more representative sample” in the future to better generalize to the larger collegiate community.

The study was supported by the Grand Alliance Concussion Assessment, Research, and Education Consortium, which was funded in part by the NCAA and the Department of Defense. The authors disclosed receiving grants and travel reimbursements from – or working as advisers or consultants for – various organizations, college programs, and sports leagues.

SOURCE: Pattinson CL, et al. JAMA Netw Open. 2020 Aug 27. doi: 10.1001/jamanetworkopen.2020.13191.

Two plasma biomarkers were notably associated with when athletes return to action after concussions, according to a new study of collegiate athletes and recovery time. “Although preliminary, the current results highlight the potential role of biomarkers in tracking neuronal recovery, which may be associated with duration of [return to sport],” wrote Cassandra L. Pattinson, PhD, of the University of Queensland, Brisbane, Australia, and the National Institutes of Health, Bethesda, Md., along with coauthors. The study was published in JAMA Network Open.

To determine if three specific blood biomarkers – total tau protein, glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL) – can help predict when athletes should return from sports-related concussions, a multicenter, prospective diagnostic study was launched and led by the Advanced Research Core (ARC) of the Concussion Assessment, Research, and Education (CARE) Consortium. The consortium is a joint effort of the National Collegiate Athletics Association (NCAA) and the U.S. Department of Defense.

From among the CARE ARC database, researchers evaluated 127 eligible student athletes who had experienced a sports-related concussion, underwent clinical testing and blood collection before and after their injuries, and returned to their sports. Their average age was 18.9 years old, 76% were men, and 65% were White. Biomarker levels were measured from nonfasting blood samples via ultrasensitive single molecule array technology. As current NCAA guidelines indicate that most athletes will be asymptomatic roughly 2 weeks after a concussion, the study used 14 days as a cutoff period.

Among the 127 athletes, the median return-to-sport time was 14 days; 65 returned to their sports in less than 14 days while 62 returned to their sports in 14 days or more. According to the study’s linear mixed models, athletes with a return-to-sport time of 14 days or longer had significantly higher total tau levels at 24-48 hours post injury (mean difference –0.51 pg/mL, 95% confidence interval, –0.88 to –0.14; P  = .008) and when symptoms had resolved (mean difference –0.71 pg/mL, 95% CI, –1.09 to –0.34; P < .001) compared with athletes with a return-to-sport time of less than 14 days. Athletes who returned in 14 days or more also had comparatively lower levels of GFAP postinjury than did those who returned in under 14 days (4.39 pg/mL versus 4.72 pg/mL; P = .04).
 

Preliminary steps toward an appropriate point-of-care test

“This particular study is one of several emerging studies on what these biomarkers look like,” Brian W. Hainline, MD, chief medical officer of the NCAA, said in an interview. “It’s all still very preliminary – you couldn’t make policy changes based on what we have – but the data is accumulating. Ultimately, we should be able to perform a multivariate analysis of all the different objective biomarkers, looking at repetitive head impact exposure, looking at imaging, looking at these blood-based biomarkers. Then you can say, ‘OK, what can we do? Can we actually predict recovery, who is likely or less likely to do well?’ ”

“It’s not realistic to be taking blood samples all the time,” said Dr. Hainline, who was not involved in the study. “Another goal, once we know which biomarkers are valuable, is to convert to a point-of-care test. You get a finger prick or even a salivary test and we get the result immediately; that’s the direction that all of this is heading. But first, we have to lay out the groundwork. We envision a day, in the not too distant future, where we can get this information much more quickly.”

The authors acknowledged their study’s limitations, including an inability to standardize the time of biomarker collection and the fact that they analyzed a “relatively small number of athletes” who met their specific criteria. That said, they emphasized that their work is based on “the largest prospective sample of sports-related concussions in athletes to date” and that they “anticipate that we will be able to continue to gather a more representative sample” in the future to better generalize to the larger collegiate community.

The study was supported by the Grand Alliance Concussion Assessment, Research, and Education Consortium, which was funded in part by the NCAA and the Department of Defense. The authors disclosed receiving grants and travel reimbursements from – or working as advisers or consultants for – various organizations, college programs, and sports leagues.

SOURCE: Pattinson CL, et al. JAMA Netw Open. 2020 Aug 27. doi: 10.1001/jamanetworkopen.2020.13191.

Two plasma biomarkers were notably associated with when athletes return to action after concussions, according to a new study of collegiate athletes and recovery time. “Although preliminary, the current results highlight the potential role of biomarkers in tracking neuronal recovery, which may be associated with duration of [return to sport],” wrote Cassandra L. Pattinson, PhD, of the University of Queensland, Brisbane, Australia, and the National Institutes of Health, Bethesda, Md., along with coauthors. The study was published in JAMA Network Open.

To determine if three specific blood biomarkers – total tau protein, glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL) – can help predict when athletes should return from sports-related concussions, a multicenter, prospective diagnostic study was launched and led by the Advanced Research Core (ARC) of the Concussion Assessment, Research, and Education (CARE) Consortium. The consortium is a joint effort of the National Collegiate Athletics Association (NCAA) and the U.S. Department of Defense.

From among the CARE ARC database, researchers evaluated 127 eligible student athletes who had experienced a sports-related concussion, underwent clinical testing and blood collection before and after their injuries, and returned to their sports. Their average age was 18.9 years old, 76% were men, and 65% were White. Biomarker levels were measured from nonfasting blood samples via ultrasensitive single molecule array technology. As current NCAA guidelines indicate that most athletes will be asymptomatic roughly 2 weeks after a concussion, the study used 14 days as a cutoff period.

Among the 127 athletes, the median return-to-sport time was 14 days; 65 returned to their sports in less than 14 days while 62 returned to their sports in 14 days or more. According to the study’s linear mixed models, athletes with a return-to-sport time of 14 days or longer had significantly higher total tau levels at 24-48 hours post injury (mean difference –0.51 pg/mL, 95% confidence interval, –0.88 to –0.14; P  = .008) and when symptoms had resolved (mean difference –0.71 pg/mL, 95% CI, –1.09 to –0.34; P < .001) compared with athletes with a return-to-sport time of less than 14 days. Athletes who returned in 14 days or more also had comparatively lower levels of GFAP postinjury than did those who returned in under 14 days (4.39 pg/mL versus 4.72 pg/mL; P = .04).
 

Preliminary steps toward an appropriate point-of-care test

“This particular study is one of several emerging studies on what these biomarkers look like,” Brian W. Hainline, MD, chief medical officer of the NCAA, said in an interview. “It’s all still very preliminary – you couldn’t make policy changes based on what we have – but the data is accumulating. Ultimately, we should be able to perform a multivariate analysis of all the different objective biomarkers, looking at repetitive head impact exposure, looking at imaging, looking at these blood-based biomarkers. Then you can say, ‘OK, what can we do? Can we actually predict recovery, who is likely or less likely to do well?’ ”

“It’s not realistic to be taking blood samples all the time,” said Dr. Hainline, who was not involved in the study. “Another goal, once we know which biomarkers are valuable, is to convert to a point-of-care test. You get a finger prick or even a salivary test and we get the result immediately; that’s the direction that all of this is heading. But first, we have to lay out the groundwork. We envision a day, in the not too distant future, where we can get this information much more quickly.”

The authors acknowledged their study’s limitations, including an inability to standardize the time of biomarker collection and the fact that they analyzed a “relatively small number of athletes” who met their specific criteria. That said, they emphasized that their work is based on “the largest prospective sample of sports-related concussions in athletes to date” and that they “anticipate that we will be able to continue to gather a more representative sample” in the future to better generalize to the larger collegiate community.

The study was supported by the Grand Alliance Concussion Assessment, Research, and Education Consortium, which was funded in part by the NCAA and the Department of Defense. The authors disclosed receiving grants and travel reimbursements from – or working as advisers or consultants for – various organizations, college programs, and sports leagues.

SOURCE: Pattinson CL, et al. JAMA Netw Open. 2020 Aug 27. doi: 10.1001/jamanetworkopen.2020.13191.

SSRIs effectively treat depression following intracerebral hemorrhage (ICH) but also increase risk for recurrent hemorrhagic stroke, particularly in patients at high risk for repeat ICH, new research indicates.

“Clinicians must exercise judgment when weighing the use of SSRIs for ICH survivors in the high risk category – especially those with multiple ICH events,” study investigator Alessandro Biffi, MD, director, Aging and Brain Health Research (ABHR) Group, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News.

The study was published online August 31 in JAMA Neurology.
 

Risks and benefits

Depression is common following stroke. SSRIs are generally considered first-line treatment for post-stroke depression but are associated with increased risk for first ICH, most likely owing to their antithrombotic effects. Less is known about SSRI use and recurrent ICH risk.

To investigate, Biffi and colleagues followed 1,279 adults (mean age, 71.3 years) for a median of 53.2 months (4.5 years) following primary ICH; 602 were women, 1049 were White, 89 Black, 77 Hispanic, and 64 were other race/ethnicity.

During follow-up, 128 adults suffered recurrent ICH (annual rate, 4.2%) and 766 (60%) were diagnosed with depression.

In multivariable analyses, SSRIs were associated with an increased likelihood of post-ICH depression remission (subhazard ratio, 1.53; 95% CI, 1.12-2.09; P = .009).

However, SSRI use was also an independent risk factor for recurrent ICH (SHR, 1.31; 95% CI, 1.08-1.59; P = .006).

High SSRI dose was associated with higher ICH recurrence risk (SHR, 1.61; 95% CI, 1.15-2.25), with a larger effect size (comparison P = .02) than low SSRI dose (SHR, 1.25; 95% CI, 1.01-1.55), but there was no difference in depression remission comparing low vs. high SSRI dose.

Among individuals at high risk for recurrent ICH, SSRI use was associated with further increased risk for ICH recurrence (SHR, 1.79; 95% CI, 1.22 - 2.64) compared with all other survivors of ICH (SHR, 1.20; 95% CI, 1.01-1.42; P = .008 for comparison of effect sizes).

These higher-risk subgroups included carriers of the APOE e2/e4 alleles, patients with lobar ICH, patients with prior ICH, and minority participants.

“Our analyses identified patients for whom the risks are higher, and therefore additional thought is warranted. This approach may in the future lead to personalized/precision medicine approaches to determining whether these patients should receive SSRIs or not,” said Biffi.
 

Experts weigh in

Commenting on the research for Medscape Medical News, Daniel G. Hackam, MD, division of clinical pharmacology, Western University, London, Ont., said the study is “an important contribution to the literature, as there are to date no data on the risk of ICH in prior ICH survivors in relation to SSRI exposure.”

“The bottom line is that I would be very cautious about initiating SSRIs in patients with a history of ICH,” said Hackam, who was not involved with the study.

“There are other nonserotonergic antidepressants that could be used instead, which do not inhibit platelet function. There was still a risk even in the lower-risk ICH survivors. ICH is a highly recurrent disease. We already avoid antiplatelets, anticoagulants, and high dose statins in these patients. I would add SSRI’s to that list, based on this study,” said Hackam.

Also weighing in, Amytis Towfighi, MD, associate professor of neurology, University of Southern California, Los Angeles, said this study addresses a “common clinical dilemma: how to manage depression among individuals with ICH, given the high risk of recurrent ICH among ICH survivors and potential for SSRIs to increase that risk. This scenario is common, and a source of debate for practicing clinicians.”

“The authors conducted an elegant study,” said Towfighi, by considering sociodemographic, historical, imaging, and genetic factors.

“One must interpret this study with caution as it is a single-center cohort study. However, it provides the most rigorous information to date regarding the associations between SSRI use and recurrent ICH,” she told Medscape Medical News.

The study was supported by the National Institutes of Health. Biffi, Hackam, and Towfighi have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

SSRIs effectively treat depression following intracerebral hemorrhage (ICH) but also increase risk for recurrent hemorrhagic stroke, particularly in patients at high risk for repeat ICH, new research indicates.

“Clinicians must exercise judgment when weighing the use of SSRIs for ICH survivors in the high risk category – especially those with multiple ICH events,” study investigator Alessandro Biffi, MD, director, Aging and Brain Health Research (ABHR) Group, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News.

The study was published online August 31 in JAMA Neurology.
 

Risks and benefits

Depression is common following stroke. SSRIs are generally considered first-line treatment for post-stroke depression but are associated with increased risk for first ICH, most likely owing to their antithrombotic effects. Less is known about SSRI use and recurrent ICH risk.

To investigate, Biffi and colleagues followed 1,279 adults (mean age, 71.3 years) for a median of 53.2 months (4.5 years) following primary ICH; 602 were women, 1049 were White, 89 Black, 77 Hispanic, and 64 were other race/ethnicity.

During follow-up, 128 adults suffered recurrent ICH (annual rate, 4.2%) and 766 (60%) were diagnosed with depression.

In multivariable analyses, SSRIs were associated with an increased likelihood of post-ICH depression remission (subhazard ratio, 1.53; 95% CI, 1.12-2.09; P = .009).

However, SSRI use was also an independent risk factor for recurrent ICH (SHR, 1.31; 95% CI, 1.08-1.59; P = .006).

High SSRI dose was associated with higher ICH recurrence risk (SHR, 1.61; 95% CI, 1.15-2.25), with a larger effect size (comparison P = .02) than low SSRI dose (SHR, 1.25; 95% CI, 1.01-1.55), but there was no difference in depression remission comparing low vs. high SSRI dose.

Among individuals at high risk for recurrent ICH, SSRI use was associated with further increased risk for ICH recurrence (SHR, 1.79; 95% CI, 1.22 - 2.64) compared with all other survivors of ICH (SHR, 1.20; 95% CI, 1.01-1.42; P = .008 for comparison of effect sizes).

These higher-risk subgroups included carriers of the APOE e2/e4 alleles, patients with lobar ICH, patients with prior ICH, and minority participants.

“Our analyses identified patients for whom the risks are higher, and therefore additional thought is warranted. This approach may in the future lead to personalized/precision medicine approaches to determining whether these patients should receive SSRIs or not,” said Biffi.
 

Experts weigh in

Commenting on the research for Medscape Medical News, Daniel G. Hackam, MD, division of clinical pharmacology, Western University, London, Ont., said the study is “an important contribution to the literature, as there are to date no data on the risk of ICH in prior ICH survivors in relation to SSRI exposure.”

“The bottom line is that I would be very cautious about initiating SSRIs in patients with a history of ICH,” said Hackam, who was not involved with the study.

“There are other nonserotonergic antidepressants that could be used instead, which do not inhibit platelet function. There was still a risk even in the lower-risk ICH survivors. ICH is a highly recurrent disease. We already avoid antiplatelets, anticoagulants, and high dose statins in these patients. I would add SSRI’s to that list, based on this study,” said Hackam.

Also weighing in, Amytis Towfighi, MD, associate professor of neurology, University of Southern California, Los Angeles, said this study addresses a “common clinical dilemma: how to manage depression among individuals with ICH, given the high risk of recurrent ICH among ICH survivors and potential for SSRIs to increase that risk. This scenario is common, and a source of debate for practicing clinicians.”

“The authors conducted an elegant study,” said Towfighi, by considering sociodemographic, historical, imaging, and genetic factors.

“One must interpret this study with caution as it is a single-center cohort study. However, it provides the most rigorous information to date regarding the associations between SSRI use and recurrent ICH,” she told Medscape Medical News.

The study was supported by the National Institutes of Health. Biffi, Hackam, and Towfighi have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

SSRIs effectively treat depression following intracerebral hemorrhage (ICH) but also increase risk for recurrent hemorrhagic stroke, particularly in patients at high risk for repeat ICH, new research indicates.

“Clinicians must exercise judgment when weighing the use of SSRIs for ICH survivors in the high risk category – especially those with multiple ICH events,” study investigator Alessandro Biffi, MD, director, Aging and Brain Health Research (ABHR) Group, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News.

The study was published online August 31 in JAMA Neurology.
 

Risks and benefits

Depression is common following stroke. SSRIs are generally considered first-line treatment for post-stroke depression but are associated with increased risk for first ICH, most likely owing to their antithrombotic effects. Less is known about SSRI use and recurrent ICH risk.

To investigate, Biffi and colleagues followed 1,279 adults (mean age, 71.3 years) for a median of 53.2 months (4.5 years) following primary ICH; 602 were women, 1049 were White, 89 Black, 77 Hispanic, and 64 were other race/ethnicity.

During follow-up, 128 adults suffered recurrent ICH (annual rate, 4.2%) and 766 (60%) were diagnosed with depression.

In multivariable analyses, SSRIs were associated with an increased likelihood of post-ICH depression remission (subhazard ratio, 1.53; 95% CI, 1.12-2.09; P = .009).

However, SSRI use was also an independent risk factor for recurrent ICH (SHR, 1.31; 95% CI, 1.08-1.59; P = .006).

High SSRI dose was associated with higher ICH recurrence risk (SHR, 1.61; 95% CI, 1.15-2.25), with a larger effect size (comparison P = .02) than low SSRI dose (SHR, 1.25; 95% CI, 1.01-1.55), but there was no difference in depression remission comparing low vs. high SSRI dose.

Among individuals at high risk for recurrent ICH, SSRI use was associated with further increased risk for ICH recurrence (SHR, 1.79; 95% CI, 1.22 - 2.64) compared with all other survivors of ICH (SHR, 1.20; 95% CI, 1.01-1.42; P = .008 for comparison of effect sizes).

These higher-risk subgroups included carriers of the APOE e2/e4 alleles, patients with lobar ICH, patients with prior ICH, and minority participants.

“Our analyses identified patients for whom the risks are higher, and therefore additional thought is warranted. This approach may in the future lead to personalized/precision medicine approaches to determining whether these patients should receive SSRIs or not,” said Biffi.
 

Experts weigh in

Commenting on the research for Medscape Medical News, Daniel G. Hackam, MD, division of clinical pharmacology, Western University, London, Ont., said the study is “an important contribution to the literature, as there are to date no data on the risk of ICH in prior ICH survivors in relation to SSRI exposure.”

“The bottom line is that I would be very cautious about initiating SSRIs in patients with a history of ICH,” said Hackam, who was not involved with the study.

“There are other nonserotonergic antidepressants that could be used instead, which do not inhibit platelet function. There was still a risk even in the lower-risk ICH survivors. ICH is a highly recurrent disease. We already avoid antiplatelets, anticoagulants, and high dose statins in these patients. I would add SSRI’s to that list, based on this study,” said Hackam.

Also weighing in, Amytis Towfighi, MD, associate professor of neurology, University of Southern California, Los Angeles, said this study addresses a “common clinical dilemma: how to manage depression among individuals with ICH, given the high risk of recurrent ICH among ICH survivors and potential for SSRIs to increase that risk. This scenario is common, and a source of debate for practicing clinicians.”

“The authors conducted an elegant study,” said Towfighi, by considering sociodemographic, historical, imaging, and genetic factors.

“One must interpret this study with caution as it is a single-center cohort study. However, it provides the most rigorous information to date regarding the associations between SSRI use and recurrent ICH,” she told Medscape Medical News.

The study was supported by the National Institutes of Health. Biffi, Hackam, and Towfighi have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A significant proportion of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia may have potentially treatable underlying autoimmune-associated small-fiber polyneuropathy (aaSFPN), pilot data suggest.

The findings, from a single-site study of 61 patients with ME/CFS, were presented August 21 at the virtual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis by Ryan Whelan, BS, a research assistant at Simmaron Research Institute, Incline Village, Nevada.

Recent evidence suggests an autoimmune etiology for some patients with ME/CFS, which is defined as experiencing for a period of at least 6 months profound, unexplained fatigue, postexertional malaise, and unrefreshing sleep, as well as cognitive dysfunction and/or orthostatic intolerance (OI).

OI is part of a spectrum of autonomic dysfunction commonly seen in ME/CFS patients, which may also include postural orthostatic tachycardia (POTS), peripheral temperature dysregulation and light sensitivity, neuropathic pain, and gastrointestinal complaints. Many of these symptoms overlap those reported by patients with aaSFPN, a common but underdiagnosed neurodegenerative disorder characterized by the loss of peripheral autonomic nerve fibers, Whelan explained.

Findings from the current study show that in more than half of ME/CFS patients, levels of at least one autoantibody were elevated. A majority had comorbid POTS or OI, and over a third had biopsy-confirmed aaSFPN.

“Given the overlap of symptoms and common etiological basis, it may be important to identify ME/CFS patients who present with comorbid aaSFPN, as it has been shown that immune modulatory agents, including intravenous gamma globulin [IVIG], reduce the autonomic symptom burden in aaSFPN patients,” Whelan said.

He noted that Anne Louise Oaklander, MD, a neurologist at Massachusetts General Hospital, Harvard Medical School, Boston, and colleagues previously linked aaSFPN with fibromyalgia. In addition, they’ve found a connection between small-fiber dysfunction and postexertional malaise, which is a hallmark ME/CFS symptom.

Asked to comment on Whelan’s presentation, IACFSME co-president Lily Chu, MD, told Medscape Medical News that the new findings are “valuable, because ME/CFS has always been looked upon as just subjective symptoms. When people have laboratory abnormalities, it can be due to a bunch of other causes, but...here’s pathology, here’s a biopsy of actual damage. It’s not just a transient finding. You can actually see it. ... It’s a solid concrete piece of evidence vs something that can fluctuate.”

Autoantibodies, Autonomic Dysfunction, and Small-Fiber Polyneuropathy

Whelan and colleagues conducted an extensive analysis of medical records of 364 patients with ME/CFS (72% female) to identify potential aaSFPN comorbidity. Such identifications were made on the basis of progress notes documenting autonomic dysfunction, laboratory results for serum autoantibodies, and questionnaire symptom self-reports.

They identified 61 patients as possibly having comorbid aaSFPN. Of those, 52% tested positive for at least 1 of 4 autoantibodies, including antimuscarinic cholinergic receptor 4 (47%), anti-beta-2 adrenergic (27%), antimuscarinic cholinergic 3 (25%), and anti-beta-1 adrenergic (13%). These autoantibodies were linked to ME/CFS in a recent Swedish cohort study.

“Evidence supports that these autoantibodies may bind to receptor sites, blocking ligands from reaching these receptors. Disturbances of adrenergic and cholinergic receptors by these autoantibodies may contribute to symptoms of autonomic dysfunction in ME/CFS,” Whelan said.

Although 22% of patients in the study group had POTS and 59% had OI, the authors found no correlation between autoantibody levels and either OI or POTS. However, 38% were confirmed to have small-fiber polyneuropathy on skin biopsy, and the vast majority of those patients (93%) had either POTS or OI.

IVIG May Be a Potential Treatment

Whelan notes that some data suggest that IVIG might help patients with small-fiber neuropathy, including those with autoimmunity.

In addition, he described anecdotal data from a single patient with ME/CFS who had neuropathic symptoms. The patient was treated at Simmaron. The 56-year-old received two IVIG infusions given 6 months apart. The patient experienced a dramatic reduction in levels of all four of the relevant autoantibodies and favorable symptom reduction, as shown in clinician follow-up records. “With the success of this case study, we intend to further evaluate IVIG as a potential treatment in ME/CFS patients. With this research, we hope to identify a subset of ME/CFS patients who will respond favorably to IVIG,” Whelan concluded.

Regarding use of IVIG, Chu commented, “We don’t know exactly how it works, but it seems to help certain conditions.” She pointed to another recent small study that reported clinical improvement in patients with ME/CFS through a different approach, immunoadsorption, for reducing the autoantibody levels.

Overall, Chu said, this line of research “is important because it shows there’s some type of abnormal biomarker for ME/CFS. And, it may lay a path toward understanding the pathophysiology of the disease and why people have certain symptoms, and could be used to target therapies. ... It’s intriguing.”

Whelan and Chu have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

A significant proportion of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia may have potentially treatable underlying autoimmune-associated small-fiber polyneuropathy (aaSFPN), pilot data suggest.

The findings, from a single-site study of 61 patients with ME/CFS, were presented August 21 at the virtual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis by Ryan Whelan, BS, a research assistant at Simmaron Research Institute, Incline Village, Nevada.

Recent evidence suggests an autoimmune etiology for some patients with ME/CFS, which is defined as experiencing for a period of at least 6 months profound, unexplained fatigue, postexertional malaise, and unrefreshing sleep, as well as cognitive dysfunction and/or orthostatic intolerance (OI).

OI is part of a spectrum of autonomic dysfunction commonly seen in ME/CFS patients, which may also include postural orthostatic tachycardia (POTS), peripheral temperature dysregulation and light sensitivity, neuropathic pain, and gastrointestinal complaints. Many of these symptoms overlap those reported by patients with aaSFPN, a common but underdiagnosed neurodegenerative disorder characterized by the loss of peripheral autonomic nerve fibers, Whelan explained.

Findings from the current study show that in more than half of ME/CFS patients, levels of at least one autoantibody were elevated. A majority had comorbid POTS or OI, and over a third had biopsy-confirmed aaSFPN.

“Given the overlap of symptoms and common etiological basis, it may be important to identify ME/CFS patients who present with comorbid aaSFPN, as it has been shown that immune modulatory agents, including intravenous gamma globulin [IVIG], reduce the autonomic symptom burden in aaSFPN patients,” Whelan said.

He noted that Anne Louise Oaklander, MD, a neurologist at Massachusetts General Hospital, Harvard Medical School, Boston, and colleagues previously linked aaSFPN with fibromyalgia. In addition, they’ve found a connection between small-fiber dysfunction and postexertional malaise, which is a hallmark ME/CFS symptom.

Asked to comment on Whelan’s presentation, IACFSME co-president Lily Chu, MD, told Medscape Medical News that the new findings are “valuable, because ME/CFS has always been looked upon as just subjective symptoms. When people have laboratory abnormalities, it can be due to a bunch of other causes, but...here’s pathology, here’s a biopsy of actual damage. It’s not just a transient finding. You can actually see it. ... It’s a solid concrete piece of evidence vs something that can fluctuate.”

Autoantibodies, Autonomic Dysfunction, and Small-Fiber Polyneuropathy

Whelan and colleagues conducted an extensive analysis of medical records of 364 patients with ME/CFS (72% female) to identify potential aaSFPN comorbidity. Such identifications were made on the basis of progress notes documenting autonomic dysfunction, laboratory results for serum autoantibodies, and questionnaire symptom self-reports.

They identified 61 patients as possibly having comorbid aaSFPN. Of those, 52% tested positive for at least 1 of 4 autoantibodies, including antimuscarinic cholinergic receptor 4 (47%), anti-beta-2 adrenergic (27%), antimuscarinic cholinergic 3 (25%), and anti-beta-1 adrenergic (13%). These autoantibodies were linked to ME/CFS in a recent Swedish cohort study.

“Evidence supports that these autoantibodies may bind to receptor sites, blocking ligands from reaching these receptors. Disturbances of adrenergic and cholinergic receptors by these autoantibodies may contribute to symptoms of autonomic dysfunction in ME/CFS,” Whelan said.

Although 22% of patients in the study group had POTS and 59% had OI, the authors found no correlation between autoantibody levels and either OI or POTS. However, 38% were confirmed to have small-fiber polyneuropathy on skin biopsy, and the vast majority of those patients (93%) had either POTS or OI.

IVIG May Be a Potential Treatment

Whelan notes that some data suggest that IVIG might help patients with small-fiber neuropathy, including those with autoimmunity.

In addition, he described anecdotal data from a single patient with ME/CFS who had neuropathic symptoms. The patient was treated at Simmaron. The 56-year-old received two IVIG infusions given 6 months apart. The patient experienced a dramatic reduction in levels of all four of the relevant autoantibodies and favorable symptom reduction, as shown in clinician follow-up records. “With the success of this case study, we intend to further evaluate IVIG as a potential treatment in ME/CFS patients. With this research, we hope to identify a subset of ME/CFS patients who will respond favorably to IVIG,” Whelan concluded.

Regarding use of IVIG, Chu commented, “We don’t know exactly how it works, but it seems to help certain conditions.” She pointed to another recent small study that reported clinical improvement in patients with ME/CFS through a different approach, immunoadsorption, for reducing the autoantibody levels.

Overall, Chu said, this line of research “is important because it shows there’s some type of abnormal biomarker for ME/CFS. And, it may lay a path toward understanding the pathophysiology of the disease and why people have certain symptoms, and could be used to target therapies. ... It’s intriguing.”

Whelan and Chu have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

A significant proportion of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia may have potentially treatable underlying autoimmune-associated small-fiber polyneuropathy (aaSFPN), pilot data suggest.

The findings, from a single-site study of 61 patients with ME/CFS, were presented August 21 at the virtual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis by Ryan Whelan, BS, a research assistant at Simmaron Research Institute, Incline Village, Nevada.

Recent evidence suggests an autoimmune etiology for some patients with ME/CFS, which is defined as experiencing for a period of at least 6 months profound, unexplained fatigue, postexertional malaise, and unrefreshing sleep, as well as cognitive dysfunction and/or orthostatic intolerance (OI).

OI is part of a spectrum of autonomic dysfunction commonly seen in ME/CFS patients, which may also include postural orthostatic tachycardia (POTS), peripheral temperature dysregulation and light sensitivity, neuropathic pain, and gastrointestinal complaints. Many of these symptoms overlap those reported by patients with aaSFPN, a common but underdiagnosed neurodegenerative disorder characterized by the loss of peripheral autonomic nerve fibers, Whelan explained.

Findings from the current study show that in more than half of ME/CFS patients, levels of at least one autoantibody were elevated. A majority had comorbid POTS or OI, and over a third had biopsy-confirmed aaSFPN.

“Given the overlap of symptoms and common etiological basis, it may be important to identify ME/CFS patients who present with comorbid aaSFPN, as it has been shown that immune modulatory agents, including intravenous gamma globulin [IVIG], reduce the autonomic symptom burden in aaSFPN patients,” Whelan said.

He noted that Anne Louise Oaklander, MD, a neurologist at Massachusetts General Hospital, Harvard Medical School, Boston, and colleagues previously linked aaSFPN with fibromyalgia. In addition, they’ve found a connection between small-fiber dysfunction and postexertional malaise, which is a hallmark ME/CFS symptom.

Asked to comment on Whelan’s presentation, IACFSME co-president Lily Chu, MD, told Medscape Medical News that the new findings are “valuable, because ME/CFS has always been looked upon as just subjective symptoms. When people have laboratory abnormalities, it can be due to a bunch of other causes, but...here’s pathology, here’s a biopsy of actual damage. It’s not just a transient finding. You can actually see it. ... It’s a solid concrete piece of evidence vs something that can fluctuate.”

Autoantibodies, Autonomic Dysfunction, and Small-Fiber Polyneuropathy

Whelan and colleagues conducted an extensive analysis of medical records of 364 patients with ME/CFS (72% female) to identify potential aaSFPN comorbidity. Such identifications were made on the basis of progress notes documenting autonomic dysfunction, laboratory results for serum autoantibodies, and questionnaire symptom self-reports.

They identified 61 patients as possibly having comorbid aaSFPN. Of those, 52% tested positive for at least 1 of 4 autoantibodies, including antimuscarinic cholinergic receptor 4 (47%), anti-beta-2 adrenergic (27%), antimuscarinic cholinergic 3 (25%), and anti-beta-1 adrenergic (13%). These autoantibodies were linked to ME/CFS in a recent Swedish cohort study.

“Evidence supports that these autoantibodies may bind to receptor sites, blocking ligands from reaching these receptors. Disturbances of adrenergic and cholinergic receptors by these autoantibodies may contribute to symptoms of autonomic dysfunction in ME/CFS,” Whelan said.

Although 22% of patients in the study group had POTS and 59% had OI, the authors found no correlation between autoantibody levels and either OI or POTS. However, 38% were confirmed to have small-fiber polyneuropathy on skin biopsy, and the vast majority of those patients (93%) had either POTS or OI.

IVIG May Be a Potential Treatment

Whelan notes that some data suggest that IVIG might help patients with small-fiber neuropathy, including those with autoimmunity.

In addition, he described anecdotal data from a single patient with ME/CFS who had neuropathic symptoms. The patient was treated at Simmaron. The 56-year-old received two IVIG infusions given 6 months apart. The patient experienced a dramatic reduction in levels of all four of the relevant autoantibodies and favorable symptom reduction, as shown in clinician follow-up records. “With the success of this case study, we intend to further evaluate IVIG as a potential treatment in ME/CFS patients. With this research, we hope to identify a subset of ME/CFS patients who will respond favorably to IVIG,” Whelan concluded.

Regarding use of IVIG, Chu commented, “We don’t know exactly how it works, but it seems to help certain conditions.” She pointed to another recent small study that reported clinical improvement in patients with ME/CFS through a different approach, immunoadsorption, for reducing the autoantibody levels.

Overall, Chu said, this line of research “is important because it shows there’s some type of abnormal biomarker for ME/CFS. And, it may lay a path toward understanding the pathophysiology of the disease and why people have certain symptoms, and could be used to target therapies. ... It’s intriguing.”

Whelan and Chu have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.