Neuromuscular Disorders

People with essential tremor (ET) have nearly three times increased risk of developing dementia, compared with the general population, new research showed.

In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.

The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Mild Cognitive Impairment Prevalence Nearly Double

For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.

At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.

During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.

The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.

“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
 

Far From Trivial

Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”

“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.

“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.

The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

People with essential tremor (ET) have nearly three times increased risk of developing dementia, compared with the general population, new research showed.

In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.

The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Mild Cognitive Impairment Prevalence Nearly Double

For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.

At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.

During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.

The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.

“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
 

Far From Trivial

Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”

“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.

“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.

The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

People with essential tremor (ET) have nearly three times increased risk of developing dementia, compared with the general population, new research showed.

In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.

The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Mild Cognitive Impairment Prevalence Nearly Double

For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.

At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.

During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.

The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.

“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
 

Far From Trivial

Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”

“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.

“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.

The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

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

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

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

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

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

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) have overlapping neurologic symptoms — particularly profound fatigue. The similarity between these two conditions has led to the question of whether they are indeed distinct central nervous system (CNS) entities, or whether they exist along a spectrum and are actually two different manifestations of the same disease process.

A new study utilized a novel methodology — unbiased quantitative mass spectrometry-based proteomics — to investigate this question by analyzing cerebrospinal fluid (CSF) in a group of patients with ME/CFS and another group of patients diagnosed with both ME/CFS and FM.

Close to 2,100 proteins were identified, of which nearly 1,800 were common to both conditions.

“ME/CFS and fibromyalgia do not appear to be distinct entities, with respect to their cerebrospinal fluid proteins,” lead author Steven Schutzer, MD, professor of medicine, Rutgers New Jersey School of Medicine, told this news organization.

“Work is underway to solve the multiple mysteries of ME/CFS, fibromyalgia, and other neurologic-associated diseases,” he continued. “We have further affirmed that we have a precise objective discovery tool in our hands. Collectively studying multiple diseases brings clarity to each individual disease.”

The study was published in the December 2023 issue of Annals of Medicine.
 

Cutting-Edge Technology

“ME/CFS is characterized by disabling fatigue, and FM is an illness characterized by body-wide pain,” Dr. Schutzer said. These “medically unexplained” illnesses often coexist by current definitions, and the overlap between them has suggested that they may be part of the “same illness spectrum.”

But co-investigator Benjamin Natelson, MD, professor of neurology and director of the Pain and Fatigue Study Center, Mount Sinai, New York, and others found in previous research that there are distinct differences between the conditions, raising the possibility that there may be different pathophysiological processes.

“The physicians and scientists on our team have had longstanding interest in studying neurologic diseases with cutting-edge tools such as mass spectrometry applied to CSF,” Dr. Schutzer said. “We have had success using this message to distinguish diseases such as ME/CFS from post-treatment Lyme disease, multiple sclerosis, and healthy normal people.”

Dr. Schutzer explained that Dr. Natelson had acquired CSF samples from “well-characterized [ME/CFS] patients and controls.”

Since the cause of ME/CFS is “unknown,” it seemed “ripe to investigate it further with the discovery tool of mass spectrometry” by harnessing the “most advanced equipment in the country at the pacific Northwest National Laboratory, which is part of the US Department of Energy.”

Dr. Schutzer noted that it was the “merger of different clinical and laboratory expertise” that enabled them to address whether ME/CFS and FM are two distinct disease processes.

The choice of analyzing CSF is that it’s the fluid closest to the brain, he added. “A lot of people have studied ME/CFS peripherally because they don’t have access to spinal fluid or it’s easier to look peripherally in the blood, but that doesn’t mean that the blood is where the real ‘action’ is occurring.”

The researchers compared the CSF of 15 patients with ME/CFS only to 15 patients with ME/CFS+FM using mass spectrometry-based proteomics, which they had employed in previous research to see whether ME/CFS was distinct from persistent neurologic Lyme disease syndrome.

This technology has become the “method of choice and discovery tool to rapidly uncover protein biomarkers that can distinguish one disease from another,” the authors stated.

In particular, in unbiased quantitative mass spectrometry-based proteomics, the researchers do not have to know in advance what’s in a sample before studying it, Dr. Schutzer explained.
 

Shared Pathophysiology?

Both groups of patients were of similar age (41.3 ± 9.4 years and 40.1 ± 11.0 years, respectively), with no differences in gender or rates of current comorbid psychiatric diagnoses between the groups.

The researchers quantified a total of 2,083 proteins, including 1,789 that were specifically quantified in all of the CSF samples, regardless of the presence or absence of FM.

Several analyses (including an ANOVA analysis with adjusted P values, a Random Forest machine learning approach that looked at relative protein abundance changes between those with ME/CFS and ME/CFS+FM, and unsupervised hierarchical clustering analyses) did not find distinguishing differences between the groups.

“The sum of these results does not support the hypothesis that ME/CFS and ME/CFS+FM are distinct entities, as currently defined,” the authors stated.

They noted that both conditions are “medically unexplained,” with core symptoms of pain, fatigue, sleep problems, and cognitive difficulty. The fact that these two syndromes coexist so often has led to the assumption that the “similarities between them outweigh the differences,” they wrote.

They pointed to some differences between the conditions, including an increase in substance P in the CSF of FM patients, but not in ME/CFS patients reported by others. There are also some immunological, physiological and genetic differences.

But if the conclusion that the two illnesses may share a similar pathophysiological basis is supported by other research that includes FM-only patients as comparators to those with ME/CFS, “this would support the notion that the two illnesses fall along a common illness spectrum and may be approached as a single entity — with implications for both diagnosis and the development of new treatment approaches,” they concluded.
 

‘Noncontributory’ Findings

Commenting on the research, Robert G. Lahita, MD, PhD, director of the Institute for Autoimmune and Rheumatic Diseases, St. Joseph Health, Wayne, New Jersey, stated that he does not regard these diseases as neurologic but rather as rheumatologic.

“Most neurologists don’t see these diseases, but as a rheumatologist, I see them every day,” said Dr. Lahita, professor of medicine at Hackensack (New Jersey) Meridian School of Medicine and a clinical professor of medicine at Rutgers New Jersey Medical School, New Brunswick. “ME/CFS isn’t as common in my practice, but we do deal with many post-COVID patients who are afflicted mostly with ME/CFS.”

He noted that an important reason for fatigue in FM is that patients generally don’t sleep, or their sleep is disrupted. This is different from the cause of fatigue in ME/CFS.

In addition, the small sample size and the lack of difference between males and females were both limitations of the current study, said Dr. Lahita, who was not involved in this research. “We know that FM disproportionately affects women — in my practice, for example, over 95% of the patients with FM are female — while ME/CFS affects both genders similarly.”

Using proteomics as a biomarker was also problematic, according to Dr. Lahita. “It would have been more valuable to investigate differences in cytokines, for example,” he suggested.

Ultimately, Dr. Lahita thinks that the study is “non-contributory to the field and, as complex as the analysis was, it does nothing to shed differentiate the two conditions or explain the syndromes themselves.”

He added that it would have been more valuable to compare ME/CFS not only to ME/CFS plus FM but also with FM without ME/CFS and to healthy controls, and perhaps to a group with an autoimmune condition, such as lupus or Hashimoto’s thyroiditis.

Dr. Schutzer acknowledged that a limitation of the current study is that his team was unable analyze the CSF of patients with only FM. He and his colleagues “combed the world’s labs” for existing CSF samples of patients with FM alone but were unable to obtain any. “We see this study as a ‘stepping stone’ and hope that future studies will include patients with FM who are willing to donate CSF samples that we can use for comparison,” he said.

The authors received support from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Neurological Disorders and Stroke. Dr. Schutzer, coauthors, and Dr. Lahita reported no relevant financial relationships.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) have overlapping neurologic symptoms — particularly profound fatigue. The similarity between these two conditions has led to the question of whether they are indeed distinct central nervous system (CNS) entities, or whether they exist along a spectrum and are actually two different manifestations of the same disease process.

A new study utilized a novel methodology — unbiased quantitative mass spectrometry-based proteomics — to investigate this question by analyzing cerebrospinal fluid (CSF) in a group of patients with ME/CFS and another group of patients diagnosed with both ME/CFS and FM.

Close to 2,100 proteins were identified, of which nearly 1,800 were common to both conditions.

“ME/CFS and fibromyalgia do not appear to be distinct entities, with respect to their cerebrospinal fluid proteins,” lead author Steven Schutzer, MD, professor of medicine, Rutgers New Jersey School of Medicine, told this news organization.

“Work is underway to solve the multiple mysteries of ME/CFS, fibromyalgia, and other neurologic-associated diseases,” he continued. “We have further affirmed that we have a precise objective discovery tool in our hands. Collectively studying multiple diseases brings clarity to each individual disease.”

The study was published in the December 2023 issue of Annals of Medicine.
 

Cutting-Edge Technology

“ME/CFS is characterized by disabling fatigue, and FM is an illness characterized by body-wide pain,” Dr. Schutzer said. These “medically unexplained” illnesses often coexist by current definitions, and the overlap between them has suggested that they may be part of the “same illness spectrum.”

But co-investigator Benjamin Natelson, MD, professor of neurology and director of the Pain and Fatigue Study Center, Mount Sinai, New York, and others found in previous research that there are distinct differences between the conditions, raising the possibility that there may be different pathophysiological processes.

“The physicians and scientists on our team have had longstanding interest in studying neurologic diseases with cutting-edge tools such as mass spectrometry applied to CSF,” Dr. Schutzer said. “We have had success using this message to distinguish diseases such as ME/CFS from post-treatment Lyme disease, multiple sclerosis, and healthy normal people.”

Dr. Schutzer explained that Dr. Natelson had acquired CSF samples from “well-characterized [ME/CFS] patients and controls.”

Since the cause of ME/CFS is “unknown,” it seemed “ripe to investigate it further with the discovery tool of mass spectrometry” by harnessing the “most advanced equipment in the country at the pacific Northwest National Laboratory, which is part of the US Department of Energy.”

Dr. Schutzer noted that it was the “merger of different clinical and laboratory expertise” that enabled them to address whether ME/CFS and FM are two distinct disease processes.

The choice of analyzing CSF is that it’s the fluid closest to the brain, he added. “A lot of people have studied ME/CFS peripherally because they don’t have access to spinal fluid or it’s easier to look peripherally in the blood, but that doesn’t mean that the blood is where the real ‘action’ is occurring.”

The researchers compared the CSF of 15 patients with ME/CFS only to 15 patients with ME/CFS+FM using mass spectrometry-based proteomics, which they had employed in previous research to see whether ME/CFS was distinct from persistent neurologic Lyme disease syndrome.

This technology has become the “method of choice and discovery tool to rapidly uncover protein biomarkers that can distinguish one disease from another,” the authors stated.

In particular, in unbiased quantitative mass spectrometry-based proteomics, the researchers do not have to know in advance what’s in a sample before studying it, Dr. Schutzer explained.
 

Shared Pathophysiology?

Both groups of patients were of similar age (41.3 ± 9.4 years and 40.1 ± 11.0 years, respectively), with no differences in gender or rates of current comorbid psychiatric diagnoses between the groups.

The researchers quantified a total of 2,083 proteins, including 1,789 that were specifically quantified in all of the CSF samples, regardless of the presence or absence of FM.

Several analyses (including an ANOVA analysis with adjusted P values, a Random Forest machine learning approach that looked at relative protein abundance changes between those with ME/CFS and ME/CFS+FM, and unsupervised hierarchical clustering analyses) did not find distinguishing differences between the groups.

“The sum of these results does not support the hypothesis that ME/CFS and ME/CFS+FM are distinct entities, as currently defined,” the authors stated.

They noted that both conditions are “medically unexplained,” with core symptoms of pain, fatigue, sleep problems, and cognitive difficulty. The fact that these two syndromes coexist so often has led to the assumption that the “similarities between them outweigh the differences,” they wrote.

They pointed to some differences between the conditions, including an increase in substance P in the CSF of FM patients, but not in ME/CFS patients reported by others. There are also some immunological, physiological and genetic differences.

But if the conclusion that the two illnesses may share a similar pathophysiological basis is supported by other research that includes FM-only patients as comparators to those with ME/CFS, “this would support the notion that the two illnesses fall along a common illness spectrum and may be approached as a single entity — with implications for both diagnosis and the development of new treatment approaches,” they concluded.
 

‘Noncontributory’ Findings

Commenting on the research, Robert G. Lahita, MD, PhD, director of the Institute for Autoimmune and Rheumatic Diseases, St. Joseph Health, Wayne, New Jersey, stated that he does not regard these diseases as neurologic but rather as rheumatologic.

“Most neurologists don’t see these diseases, but as a rheumatologist, I see them every day,” said Dr. Lahita, professor of medicine at Hackensack (New Jersey) Meridian School of Medicine and a clinical professor of medicine at Rutgers New Jersey Medical School, New Brunswick. “ME/CFS isn’t as common in my practice, but we do deal with many post-COVID patients who are afflicted mostly with ME/CFS.”

He noted that an important reason for fatigue in FM is that patients generally don’t sleep, or their sleep is disrupted. This is different from the cause of fatigue in ME/CFS.

In addition, the small sample size and the lack of difference between males and females were both limitations of the current study, said Dr. Lahita, who was not involved in this research. “We know that FM disproportionately affects women — in my practice, for example, over 95% of the patients with FM are female — while ME/CFS affects both genders similarly.”

Using proteomics as a biomarker was also problematic, according to Dr. Lahita. “It would have been more valuable to investigate differences in cytokines, for example,” he suggested.

Ultimately, Dr. Lahita thinks that the study is “non-contributory to the field and, as complex as the analysis was, it does nothing to shed differentiate the two conditions or explain the syndromes themselves.”

He added that it would have been more valuable to compare ME/CFS not only to ME/CFS plus FM but also with FM without ME/CFS and to healthy controls, and perhaps to a group with an autoimmune condition, such as lupus or Hashimoto’s thyroiditis.

Dr. Schutzer acknowledged that a limitation of the current study is that his team was unable analyze the CSF of patients with only FM. He and his colleagues “combed the world’s labs” for existing CSF samples of patients with FM alone but were unable to obtain any. “We see this study as a ‘stepping stone’ and hope that future studies will include patients with FM who are willing to donate CSF samples that we can use for comparison,” he said.

The authors received support from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Neurological Disorders and Stroke. Dr. Schutzer, coauthors, and Dr. Lahita reported no relevant financial relationships.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) have overlapping neurologic symptoms — particularly profound fatigue. The similarity between these two conditions has led to the question of whether they are indeed distinct central nervous system (CNS) entities, or whether they exist along a spectrum and are actually two different manifestations of the same disease process.

A new study utilized a novel methodology — unbiased quantitative mass spectrometry-based proteomics — to investigate this question by analyzing cerebrospinal fluid (CSF) in a group of patients with ME/CFS and another group of patients diagnosed with both ME/CFS and FM.

Close to 2,100 proteins were identified, of which nearly 1,800 were common to both conditions.

“ME/CFS and fibromyalgia do not appear to be distinct entities, with respect to their cerebrospinal fluid proteins,” lead author Steven Schutzer, MD, professor of medicine, Rutgers New Jersey School of Medicine, told this news organization.

“Work is underway to solve the multiple mysteries of ME/CFS, fibromyalgia, and other neurologic-associated diseases,” he continued. “We have further affirmed that we have a precise objective discovery tool in our hands. Collectively studying multiple diseases brings clarity to each individual disease.”

The study was published in the December 2023 issue of Annals of Medicine.
 

Cutting-Edge Technology

“ME/CFS is characterized by disabling fatigue, and FM is an illness characterized by body-wide pain,” Dr. Schutzer said. These “medically unexplained” illnesses often coexist by current definitions, and the overlap between them has suggested that they may be part of the “same illness spectrum.”

But co-investigator Benjamin Natelson, MD, professor of neurology and director of the Pain and Fatigue Study Center, Mount Sinai, New York, and others found in previous research that there are distinct differences between the conditions, raising the possibility that there may be different pathophysiological processes.

“The physicians and scientists on our team have had longstanding interest in studying neurologic diseases with cutting-edge tools such as mass spectrometry applied to CSF,” Dr. Schutzer said. “We have had success using this message to distinguish diseases such as ME/CFS from post-treatment Lyme disease, multiple sclerosis, and healthy normal people.”

Dr. Schutzer explained that Dr. Natelson had acquired CSF samples from “well-characterized [ME/CFS] patients and controls.”

Since the cause of ME/CFS is “unknown,” it seemed “ripe to investigate it further with the discovery tool of mass spectrometry” by harnessing the “most advanced equipment in the country at the pacific Northwest National Laboratory, which is part of the US Department of Energy.”

Dr. Schutzer noted that it was the “merger of different clinical and laboratory expertise” that enabled them to address whether ME/CFS and FM are two distinct disease processes.

The choice of analyzing CSF is that it’s the fluid closest to the brain, he added. “A lot of people have studied ME/CFS peripherally because they don’t have access to spinal fluid or it’s easier to look peripherally in the blood, but that doesn’t mean that the blood is where the real ‘action’ is occurring.”

The researchers compared the CSF of 15 patients with ME/CFS only to 15 patients with ME/CFS+FM using mass spectrometry-based proteomics, which they had employed in previous research to see whether ME/CFS was distinct from persistent neurologic Lyme disease syndrome.

This technology has become the “method of choice and discovery tool to rapidly uncover protein biomarkers that can distinguish one disease from another,” the authors stated.

In particular, in unbiased quantitative mass spectrometry-based proteomics, the researchers do not have to know in advance what’s in a sample before studying it, Dr. Schutzer explained.
 

Shared Pathophysiology?

Both groups of patients were of similar age (41.3 ± 9.4 years and 40.1 ± 11.0 years, respectively), with no differences in gender or rates of current comorbid psychiatric diagnoses between the groups.

The researchers quantified a total of 2,083 proteins, including 1,789 that were specifically quantified in all of the CSF samples, regardless of the presence or absence of FM.

Several analyses (including an ANOVA analysis with adjusted P values, a Random Forest machine learning approach that looked at relative protein abundance changes between those with ME/CFS and ME/CFS+FM, and unsupervised hierarchical clustering analyses) did not find distinguishing differences between the groups.

“The sum of these results does not support the hypothesis that ME/CFS and ME/CFS+FM are distinct entities, as currently defined,” the authors stated.

They noted that both conditions are “medically unexplained,” with core symptoms of pain, fatigue, sleep problems, and cognitive difficulty. The fact that these two syndromes coexist so often has led to the assumption that the “similarities between them outweigh the differences,” they wrote.

They pointed to some differences between the conditions, including an increase in substance P in the CSF of FM patients, but not in ME/CFS patients reported by others. There are also some immunological, physiological and genetic differences.

But if the conclusion that the two illnesses may share a similar pathophysiological basis is supported by other research that includes FM-only patients as comparators to those with ME/CFS, “this would support the notion that the two illnesses fall along a common illness spectrum and may be approached as a single entity — with implications for both diagnosis and the development of new treatment approaches,” they concluded.
 

‘Noncontributory’ Findings

Commenting on the research, Robert G. Lahita, MD, PhD, director of the Institute for Autoimmune and Rheumatic Diseases, St. Joseph Health, Wayne, New Jersey, stated that he does not regard these diseases as neurologic but rather as rheumatologic.

“Most neurologists don’t see these diseases, but as a rheumatologist, I see them every day,” said Dr. Lahita, professor of medicine at Hackensack (New Jersey) Meridian School of Medicine and a clinical professor of medicine at Rutgers New Jersey Medical School, New Brunswick. “ME/CFS isn’t as common in my practice, but we do deal with many post-COVID patients who are afflicted mostly with ME/CFS.”

He noted that an important reason for fatigue in FM is that patients generally don’t sleep, or their sleep is disrupted. This is different from the cause of fatigue in ME/CFS.

In addition, the small sample size and the lack of difference between males and females were both limitations of the current study, said Dr. Lahita, who was not involved in this research. “We know that FM disproportionately affects women — in my practice, for example, over 95% of the patients with FM are female — while ME/CFS affects both genders similarly.”

Using proteomics as a biomarker was also problematic, according to Dr. Lahita. “It would have been more valuable to investigate differences in cytokines, for example,” he suggested.

Ultimately, Dr. Lahita thinks that the study is “non-contributory to the field and, as complex as the analysis was, it does nothing to shed differentiate the two conditions or explain the syndromes themselves.”

He added that it would have been more valuable to compare ME/CFS not only to ME/CFS plus FM but also with FM without ME/CFS and to healthy controls, and perhaps to a group with an autoimmune condition, such as lupus or Hashimoto’s thyroiditis.

Dr. Schutzer acknowledged that a limitation of the current study is that his team was unable analyze the CSF of patients with only FM. He and his colleagues “combed the world’s labs” for existing CSF samples of patients with FM alone but were unable to obtain any. “We see this study as a ‘stepping stone’ and hope that future studies will include patients with FM who are willing to donate CSF samples that we can use for comparison,” he said.

The authors received support from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Neurological Disorders and Stroke. Dr. Schutzer, coauthors, and Dr. Lahita reported no relevant financial relationships.

In the first study of its kind, U.K. and French researchers reported that exercise positively affected physical and cognitive health in persons with Down syndrome. “The findings are significant and offer a crucial challenge to the [Down syndrome] and wider societies,” wrote a team led by Dan Gordon, PhD, associate professor of cardiorespiratory exercise physiology at Anglia Ruskin University in Cambridge, England. “Impact of Prescribed Exercise on the Physical and Cognitive Health of Adults with Down Syndrome: The MinDSets Study” was published in the International Journal of Environmental Research and Public Health.

“Through the simple application of walking, a form of exercise which requires little to no equipment or expense, there were significant increases in cognitive and executive function, reflecting improved capabilities in key attributes of information processing, vigilance, and selective attention,” the researchers wrote.

Dr. Gordon

“Increased cognitive function will help foster increased societal integration and quality of life, which, given that this is the first generation of those with [Down syndrome] to outlive their parents and caregivers, is of importance,” they wrote.

For example, those in an exercise-only intervention arm had an 11.4% improvement on the distance covered in the Six-Minute Walk Test, going from a mean of 498.8 meters before intervention to 522.1 meters afterward. Those in a group that combined group exercise with cognitive training increased the distance walked by 9.9%, or 49.2 meters. Groups that got cognitive training only or no intervention showed no significant changes.

In measures of cognitive function, the exercise group showed a 38% increase in selective attention, with the cognitive and combined groups showing changes for the same measure of 16.5% and 55.3%, respectively. The changes for concentration in the exercise-alone group was 31.5%, while those receiving cognitive training alone or combined exercise plus cognitive training showed improvements in concentration of 21% and 15%, respectively.

Asked why a combination intervention was not superior to exercise alone, Dr. Gordon said in an interview, “Something we’re looking at in the data but can’t fully confirm is that the combined group started to become fatigued due to the double dose of the intervention, and this prevented them in the final tests from doing quite so well as the exercise-alone group. Irrespective of the magnitude of change, any cognitive adaptation observed will be beneficial to this population.”

The evidence for the benefits of exercise on both physical and cognitive health in a non–Down syndrome population are well established, he said, but there were few data on its effect on the Down syndrome population.

One small study showed physical and neurocognitive benefits with resistance training.

“The evidence from previous studies showed increased levels of inactivity and sitting time in Down syndrome individuals compared with non–[Down syndrome] controls, so we hypothesized that exercise, albeit small amounts, would increase their physical fitness,” Dr. Gordon said.

His team also hypothesized that walking would stimulate cognitive development since it requires heightened cognitive engagement compared with inactivity. “What surprised us was the degree of improvement,” Dr. Gordon said.

The process of walking requires the brain to interpret information on a real-time basis from both internal and external cues, he continued. “For most of us this process requires low-level cognitive engagement. However, in the [Down syndrome] population, where motor control is impaired and accompanied by poor muscle tone, walking imposes a heightened cognitive load.” It requires them to concentrate on the action, be aware of their surroundings, and make the right decisions, all of which stimulate areas of the brain that control these functions.
 

Study details

Eighty-three adult participants were available for final analysis – 67 from North America, 8 from Europe, 5 from Africa, 2 from Asia, and 1 from Australia. The mean age of participants was 27.1 years, 40 were female, and all had caregiver support during the study.

Those unable to visualize information on computer and mobile/tablet screens or to listen to instructions/auditory cues were excluded. All were provided with instructions and a mobile monitoring tool set to record steps completed, distances covered, speeds, and heart rate.

Each was assigned to one of four groups. Exercise intervention-only consisted of 8 weeks of cardiorespiratory exercise defined as either walking or jogging three times a week for 30 minutes. Cognitive training included eight levels (about 20 minutes) of cognitive and executive function exercises six times per week. The combined group completed both the cardiorespiratory and cognitive interventions, while the fourth group acted as controls with no intervention.

According to the authors, the study offers a real-life scenario that can be readily adopted within the Down syndrome community.

This study was commissioned by the Canadian Down Syndrome Society. The authors had no conflicts of interest to declare.

In the first study of its kind, U.K. and French researchers reported that exercise positively affected physical and cognitive health in persons with Down syndrome. “The findings are significant and offer a crucial challenge to the [Down syndrome] and wider societies,” wrote a team led by Dan Gordon, PhD, associate professor of cardiorespiratory exercise physiology at Anglia Ruskin University in Cambridge, England. “Impact of Prescribed Exercise on the Physical and Cognitive Health of Adults with Down Syndrome: The MinDSets Study” was published in the International Journal of Environmental Research and Public Health.

“Through the simple application of walking, a form of exercise which requires little to no equipment or expense, there were significant increases in cognitive and executive function, reflecting improved capabilities in key attributes of information processing, vigilance, and selective attention,” the researchers wrote.

Dr. Gordon

“Increased cognitive function will help foster increased societal integration and quality of life, which, given that this is the first generation of those with [Down syndrome] to outlive their parents and caregivers, is of importance,” they wrote.

For example, those in an exercise-only intervention arm had an 11.4% improvement on the distance covered in the Six-Minute Walk Test, going from a mean of 498.8 meters before intervention to 522.1 meters afterward. Those in a group that combined group exercise with cognitive training increased the distance walked by 9.9%, or 49.2 meters. Groups that got cognitive training only or no intervention showed no significant changes.

In measures of cognitive function, the exercise group showed a 38% increase in selective attention, with the cognitive and combined groups showing changes for the same measure of 16.5% and 55.3%, respectively. The changes for concentration in the exercise-alone group was 31.5%, while those receiving cognitive training alone or combined exercise plus cognitive training showed improvements in concentration of 21% and 15%, respectively.

Asked why a combination intervention was not superior to exercise alone, Dr. Gordon said in an interview, “Something we’re looking at in the data but can’t fully confirm is that the combined group started to become fatigued due to the double dose of the intervention, and this prevented them in the final tests from doing quite so well as the exercise-alone group. Irrespective of the magnitude of change, any cognitive adaptation observed will be beneficial to this population.”

The evidence for the benefits of exercise on both physical and cognitive health in a non–Down syndrome population are well established, he said, but there were few data on its effect on the Down syndrome population.

One small study showed physical and neurocognitive benefits with resistance training.

“The evidence from previous studies showed increased levels of inactivity and sitting time in Down syndrome individuals compared with non–[Down syndrome] controls, so we hypothesized that exercise, albeit small amounts, would increase their physical fitness,” Dr. Gordon said.

His team also hypothesized that walking would stimulate cognitive development since it requires heightened cognitive engagement compared with inactivity. “What surprised us was the degree of improvement,” Dr. Gordon said.

The process of walking requires the brain to interpret information on a real-time basis from both internal and external cues, he continued. “For most of us this process requires low-level cognitive engagement. However, in the [Down syndrome] population, where motor control is impaired and accompanied by poor muscle tone, walking imposes a heightened cognitive load.” It requires them to concentrate on the action, be aware of their surroundings, and make the right decisions, all of which stimulate areas of the brain that control these functions.
 

Study details

Eighty-three adult participants were available for final analysis – 67 from North America, 8 from Europe, 5 from Africa, 2 from Asia, and 1 from Australia. The mean age of participants was 27.1 years, 40 were female, and all had caregiver support during the study.

Those unable to visualize information on computer and mobile/tablet screens or to listen to instructions/auditory cues were excluded. All were provided with instructions and a mobile monitoring tool set to record steps completed, distances covered, speeds, and heart rate.

Each was assigned to one of four groups. Exercise intervention-only consisted of 8 weeks of cardiorespiratory exercise defined as either walking or jogging three times a week for 30 minutes. Cognitive training included eight levels (about 20 minutes) of cognitive and executive function exercises six times per week. The combined group completed both the cardiorespiratory and cognitive interventions, while the fourth group acted as controls with no intervention.

According to the authors, the study offers a real-life scenario that can be readily adopted within the Down syndrome community.

This study was commissioned by the Canadian Down Syndrome Society. The authors had no conflicts of interest to declare.

In the first study of its kind, U.K. and French researchers reported that exercise positively affected physical and cognitive health in persons with Down syndrome. “The findings are significant and offer a crucial challenge to the [Down syndrome] and wider societies,” wrote a team led by Dan Gordon, PhD, associate professor of cardiorespiratory exercise physiology at Anglia Ruskin University in Cambridge, England. “Impact of Prescribed Exercise on the Physical and Cognitive Health of Adults with Down Syndrome: The MinDSets Study” was published in the International Journal of Environmental Research and Public Health.

“Through the simple application of walking, a form of exercise which requires little to no equipment or expense, there were significant increases in cognitive and executive function, reflecting improved capabilities in key attributes of information processing, vigilance, and selective attention,” the researchers wrote.

Dr. Gordon

“Increased cognitive function will help foster increased societal integration and quality of life, which, given that this is the first generation of those with [Down syndrome] to outlive their parents and caregivers, is of importance,” they wrote.

For example, those in an exercise-only intervention arm had an 11.4% improvement on the distance covered in the Six-Minute Walk Test, going from a mean of 498.8 meters before intervention to 522.1 meters afterward. Those in a group that combined group exercise with cognitive training increased the distance walked by 9.9%, or 49.2 meters. Groups that got cognitive training only or no intervention showed no significant changes.

In measures of cognitive function, the exercise group showed a 38% increase in selective attention, with the cognitive and combined groups showing changes for the same measure of 16.5% and 55.3%, respectively. The changes for concentration in the exercise-alone group was 31.5%, while those receiving cognitive training alone or combined exercise plus cognitive training showed improvements in concentration of 21% and 15%, respectively.

Asked why a combination intervention was not superior to exercise alone, Dr. Gordon said in an interview, “Something we’re looking at in the data but can’t fully confirm is that the combined group started to become fatigued due to the double dose of the intervention, and this prevented them in the final tests from doing quite so well as the exercise-alone group. Irrespective of the magnitude of change, any cognitive adaptation observed will be beneficial to this population.”

The evidence for the benefits of exercise on both physical and cognitive health in a non–Down syndrome population are well established, he said, but there were few data on its effect on the Down syndrome population.

One small study showed physical and neurocognitive benefits with resistance training.

“The evidence from previous studies showed increased levels of inactivity and sitting time in Down syndrome individuals compared with non–[Down syndrome] controls, so we hypothesized that exercise, albeit small amounts, would increase their physical fitness,” Dr. Gordon said.

His team also hypothesized that walking would stimulate cognitive development since it requires heightened cognitive engagement compared with inactivity. “What surprised us was the degree of improvement,” Dr. Gordon said.

The process of walking requires the brain to interpret information on a real-time basis from both internal and external cues, he continued. “For most of us this process requires low-level cognitive engagement. However, in the [Down syndrome] population, where motor control is impaired and accompanied by poor muscle tone, walking imposes a heightened cognitive load.” It requires them to concentrate on the action, be aware of their surroundings, and make the right decisions, all of which stimulate areas of the brain that control these functions.
 

Study details

Eighty-three adult participants were available for final analysis – 67 from North America, 8 from Europe, 5 from Africa, 2 from Asia, and 1 from Australia. The mean age of participants was 27.1 years, 40 were female, and all had caregiver support during the study.

Those unable to visualize information on computer and mobile/tablet screens or to listen to instructions/auditory cues were excluded. All were provided with instructions and a mobile monitoring tool set to record steps completed, distances covered, speeds, and heart rate.

Each was assigned to one of four groups. Exercise intervention-only consisted of 8 weeks of cardiorespiratory exercise defined as either walking or jogging three times a week for 30 minutes. Cognitive training included eight levels (about 20 minutes) of cognitive and executive function exercises six times per week. The combined group completed both the cardiorespiratory and cognitive interventions, while the fourth group acted as controls with no intervention.

According to the authors, the study offers a real-life scenario that can be readily adopted within the Down syndrome community.

This study was commissioned by the Canadian Down Syndrome Society. The authors had no conflicts of interest to declare.

PHOENIX – New treatments for myasthenia gravis are bringing new promise to patients, but their use must be balanced against short-term and long-term risks, according to Pushpa Narayanaswami, MD, who discussed the topic at the 2023 annual meeting of the American Association for Neuromuscular & Electrodiagnostic Medicine (AANEM).

The first Food and Drug Administration–approved drug was pyridostigmine in 1955, and it was more than 60 years before the second drug, eculizumab, gained FDA approval in 2017. Activity in more recent years has been much more brisk with the approvals of efgartigimod in 2021; ravulizumab in 2022; and efgartigimod SQ, rozanolixizumab, and zilucoplan (Japan) in 2023. Eculizumab, efgartigimod, efgartigimod SQ, ravulizumab, and rozanolixizumab are approved for patients who are anti–acetylcholine receptor (AchR) positive. Rozanolixizumab is also approved for patients who are anti–muscle-specific tyrosine kinase (MuSK) antibody positive.

The new drugs have novel mechanisms of action, giving physicians more tools to treat the condition. The mechanisms fall into two general groups: C5-complement inhibitors and neonatal Fc receptor (FcRn) agonists. Dr. Narayanaswami sought to provide guidance in thinking about how to prescribe the new drugs. “How do we really use these drugs? It’s sort of confusing in terms of where they fit in in the algorithm. I don’t pretend to have the answers, but I’m going to sort of give you a general overview of how I look at these based on the trial data and based on what we’ve done in the past,” she said during her talk.
 

Assessing the risk/benefit ratio

Myasthenia gravis treatment strategies should take into account both disease control and minimization of the adverse effects of treatment, which can include both short- and long-term concerns such as hematologic issues, changes in mood and sleep, diarrhea, infection risk, detriments to bone health, hypertension, diabetes mellitus, glaucoma, and cancer.

Disease control can be subjective. “Each patient may have a different approach to what their disease control means, so we don’t quite understand what the definition of disease control is,” said Dr. Narayanaswami. For example, “[a physician] may think of a sleep disturbance as mild, but [the patient] may not. They may not be able to function, so a lot of conversations [are needed] there,” she added.

The international consensus guidance for myasthenia gravis, first published in 2016 and updated a few years later, which Dr. Narayanaswami coauthored, suggested that minimal manifestation of disease is achievable and is relevant to patients. “These are patients who are doing well, they come to your office and say, ‘I’m doing well, I really don’t have any problem [though they may have some weakness],’ ” said Dr. Narayanaswami. In such patients, mild, grade 1 side effects from medications are acceptable.

Dr. Narayanaswami discussed the efficacy of older drugs, including evidence from a 2022 study of 367 patients, that found that 72% of patients achieved MGFA-PIS (postintervention status) of minimal manifestations within 2 years of treatment. That rose to 76% within 3 years and 84% within 5 years. “The incremental benefit [after the first 2] years was not huge, and I think that’s something to pay attention to,” said Dr. Narayanaswami. The study also found that disease duration at first visit was shorter among patients who achieved minimal manifestation at 12 months versus at 16 months. That finding follows a trend in current thinking about treatment of myasthenia gravis. “Chip (James) Howard [of Duke University], who’s my sort of guru, says you’ve got to address this like MS. You’ve got to hit them early and hit them hard. And I think we’re seeing more and more of this. If you think about it even in your clinical practice, patients who did well tended to do well early on,” said Dr. Narayanaswami. She noted an important limitation in that the study did not adjust for confounders or covariates.

In addition, the PROMISE-MG study, which Dr. Narayanaswami coauthored, found that 57%-89% of patients treated with azathioprine or mycophenolate achieved clinically meaningful improvement in a variety of different outcome measures. “More than half to two-thirds of patients do well in clinical practice with the older drugs,” said Dr. Narayanaswami. In terms of time to outcomes, the study found that it took 2-6 months of azathioprine treatment and 2-3 months of mycophenolate mofetil (MMF) treatment for 25% of patients to experience clinically meaningful improvements. It took 14-22 months and 13-18 months, respectively, for 75% of patients to achieve this benchmark.

Regarding when to consider switching to newer therapies, Dr. Narayanaswami pointed out that there is no FDA requirement that patients fail previous therapies, but insurance companies often require it before reimbursement.

Dr. Narayanaswami said that the benefits of these drugs are well known, so she focused instead on their safety profiles in clinical practice. C-5 complement inhibitors carry a risk of meningococcal infection, which has been addressed in various postmarketing studies. “I will say that data is difficult to interpret for various reasons … but the point is that there is a risk for meningococcal infections. The risk appears to be low, but it’s not zero, even if you immunize patients, and I think that’s the conversation we need to have [with patients],” she said. Other issues with C5-complement inhibitors can include headache, nasopharyngitis, diarrhea, abdominal pain, back pain, nausea, and other infections.

FcRn antagonists have a range of potential side effects, but Dr. Narayanaswami emphasized timing of vaccinations, since the drugs antagonize recycling of IgG. She said vaccines should be given before the first dose of the cycle. There are no data on their use in pregnancy, but the agents could potentially reduce the passive transfer of IgG antibodies to the fetus.
 

Treatment strategies

In clinical practice, Dr. Narayanaswami employs the newer drugs in patients who have failed older drugs, or who experience intolerable side effects. An important consideration is how long to wait before determining a failure on previous therapies. Her current inclination is to treat earlier, which leads her to consider newer drugs at 2 years after disease onset, or after 1 year if the patient has had no improvement at all. She would consider the therapies as first-line therapies in patients for whom she doesn’t feel comfortable prescribing older medications, often older or more frail patients, or patients at any age when comorbidities might contraindicate glucocorticoids.

During the Q&A session after the talk, an attendee asked Dr. Narayanaswami what she does when payers balk at paying for new drugs. She noted that payers don’t necessarily have a specific number of months in mind for patients who are quite sick. “They just want somebody to try something. That has been my experience,” she said. She also goes peer-to-peer when disputing coverage. “Sometimes you can convince them on a peer-to-peer [basis] because they don’t really know myasthenia gravis.”

Another questioner wondered if clinical trials have been done or are in progress to demonstrate that earlier treatment can lead to better results. Dr. Narayanaswami responded that several observational trials are looking at the question. “It’s challenging because sometimes we don’t know the time from diagnosis. We know the first time they came in, which is not necessarily the same as the time from diagnosis, and sometimes that can be hard to get. And, again, it’s observational data, which can be dirty,” she said.

Dr. Narayanaswami disclosed ties with Alexion, Argenx, Dianthus, GSK, Janssen, Patient Centered Outcomes Research Institute, Sanofi, and UCB.

PHOENIX – New treatments for myasthenia gravis are bringing new promise to patients, but their use must be balanced against short-term and long-term risks, according to Pushpa Narayanaswami, MD, who discussed the topic at the 2023 annual meeting of the American Association for Neuromuscular & Electrodiagnostic Medicine (AANEM).

The first Food and Drug Administration–approved drug was pyridostigmine in 1955, and it was more than 60 years before the second drug, eculizumab, gained FDA approval in 2017. Activity in more recent years has been much more brisk with the approvals of efgartigimod in 2021; ravulizumab in 2022; and efgartigimod SQ, rozanolixizumab, and zilucoplan (Japan) in 2023. Eculizumab, efgartigimod, efgartigimod SQ, ravulizumab, and rozanolixizumab are approved for patients who are anti–acetylcholine receptor (AchR) positive. Rozanolixizumab is also approved for patients who are anti–muscle-specific tyrosine kinase (MuSK) antibody positive.

The new drugs have novel mechanisms of action, giving physicians more tools to treat the condition. The mechanisms fall into two general groups: C5-complement inhibitors and neonatal Fc receptor (FcRn) agonists. Dr. Narayanaswami sought to provide guidance in thinking about how to prescribe the new drugs. “How do we really use these drugs? It’s sort of confusing in terms of where they fit in in the algorithm. I don’t pretend to have the answers, but I’m going to sort of give you a general overview of how I look at these based on the trial data and based on what we’ve done in the past,” she said during her talk.
 

Assessing the risk/benefit ratio

Myasthenia gravis treatment strategies should take into account both disease control and minimization of the adverse effects of treatment, which can include both short- and long-term concerns such as hematologic issues, changes in mood and sleep, diarrhea, infection risk, detriments to bone health, hypertension, diabetes mellitus, glaucoma, and cancer.

Disease control can be subjective. “Each patient may have a different approach to what their disease control means, so we don’t quite understand what the definition of disease control is,” said Dr. Narayanaswami. For example, “[a physician] may think of a sleep disturbance as mild, but [the patient] may not. They may not be able to function, so a lot of conversations [are needed] there,” she added.

The international consensus guidance for myasthenia gravis, first published in 2016 and updated a few years later, which Dr. Narayanaswami coauthored, suggested that minimal manifestation of disease is achievable and is relevant to patients. “These are patients who are doing well, they come to your office and say, ‘I’m doing well, I really don’t have any problem [though they may have some weakness],’ ” said Dr. Narayanaswami. In such patients, mild, grade 1 side effects from medications are acceptable.

Dr. Narayanaswami discussed the efficacy of older drugs, including evidence from a 2022 study of 367 patients, that found that 72% of patients achieved MGFA-PIS (postintervention status) of minimal manifestations within 2 years of treatment. That rose to 76% within 3 years and 84% within 5 years. “The incremental benefit [after the first 2] years was not huge, and I think that’s something to pay attention to,” said Dr. Narayanaswami. The study also found that disease duration at first visit was shorter among patients who achieved minimal manifestation at 12 months versus at 16 months. That finding follows a trend in current thinking about treatment of myasthenia gravis. “Chip (James) Howard [of Duke University], who’s my sort of guru, says you’ve got to address this like MS. You’ve got to hit them early and hit them hard. And I think we’re seeing more and more of this. If you think about it even in your clinical practice, patients who did well tended to do well early on,” said Dr. Narayanaswami. She noted an important limitation in that the study did not adjust for confounders or covariates.

In addition, the PROMISE-MG study, which Dr. Narayanaswami coauthored, found that 57%-89% of patients treated with azathioprine or mycophenolate achieved clinically meaningful improvement in a variety of different outcome measures. “More than half to two-thirds of patients do well in clinical practice with the older drugs,” said Dr. Narayanaswami. In terms of time to outcomes, the study found that it took 2-6 months of azathioprine treatment and 2-3 months of mycophenolate mofetil (MMF) treatment for 25% of patients to experience clinically meaningful improvements. It took 14-22 months and 13-18 months, respectively, for 75% of patients to achieve this benchmark.

Regarding when to consider switching to newer therapies, Dr. Narayanaswami pointed out that there is no FDA requirement that patients fail previous therapies, but insurance companies often require it before reimbursement.

Dr. Narayanaswami said that the benefits of these drugs are well known, so she focused instead on their safety profiles in clinical practice. C-5 complement inhibitors carry a risk of meningococcal infection, which has been addressed in various postmarketing studies. “I will say that data is difficult to interpret for various reasons … but the point is that there is a risk for meningococcal infections. The risk appears to be low, but it’s not zero, even if you immunize patients, and I think that’s the conversation we need to have [with patients],” she said. Other issues with C5-complement inhibitors can include headache, nasopharyngitis, diarrhea, abdominal pain, back pain, nausea, and other infections.

FcRn antagonists have a range of potential side effects, but Dr. Narayanaswami emphasized timing of vaccinations, since the drugs antagonize recycling of IgG. She said vaccines should be given before the first dose of the cycle. There are no data on their use in pregnancy, but the agents could potentially reduce the passive transfer of IgG antibodies to the fetus.
 

Treatment strategies

In clinical practice, Dr. Narayanaswami employs the newer drugs in patients who have failed older drugs, or who experience intolerable side effects. An important consideration is how long to wait before determining a failure on previous therapies. Her current inclination is to treat earlier, which leads her to consider newer drugs at 2 years after disease onset, or after 1 year if the patient has had no improvement at all. She would consider the therapies as first-line therapies in patients for whom she doesn’t feel comfortable prescribing older medications, often older or more frail patients, or patients at any age when comorbidities might contraindicate glucocorticoids.

During the Q&A session after the talk, an attendee asked Dr. Narayanaswami what she does when payers balk at paying for new drugs. She noted that payers don’t necessarily have a specific number of months in mind for patients who are quite sick. “They just want somebody to try something. That has been my experience,” she said. She also goes peer-to-peer when disputing coverage. “Sometimes you can convince them on a peer-to-peer [basis] because they don’t really know myasthenia gravis.”

Another questioner wondered if clinical trials have been done or are in progress to demonstrate that earlier treatment can lead to better results. Dr. Narayanaswami responded that several observational trials are looking at the question. “It’s challenging because sometimes we don’t know the time from diagnosis. We know the first time they came in, which is not necessarily the same as the time from diagnosis, and sometimes that can be hard to get. And, again, it’s observational data, which can be dirty,” she said.

Dr. Narayanaswami disclosed ties with Alexion, Argenx, Dianthus, GSK, Janssen, Patient Centered Outcomes Research Institute, Sanofi, and UCB.

PHOENIX – New treatments for myasthenia gravis are bringing new promise to patients, but their use must be balanced against short-term and long-term risks, according to Pushpa Narayanaswami, MD, who discussed the topic at the 2023 annual meeting of the American Association for Neuromuscular & Electrodiagnostic Medicine (AANEM).

The first Food and Drug Administration–approved drug was pyridostigmine in 1955, and it was more than 60 years before the second drug, eculizumab, gained FDA approval in 2017. Activity in more recent years has been much more brisk with the approvals of efgartigimod in 2021; ravulizumab in 2022; and efgartigimod SQ, rozanolixizumab, and zilucoplan (Japan) in 2023. Eculizumab, efgartigimod, efgartigimod SQ, ravulizumab, and rozanolixizumab are approved for patients who are anti–acetylcholine receptor (AchR) positive. Rozanolixizumab is also approved for patients who are anti–muscle-specific tyrosine kinase (MuSK) antibody positive.

The new drugs have novel mechanisms of action, giving physicians more tools to treat the condition. The mechanisms fall into two general groups: C5-complement inhibitors and neonatal Fc receptor (FcRn) agonists. Dr. Narayanaswami sought to provide guidance in thinking about how to prescribe the new drugs. “How do we really use these drugs? It’s sort of confusing in terms of where they fit in in the algorithm. I don’t pretend to have the answers, but I’m going to sort of give you a general overview of how I look at these based on the trial data and based on what we’ve done in the past,” she said during her talk.
 

Assessing the risk/benefit ratio

Myasthenia gravis treatment strategies should take into account both disease control and minimization of the adverse effects of treatment, which can include both short- and long-term concerns such as hematologic issues, changes in mood and sleep, diarrhea, infection risk, detriments to bone health, hypertension, diabetes mellitus, glaucoma, and cancer.

Disease control can be subjective. “Each patient may have a different approach to what their disease control means, so we don’t quite understand what the definition of disease control is,” said Dr. Narayanaswami. For example, “[a physician] may think of a sleep disturbance as mild, but [the patient] may not. They may not be able to function, so a lot of conversations [are needed] there,” she added.

The international consensus guidance for myasthenia gravis, first published in 2016 and updated a few years later, which Dr. Narayanaswami coauthored, suggested that minimal manifestation of disease is achievable and is relevant to patients. “These are patients who are doing well, they come to your office and say, ‘I’m doing well, I really don’t have any problem [though they may have some weakness],’ ” said Dr. Narayanaswami. In such patients, mild, grade 1 side effects from medications are acceptable.

Dr. Narayanaswami discussed the efficacy of older drugs, including evidence from a 2022 study of 367 patients, that found that 72% of patients achieved MGFA-PIS (postintervention status) of minimal manifestations within 2 years of treatment. That rose to 76% within 3 years and 84% within 5 years. “The incremental benefit [after the first 2] years was not huge, and I think that’s something to pay attention to,” said Dr. Narayanaswami. The study also found that disease duration at first visit was shorter among patients who achieved minimal manifestation at 12 months versus at 16 months. That finding follows a trend in current thinking about treatment of myasthenia gravis. “Chip (James) Howard [of Duke University], who’s my sort of guru, says you’ve got to address this like MS. You’ve got to hit them early and hit them hard. And I think we’re seeing more and more of this. If you think about it even in your clinical practice, patients who did well tended to do well early on,” said Dr. Narayanaswami. She noted an important limitation in that the study did not adjust for confounders or covariates.

In addition, the PROMISE-MG study, which Dr. Narayanaswami coauthored, found that 57%-89% of patients treated with azathioprine or mycophenolate achieved clinically meaningful improvement in a variety of different outcome measures. “More than half to two-thirds of patients do well in clinical practice with the older drugs,” said Dr. Narayanaswami. In terms of time to outcomes, the study found that it took 2-6 months of azathioprine treatment and 2-3 months of mycophenolate mofetil (MMF) treatment for 25% of patients to experience clinically meaningful improvements. It took 14-22 months and 13-18 months, respectively, for 75% of patients to achieve this benchmark.

Regarding when to consider switching to newer therapies, Dr. Narayanaswami pointed out that there is no FDA requirement that patients fail previous therapies, but insurance companies often require it before reimbursement.

Dr. Narayanaswami said that the benefits of these drugs are well known, so she focused instead on their safety profiles in clinical practice. C-5 complement inhibitors carry a risk of meningococcal infection, which has been addressed in various postmarketing studies. “I will say that data is difficult to interpret for various reasons … but the point is that there is a risk for meningococcal infections. The risk appears to be low, but it’s not zero, even if you immunize patients, and I think that’s the conversation we need to have [with patients],” she said. Other issues with C5-complement inhibitors can include headache, nasopharyngitis, diarrhea, abdominal pain, back pain, nausea, and other infections.

FcRn antagonists have a range of potential side effects, but Dr. Narayanaswami emphasized timing of vaccinations, since the drugs antagonize recycling of IgG. She said vaccines should be given before the first dose of the cycle. There are no data on their use in pregnancy, but the agents could potentially reduce the passive transfer of IgG antibodies to the fetus.
 

Treatment strategies

In clinical practice, Dr. Narayanaswami employs the newer drugs in patients who have failed older drugs, or who experience intolerable side effects. An important consideration is how long to wait before determining a failure on previous therapies. Her current inclination is to treat earlier, which leads her to consider newer drugs at 2 years after disease onset, or after 1 year if the patient has had no improvement at all. She would consider the therapies as first-line therapies in patients for whom she doesn’t feel comfortable prescribing older medications, often older or more frail patients, or patients at any age when comorbidities might contraindicate glucocorticoids.

During the Q&A session after the talk, an attendee asked Dr. Narayanaswami what she does when payers balk at paying for new drugs. She noted that payers don’t necessarily have a specific number of months in mind for patients who are quite sick. “They just want somebody to try something. That has been my experience,” she said. She also goes peer-to-peer when disputing coverage. “Sometimes you can convince them on a peer-to-peer [basis] because they don’t really know myasthenia gravis.”

Another questioner wondered if clinical trials have been done or are in progress to demonstrate that earlier treatment can lead to better results. Dr. Narayanaswami responded that several observational trials are looking at the question. “It’s challenging because sometimes we don’t know the time from diagnosis. We know the first time they came in, which is not necessarily the same as the time from diagnosis, and sometimes that can be hard to get. And, again, it’s observational data, which can be dirty,” she said.

Dr. Narayanaswami disclosed ties with Alexion, Argenx, Dianthus, GSK, Janssen, Patient Centered Outcomes Research Institute, Sanofi, and UCB.

PHOENIX – Early responders to zilucoplan, the newly approved medication for myasthenia gravis, have sustained benefit for up to 60 weeks, a new analyses show.

“The information [in the studies] is valuable in making clinical decisions in managing myasthenia gravis, which is a chronic autoimmune condition that requires long-term use of immunosuppressives,” said Xinli Du, MD, PhD, an assistant professor in the department of neurology at Virginia Commonwealth University in Richmond, who was not involved in the research.

“Compared with conventional immunosuppressants, which take 3-9 months to know if the patient will respond, this is definitely a game-changer,” she said.

The research was presented at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).
 

FDA approval

Approved by the U.S. Food and Drug Administration in October, the targeted peptide inhibitor of complement component 5 represents the only once-daily self-administered subcutaneous injection for adult patients with acetylcholine receptor autoantibody–positive (AChR+) generalized myasthenia gravis.

The multicenter, phase 3, placebo-controlled RAISE trial demonstrated that zilucoplan was associated with significant improvement in myasthenia gravis–specific outcomes in adult patients with mild to severe AChR+ generalized myasthenia gravis.

Of note, approximately 40% of patients in the zilucoplan phase 2 and 3 clinical trials have a significant response as early as the first week of treatment. For the current post hoc analysis, first author Miriam Freimer, MD, and colleagues took a closer look at the longer-term outcomes in these patients in the ongoing RAISE-XT open-label extension study.

In these two double-blind studies, patients were randomly assigned to receive either daily subcutaneous injections of 0.3 mg/kg zilucoplan or placebo.

Among 93 patients receiving zilucoplan in the two studies, 40 (43%) were identified as early responders based on having at least a 3-point reduction from baseline on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL) within 1 week of treatment, and 31 (33%) qualified based on having at least 5-point reductions in Quantitative Myasthenia Gravis (QMG), at week 1.

Of these early responders, more than 80% meeting the MG-ADL and 85% meeting QMG criteria continued to show a treatment response at each assessment through week 60 in the open-label RAISE-XT trial.

Furthermore, week 1 responders maintained their response for 88.1% of their total treatment time in the MG-ADL group and 88.8% of their total treatment time on treatment in the QMG group, representing a median zilucoplan treatment duration of 450 days.

Of note, the week 1 early responders had no significant differences, compared with the study’s overall population. Participants had a mean age of 49.6 years versus 52.9 years in the overall population. Approximately 40% of patients in both studies were men, and 60%-64% were disease class III as assessed by the Myasthenia Gravis Foundation of America criteria.

“It is very exciting to see such a high response of rapid responders. This means that some patients may be able to avoid steroids or be able to taper them faster than with other accepted treatments for myasthenia gravis,” said Dr. Freimer, director of the division of neuromuscular disorders and the codirector of the Myasthenia Gravis Clinic at the Ohio State University in Columbus.
 

Impact on fatigue

In a separate post hoc analysis of patients who entered RAISE-XT, the researchers evaluated long-term effects of zilucoplan on fatigue.

Improvements in fatigue were already apparent at the end of the RAISE trial, with the least squares mean (LSM) change from baseline in fatigue assessed after 12 weeks with the Neuro-QOL T-score being –6.26 for zilucoplan (n = 86) compared with an increase of 2.65 for placebo (n = 88; LSM difference, –3.61; nominal P = .0060).

Patients who received placebo in the RAISE trial were able to switch to zilucoplan in the RAISE-XT open-label trail, and among those who did, fatigue, as measured in the T-scores, improved significantly within 1 week of switching.

Fatigue further improved out to week 16 in terms of T-scores for the placebo-switch as well as zilucoplan groups, and the improvements in the scores were sustained through week 60 (mean change from RAISE baseline, –10.71 [n = 42] and –9.15 [n = 42], respectively).

“Fatigue is a challenge for patients with [generalized myasthenia gravis]. Zilucoplan significantly and clinically meaningfully improved myasthenic fatigue versus placebo during RAISE,” the investigators report.

“Further improvements were observed during RAISE-XT and were sustained up to 60 weeks of treatment,” they added.
 

Favorable safety profile

Zilucoplan continued to show a favorable safety profile in the RAISE-XT trial and was well tolerated in the long term.

The most common adverse reactions (10% or more) in patients with generalized myasthenia gravis were injection-site reactions, upper respiratory tract infection, and diarrhea.

Though additional therapies have also recently entered the market for generalized myasthenia gravis, they are either intravenous or subcutaneous infusions requiring a health care professional to administer them.

“This self-administered medication allows patients to be more independent and can even travel since it is not dependent on an infusion center,” Dr. Freimer noted.

However, similar to the other complement inhibitors, zilucoplan carries a risk for infection, particularly meningitis, Dr. Du noted. “Complement meningitis vaccination protocol and close monitoring for signs of infection are required,” she said.

However, she added, “the rapid action benefits shown as early as week 1 are impressive, and potentially open the door to use as adjunctive therapy in myasthenia gravis crisis.”

“I think zilucoplan definitely adds more excitement to the already active field of myasthenia gravis management,” she said.

The study was funded by UCB Pharma. Dr. Freimer has reports she has served as a paid consultant for argenx, UCB Pharma, and Alexion Pharmaceuticals and reports research support from the National Institutes of Health, UCB Pharma, Jansen Pharmaceuticals, Alnylam, Avidity, and Fulcrum. Dr. Du reports no disclosures.

A version of this article appeared on Medscape.com.

PHOENIX – Early responders to zilucoplan, the newly approved medication for myasthenia gravis, have sustained benefit for up to 60 weeks, a new analyses show.

“The information [in the studies] is valuable in making clinical decisions in managing myasthenia gravis, which is a chronic autoimmune condition that requires long-term use of immunosuppressives,” said Xinli Du, MD, PhD, an assistant professor in the department of neurology at Virginia Commonwealth University in Richmond, who was not involved in the research.

“Compared with conventional immunosuppressants, which take 3-9 months to know if the patient will respond, this is definitely a game-changer,” she said.

The research was presented at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).
 

FDA approval

Approved by the U.S. Food and Drug Administration in October, the targeted peptide inhibitor of complement component 5 represents the only once-daily self-administered subcutaneous injection for adult patients with acetylcholine receptor autoantibody–positive (AChR+) generalized myasthenia gravis.

The multicenter, phase 3, placebo-controlled RAISE trial demonstrated that zilucoplan was associated with significant improvement in myasthenia gravis–specific outcomes in adult patients with mild to severe AChR+ generalized myasthenia gravis.

Of note, approximately 40% of patients in the zilucoplan phase 2 and 3 clinical trials have a significant response as early as the first week of treatment. For the current post hoc analysis, first author Miriam Freimer, MD, and colleagues took a closer look at the longer-term outcomes in these patients in the ongoing RAISE-XT open-label extension study.

In these two double-blind studies, patients were randomly assigned to receive either daily subcutaneous injections of 0.3 mg/kg zilucoplan or placebo.

Among 93 patients receiving zilucoplan in the two studies, 40 (43%) were identified as early responders based on having at least a 3-point reduction from baseline on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL) within 1 week of treatment, and 31 (33%) qualified based on having at least 5-point reductions in Quantitative Myasthenia Gravis (QMG), at week 1.

Of these early responders, more than 80% meeting the MG-ADL and 85% meeting QMG criteria continued to show a treatment response at each assessment through week 60 in the open-label RAISE-XT trial.

Furthermore, week 1 responders maintained their response for 88.1% of their total treatment time in the MG-ADL group and 88.8% of their total treatment time on treatment in the QMG group, representing a median zilucoplan treatment duration of 450 days.

Of note, the week 1 early responders had no significant differences, compared with the study’s overall population. Participants had a mean age of 49.6 years versus 52.9 years in the overall population. Approximately 40% of patients in both studies were men, and 60%-64% were disease class III as assessed by the Myasthenia Gravis Foundation of America criteria.

“It is very exciting to see such a high response of rapid responders. This means that some patients may be able to avoid steroids or be able to taper them faster than with other accepted treatments for myasthenia gravis,” said Dr. Freimer, director of the division of neuromuscular disorders and the codirector of the Myasthenia Gravis Clinic at the Ohio State University in Columbus.
 

Impact on fatigue

In a separate post hoc analysis of patients who entered RAISE-XT, the researchers evaluated long-term effects of zilucoplan on fatigue.

Improvements in fatigue were already apparent at the end of the RAISE trial, with the least squares mean (LSM) change from baseline in fatigue assessed after 12 weeks with the Neuro-QOL T-score being –6.26 for zilucoplan (n = 86) compared with an increase of 2.65 for placebo (n = 88; LSM difference, –3.61; nominal P = .0060).

Patients who received placebo in the RAISE trial were able to switch to zilucoplan in the RAISE-XT open-label trail, and among those who did, fatigue, as measured in the T-scores, improved significantly within 1 week of switching.

Fatigue further improved out to week 16 in terms of T-scores for the placebo-switch as well as zilucoplan groups, and the improvements in the scores were sustained through week 60 (mean change from RAISE baseline, –10.71 [n = 42] and –9.15 [n = 42], respectively).

“Fatigue is a challenge for patients with [generalized myasthenia gravis]. Zilucoplan significantly and clinically meaningfully improved myasthenic fatigue versus placebo during RAISE,” the investigators report.

“Further improvements were observed during RAISE-XT and were sustained up to 60 weeks of treatment,” they added.
 

Favorable safety profile

Zilucoplan continued to show a favorable safety profile in the RAISE-XT trial and was well tolerated in the long term.

The most common adverse reactions (10% or more) in patients with generalized myasthenia gravis were injection-site reactions, upper respiratory tract infection, and diarrhea.

Though additional therapies have also recently entered the market for generalized myasthenia gravis, they are either intravenous or subcutaneous infusions requiring a health care professional to administer them.

“This self-administered medication allows patients to be more independent and can even travel since it is not dependent on an infusion center,” Dr. Freimer noted.

However, similar to the other complement inhibitors, zilucoplan carries a risk for infection, particularly meningitis, Dr. Du noted. “Complement meningitis vaccination protocol and close monitoring for signs of infection are required,” she said.

However, she added, “the rapid action benefits shown as early as week 1 are impressive, and potentially open the door to use as adjunctive therapy in myasthenia gravis crisis.”

“I think zilucoplan definitely adds more excitement to the already active field of myasthenia gravis management,” she said.

The study was funded by UCB Pharma. Dr. Freimer has reports she has served as a paid consultant for argenx, UCB Pharma, and Alexion Pharmaceuticals and reports research support from the National Institutes of Health, UCB Pharma, Jansen Pharmaceuticals, Alnylam, Avidity, and Fulcrum. Dr. Du reports no disclosures.

A version of this article appeared on Medscape.com.

PHOENIX – Early responders to zilucoplan, the newly approved medication for myasthenia gravis, have sustained benefit for up to 60 weeks, a new analyses show.

“The information [in the studies] is valuable in making clinical decisions in managing myasthenia gravis, which is a chronic autoimmune condition that requires long-term use of immunosuppressives,” said Xinli Du, MD, PhD, an assistant professor in the department of neurology at Virginia Commonwealth University in Richmond, who was not involved in the research.

“Compared with conventional immunosuppressants, which take 3-9 months to know if the patient will respond, this is definitely a game-changer,” she said.

The research was presented at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM).
 

FDA approval

Approved by the U.S. Food and Drug Administration in October, the targeted peptide inhibitor of complement component 5 represents the only once-daily self-administered subcutaneous injection for adult patients with acetylcholine receptor autoantibody–positive (AChR+) generalized myasthenia gravis.

The multicenter, phase 3, placebo-controlled RAISE trial demonstrated that zilucoplan was associated with significant improvement in myasthenia gravis–specific outcomes in adult patients with mild to severe AChR+ generalized myasthenia gravis.

Of note, approximately 40% of patients in the zilucoplan phase 2 and 3 clinical trials have a significant response as early as the first week of treatment. For the current post hoc analysis, first author Miriam Freimer, MD, and colleagues took a closer look at the longer-term outcomes in these patients in the ongoing RAISE-XT open-label extension study.

In these two double-blind studies, patients were randomly assigned to receive either daily subcutaneous injections of 0.3 mg/kg zilucoplan or placebo.

Among 93 patients receiving zilucoplan in the two studies, 40 (43%) were identified as early responders based on having at least a 3-point reduction from baseline on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL) within 1 week of treatment, and 31 (33%) qualified based on having at least 5-point reductions in Quantitative Myasthenia Gravis (QMG), at week 1.

Of these early responders, more than 80% meeting the MG-ADL and 85% meeting QMG criteria continued to show a treatment response at each assessment through week 60 in the open-label RAISE-XT trial.

Furthermore, week 1 responders maintained their response for 88.1% of their total treatment time in the MG-ADL group and 88.8% of their total treatment time on treatment in the QMG group, representing a median zilucoplan treatment duration of 450 days.

Of note, the week 1 early responders had no significant differences, compared with the study’s overall population. Participants had a mean age of 49.6 years versus 52.9 years in the overall population. Approximately 40% of patients in both studies were men, and 60%-64% were disease class III as assessed by the Myasthenia Gravis Foundation of America criteria.

“It is very exciting to see such a high response of rapid responders. This means that some patients may be able to avoid steroids or be able to taper them faster than with other accepted treatments for myasthenia gravis,” said Dr. Freimer, director of the division of neuromuscular disorders and the codirector of the Myasthenia Gravis Clinic at the Ohio State University in Columbus.
 

Impact on fatigue

In a separate post hoc analysis of patients who entered RAISE-XT, the researchers evaluated long-term effects of zilucoplan on fatigue.

Improvements in fatigue were already apparent at the end of the RAISE trial, with the least squares mean (LSM) change from baseline in fatigue assessed after 12 weeks with the Neuro-QOL T-score being –6.26 for zilucoplan (n = 86) compared with an increase of 2.65 for placebo (n = 88; LSM difference, –3.61; nominal P = .0060).

Patients who received placebo in the RAISE trial were able to switch to zilucoplan in the RAISE-XT open-label trail, and among those who did, fatigue, as measured in the T-scores, improved significantly within 1 week of switching.

Fatigue further improved out to week 16 in terms of T-scores for the placebo-switch as well as zilucoplan groups, and the improvements in the scores were sustained through week 60 (mean change from RAISE baseline, –10.71 [n = 42] and –9.15 [n = 42], respectively).

“Fatigue is a challenge for patients with [generalized myasthenia gravis]. Zilucoplan significantly and clinically meaningfully improved myasthenic fatigue versus placebo during RAISE,” the investigators report.

“Further improvements were observed during RAISE-XT and were sustained up to 60 weeks of treatment,” they added.
 

Favorable safety profile

Zilucoplan continued to show a favorable safety profile in the RAISE-XT trial and was well tolerated in the long term.

The most common adverse reactions (10% or more) in patients with generalized myasthenia gravis were injection-site reactions, upper respiratory tract infection, and diarrhea.

Though additional therapies have also recently entered the market for generalized myasthenia gravis, they are either intravenous or subcutaneous infusions requiring a health care professional to administer them.

“This self-administered medication allows patients to be more independent and can even travel since it is not dependent on an infusion center,” Dr. Freimer noted.

However, similar to the other complement inhibitors, zilucoplan carries a risk for infection, particularly meningitis, Dr. Du noted. “Complement meningitis vaccination protocol and close monitoring for signs of infection are required,” she said.

However, she added, “the rapid action benefits shown as early as week 1 are impressive, and potentially open the door to use as adjunctive therapy in myasthenia gravis crisis.”

“I think zilucoplan definitely adds more excitement to the already active field of myasthenia gravis management,” she said.

The study was funded by UCB Pharma. Dr. Freimer has reports she has served as a paid consultant for argenx, UCB Pharma, and Alexion Pharmaceuticals and reports research support from the National Institutes of Health, UCB Pharma, Jansen Pharmaceuticals, Alnylam, Avidity, and Fulcrum. Dr. Du reports no disclosures.

A version of this article appeared on Medscape.com.

PHOENIX – Chemotherapy-induced peripheral neuropathy (CIPN) is linked to a decline in executive and neuromuscular function, a new finding that may increase the risk for compromised mobility and fall risk.

“Among older cancer survivors treated with chemotherapy, the presence of CIPN was independently associated with reduced executive function,” said study investigator Brendan L. McNeish, MD, of the department of physical medicine and rehabilitation, University of Pittsburgh.

“Importantly, given the emerging relationship of executive function with mobility in this population, stakeholders and clinicians are called to acknowledge that chemotherapy-related mobility declines in CIPN survivors are likely due to both neuromuscular and executive dysfunction,” he said.

The findings were presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
 

Research gap

Characterized by numbness, tingling, pain, and motor impairment, CIPN affects up to 50% of all patients with cancer that is treated with taxane-, platinum-, or vinca alkaloid–based chemotherapy. The condition is among the leading dose-limiting toxicities, potentially increasing mortality risk.

Though the effects of chemotherapy on cognitive function are well-established, less is known about a potential relationship between this side effect and CIPN, Dr. McNeish said.

“Chemotherapy can be neurotoxic, but few studies have linked neurotoxicity to the central nervous system and peripheral nervous system,” Dr. McNeish said.

To compare cognitive outcomes in patients treated with chemotherapy who did and did not develop CIPN, the investigators conducted a cross-sectional study that included 50 chemotherapy-treated cancer survivors at a single time point post chemotherapy. The mean age of participants was 65.6 years, and 90% were women.

Twenty-two (44%) patients had CIPN on the basis of patient-reported distal paresthesias or numbness that started when chemotherapy was initiated and was present at the time of study enrollment.

Patients with CIPN had a greater decline in executive function, compared with those without the condition, as measured by the Trail Making Test Part B (TMT-B; CIPN-positive, 84.9 sec vs. 59.1 sec, respectively; P = .01) and the Stroop Color and Word Test (SCWT; CIPN-positive, 178.1 sec vs. CIPN-negative, 152.7 sec; P = .04), as well as lower rapid reaction accuracy (CIPN-positive, 60.3% vs. CIPN-negative, 70.6%; P = .01).

The association between CIPN and decreased executive function remained after multivariate adjusting for age, gender, depression, and benzodiazepine use for TMT-B (beta, 18.7; P = .046) and rapid reaction accuracy (beta, -.088; P = .018) but not SCWT (beta, 9.52; P = .233).
 

Clinical guidance

A recent study by the same investigators showed a link between executive function and balance in cancer survivors (mean age, 65.6 years; 88% women) treated with chemotherapy.

Another study of 116 patients treated with chemotherapy, including 32 who developed CIPN, showed that those with CIPN were nearly three times more likely to report a fall or near fall than were those without CIPN symptoms. In addition, those with CIPN symptoms were also more likely to have received medical care for falls.

Based on the current findings, the research suggests that “current clinical approaches to caring for this growing population [of cancer patients] should not assume that the well-known increased fall risk is solely related to CIPN.”

Dr. McNeish speculated that two potential hypotheses could explain the association between CIPN and reduced executive function in older cancer survivors.

“First, CIPN is associated with other conditions such as depression and anxiety, which are associated with reduced executive function,” he said.

“The second is that cancer-related cognitive dysfunction and CIPN share pathogenic mechanisms of neuronal injury, inflammation, and advanced aging, and thus some patients are vulnerable to both central (cancer-related cognitive function) and peripheral neurotoxicity.”

Either way, Dr. McNeish noted that “all interventions should measure both CIPN and executive function, as one could confound the other.”
 

Need for increased awareness

Commenting on the study, Ting Bao, MD, co-director of the Leonard P. Zakim Center for Integrative Therapies & Healthy Living at the Dana-Farber Cancer Institute, Boston, said that the findings underscore that “there is a need for increased awareness of the diverse manifestations of chemotherapy-induced neuropathy.”

These include the fact that “neurotoxic chemotherapy impacts both the peripheral and central nervous systems, affecting balance through distinct mechanisms.”

Although treatments routinely recommended for CIPN include duloxetine, tricyclic antidepressants, or gabapentin as well as topical agents such as lidocaine, evidence also shows benefits of nonpharmacologic approaches including exercise, acupuncture, and yoga. Dr. Bao’s own research has suggested that those benefits can extend improved balance and reduced fall risk.

Dr. Bao and colleagues recently conducted a randomized study that included 41 patients with CIPN to receive either yoga or usual care.

“The findings revealed that after eight biweekly sessions of yoga, there was a notable improvement in the far-reach test, which is a predictor of fall risk,” she said.

To validate these findings, the researchers are currently conducting a larger randomized controlled trial, she said.

In the meantime, “further research into the mechanisms and effective treatments for chemotherapy-induced neurotoxicity is essential,” added Dr. Bao.

Dr. McNeish and Dr. Bao report no relevant disclosures.

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

PHOENIX – Chemotherapy-induced peripheral neuropathy (CIPN) is linked to a decline in executive and neuromuscular function, a new finding that may increase the risk for compromised mobility and fall risk.

“Among older cancer survivors treated with chemotherapy, the presence of CIPN was independently associated with reduced executive function,” said study investigator Brendan L. McNeish, MD, of the department of physical medicine and rehabilitation, University of Pittsburgh.

“Importantly, given the emerging relationship of executive function with mobility in this population, stakeholders and clinicians are called to acknowledge that chemotherapy-related mobility declines in CIPN survivors are likely due to both neuromuscular and executive dysfunction,” he said.

The findings were presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
 

Research gap

Characterized by numbness, tingling, pain, and motor impairment, CIPN affects up to 50% of all patients with cancer that is treated with taxane-, platinum-, or vinca alkaloid–based chemotherapy. The condition is among the leading dose-limiting toxicities, potentially increasing mortality risk.

Though the effects of chemotherapy on cognitive function are well-established, less is known about a potential relationship between this side effect and CIPN, Dr. McNeish said.

“Chemotherapy can be neurotoxic, but few studies have linked neurotoxicity to the central nervous system and peripheral nervous system,” Dr. McNeish said.

To compare cognitive outcomes in patients treated with chemotherapy who did and did not develop CIPN, the investigators conducted a cross-sectional study that included 50 chemotherapy-treated cancer survivors at a single time point post chemotherapy. The mean age of participants was 65.6 years, and 90% were women.

Twenty-two (44%) patients had CIPN on the basis of patient-reported distal paresthesias or numbness that started when chemotherapy was initiated and was present at the time of study enrollment.

Patients with CIPN had a greater decline in executive function, compared with those without the condition, as measured by the Trail Making Test Part B (TMT-B; CIPN-positive, 84.9 sec vs. 59.1 sec, respectively; P = .01) and the Stroop Color and Word Test (SCWT; CIPN-positive, 178.1 sec vs. CIPN-negative, 152.7 sec; P = .04), as well as lower rapid reaction accuracy (CIPN-positive, 60.3% vs. CIPN-negative, 70.6%; P = .01).

The association between CIPN and decreased executive function remained after multivariate adjusting for age, gender, depression, and benzodiazepine use for TMT-B (beta, 18.7; P = .046) and rapid reaction accuracy (beta, -.088; P = .018) but not SCWT (beta, 9.52; P = .233).
 

Clinical guidance

A recent study by the same investigators showed a link between executive function and balance in cancer survivors (mean age, 65.6 years; 88% women) treated with chemotherapy.

Another study of 116 patients treated with chemotherapy, including 32 who developed CIPN, showed that those with CIPN were nearly three times more likely to report a fall or near fall than were those without CIPN symptoms. In addition, those with CIPN symptoms were also more likely to have received medical care for falls.

Based on the current findings, the research suggests that “current clinical approaches to caring for this growing population [of cancer patients] should not assume that the well-known increased fall risk is solely related to CIPN.”

Dr. McNeish speculated that two potential hypotheses could explain the association between CIPN and reduced executive function in older cancer survivors.

“First, CIPN is associated with other conditions such as depression and anxiety, which are associated with reduced executive function,” he said.

“The second is that cancer-related cognitive dysfunction and CIPN share pathogenic mechanisms of neuronal injury, inflammation, and advanced aging, and thus some patients are vulnerable to both central (cancer-related cognitive function) and peripheral neurotoxicity.”

Either way, Dr. McNeish noted that “all interventions should measure both CIPN and executive function, as one could confound the other.”
 

Need for increased awareness

Commenting on the study, Ting Bao, MD, co-director of the Leonard P. Zakim Center for Integrative Therapies & Healthy Living at the Dana-Farber Cancer Institute, Boston, said that the findings underscore that “there is a need for increased awareness of the diverse manifestations of chemotherapy-induced neuropathy.”

These include the fact that “neurotoxic chemotherapy impacts both the peripheral and central nervous systems, affecting balance through distinct mechanisms.”

Although treatments routinely recommended for CIPN include duloxetine, tricyclic antidepressants, or gabapentin as well as topical agents such as lidocaine, evidence also shows benefits of nonpharmacologic approaches including exercise, acupuncture, and yoga. Dr. Bao’s own research has suggested that those benefits can extend improved balance and reduced fall risk.

Dr. Bao and colleagues recently conducted a randomized study that included 41 patients with CIPN to receive either yoga or usual care.

“The findings revealed that after eight biweekly sessions of yoga, there was a notable improvement in the far-reach test, which is a predictor of fall risk,” she said.

To validate these findings, the researchers are currently conducting a larger randomized controlled trial, she said.

In the meantime, “further research into the mechanisms and effective treatments for chemotherapy-induced neurotoxicity is essential,” added Dr. Bao.

Dr. McNeish and Dr. Bao report no relevant disclosures.

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

PHOENIX – Chemotherapy-induced peripheral neuropathy (CIPN) is linked to a decline in executive and neuromuscular function, a new finding that may increase the risk for compromised mobility and fall risk.

“Among older cancer survivors treated with chemotherapy, the presence of CIPN was independently associated with reduced executive function,” said study investigator Brendan L. McNeish, MD, of the department of physical medicine and rehabilitation, University of Pittsburgh.

“Importantly, given the emerging relationship of executive function with mobility in this population, stakeholders and clinicians are called to acknowledge that chemotherapy-related mobility declines in CIPN survivors are likely due to both neuromuscular and executive dysfunction,” he said.

The findings were presented at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).
 

Research gap

Characterized by numbness, tingling, pain, and motor impairment, CIPN affects up to 50% of all patients with cancer that is treated with taxane-, platinum-, or vinca alkaloid–based chemotherapy. The condition is among the leading dose-limiting toxicities, potentially increasing mortality risk.

Though the effects of chemotherapy on cognitive function are well-established, less is known about a potential relationship between this side effect and CIPN, Dr. McNeish said.

“Chemotherapy can be neurotoxic, but few studies have linked neurotoxicity to the central nervous system and peripheral nervous system,” Dr. McNeish said.

To compare cognitive outcomes in patients treated with chemotherapy who did and did not develop CIPN, the investigators conducted a cross-sectional study that included 50 chemotherapy-treated cancer survivors at a single time point post chemotherapy. The mean age of participants was 65.6 years, and 90% were women.

Twenty-two (44%) patients had CIPN on the basis of patient-reported distal paresthesias or numbness that started when chemotherapy was initiated and was present at the time of study enrollment.

Patients with CIPN had a greater decline in executive function, compared with those without the condition, as measured by the Trail Making Test Part B (TMT-B; CIPN-positive, 84.9 sec vs. 59.1 sec, respectively; P = .01) and the Stroop Color and Word Test (SCWT; CIPN-positive, 178.1 sec vs. CIPN-negative, 152.7 sec; P = .04), as well as lower rapid reaction accuracy (CIPN-positive, 60.3% vs. CIPN-negative, 70.6%; P = .01).

The association between CIPN and decreased executive function remained after multivariate adjusting for age, gender, depression, and benzodiazepine use for TMT-B (beta, 18.7; P = .046) and rapid reaction accuracy (beta, -.088; P = .018) but not SCWT (beta, 9.52; P = .233).
 

Clinical guidance

A recent study by the same investigators showed a link between executive function and balance in cancer survivors (mean age, 65.6 years; 88% women) treated with chemotherapy.

Another study of 116 patients treated with chemotherapy, including 32 who developed CIPN, showed that those with CIPN were nearly three times more likely to report a fall or near fall than were those without CIPN symptoms. In addition, those with CIPN symptoms were also more likely to have received medical care for falls.

Based on the current findings, the research suggests that “current clinical approaches to caring for this growing population [of cancer patients] should not assume that the well-known increased fall risk is solely related to CIPN.”

Dr. McNeish speculated that two potential hypotheses could explain the association between CIPN and reduced executive function in older cancer survivors.

“First, CIPN is associated with other conditions such as depression and anxiety, which are associated with reduced executive function,” he said.

“The second is that cancer-related cognitive dysfunction and CIPN share pathogenic mechanisms of neuronal injury, inflammation, and advanced aging, and thus some patients are vulnerable to both central (cancer-related cognitive function) and peripheral neurotoxicity.”

Either way, Dr. McNeish noted that “all interventions should measure both CIPN and executive function, as one could confound the other.”
 

Need for increased awareness

Commenting on the study, Ting Bao, MD, co-director of the Leonard P. Zakim Center for Integrative Therapies & Healthy Living at the Dana-Farber Cancer Institute, Boston, said that the findings underscore that “there is a need for increased awareness of the diverse manifestations of chemotherapy-induced neuropathy.”

These include the fact that “neurotoxic chemotherapy impacts both the peripheral and central nervous systems, affecting balance through distinct mechanisms.”

Although treatments routinely recommended for CIPN include duloxetine, tricyclic antidepressants, or gabapentin as well as topical agents such as lidocaine, evidence also shows benefits of nonpharmacologic approaches including exercise, acupuncture, and yoga. Dr. Bao’s own research has suggested that those benefits can extend improved balance and reduced fall risk.

Dr. Bao and colleagues recently conducted a randomized study that included 41 patients with CIPN to receive either yoga or usual care.

“The findings revealed that after eight biweekly sessions of yoga, there was a notable improvement in the far-reach test, which is a predictor of fall risk,” she said.

To validate these findings, the researchers are currently conducting a larger randomized controlled trial, she said.

In the meantime, “further research into the mechanisms and effective treatments for chemotherapy-induced neurotoxicity is essential,” added Dr. Bao.

Dr. McNeish and Dr. Bao report no relevant disclosures.

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

PHOENIX – Artificial intelligence (AI) is poised to dramatically alter health care, and it presents opportunities for increased production and automation of some tasks. However, it is prone to error and ‘hallucinations’ despite an authoritative tone, so its conclusions must be verified.

Those were some of the messages from a talk by John Morren, MD, an associate professor of neurology at Case Western Reserve University, Cleveland, who spoke about AI at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

He encouraged attendees to get involved in the conversation of AI, because it is here to stay and will have a big impact on health care. “If we’re not around the table making decisions, decisions will be made for us in our absence and won’t be in our favor,” said Dr. Morren.

He started out his talk by asking if anyone in the room had used AI. After about half raised their hands, he countered that nearly everyone likely had. Voice assistants like SIRI and Alexa, social media with curated feeds, online shopping tools that provide product suggestions, and content recommendations from streaming services like Netflix all rely on AI technology.

Within medicine, AI is already playing a role in various fields, including medical imaging, disease diagnosis, drug discovery and development, predictive analytics, personalized medicine, telemedicine, and health care management.

It also has potential to be used on the job. For example, ChatGPT can generate and refine conversations towards a specific length, format, style, and level of detail. Alternatives include Bing AI from Microsoft, Bard AI from Google, Writesonic, Copy.ai, SpinBot, HIX.AI, and Chatsonic.

Specific to medicine, Consensus is a search engine that uses AI to search for, summarize, and synthesize studies from peer-reviewed literature.
 

Trust, but verify

Dr. Morren presented some specific use cases, including patient education and responses to patient inquiries, as well as generating letters to insurance companies appealing denial of coverage claims. He also showed an example where he asked Bing AI to explain to a patient, at a sixth- to seventh-grade reading level, the red-flag symptoms of myasthenic crisis.

AI can generate summaries of clinical evidence of previous studies. Asked by this reporter how to trust the accuracies of the summaries if the user hasn’t thoroughly read the papers, he acknowledged the imperfection of AI. “I would say that if you’re going to make a decision that you would not have made normally based on the summary that it’s giving, if you can find the fact that you’re anchoring the decision on, go into the article yourself and make sure that it’s well vetted. The AI is just good to tap you on your shoulder and say, ‘hey, just consider this.’ That’s all it is. You should always trust, but verify. If the AI is forcing you to say something new that you would not say, maybe don’t do it – or at least research it to know that it’s the truth and then you elevate yourself and get yourself to the next level.”
 

Limitations

The need to verify can create its own burden, according to one attendee. “I often find I end up spending more time verifying [what ChatGPT has provided]. This seems to take more time than a traditional way of going to PubMed or UpToDate or any of the other human generated consensus way,” he said.

Dr. Morren replied that he wouldn’t recommend using ChatGPT to query medical literature. Instead he recommended Consensus, which only searches the peer-reviewed medical literature.

Another key limitation is that most AI programs are date limited: For example, ChatGPT doesn’t include information after September 2021, though this may change with paid subscriptions. He also starkly warned the audience to never enter sensitive information, including patient identifiers.

There are legal and ethical considerations to AI. Dr. Morren warned against overreliance on AI, as this could undermine compassion and lead to erosion of trust, which makes it important to disclose any use of AI-generated content.

Another attendee raised concerns that AI may be generating research content, including slides for presentations, abstracts, titles, or article text. Dr. Morren said that some organizations, such as the International Committee of Medical Journal Editors, have incorporated AI in their recommendations, stating that authors should disclose any contributions of AI to their publications. However, there is little that can be done to identify AI-generated content, leaving it up to the honor code.

Asked to make predictions about how AI will evolve in the clinic over the next 2-3 years, Dr. Morren suggested that it will likely be embedded in electronic medical records. He anticipated that it will save physicians time so that they can spend more time interacting directly with patients. He quoted Eric Topol, MD, professor of medicine at Scripps Research Translational Institute, La Jolla, Calif., as saying that AI could save 20% of a physician’s time, which could be spent with patients. Dr. Morren saw it differently. “I know where that 20% of time liberated is going to go. I’m going to see 20% more patients. I’m a realist,” he said, to audience laughter.

He also predicted that AI will be found in wearables and devices, allowing health care to expand into the patient’s home in real time. “A lot of what we’re wearing is going to be an extension of the doctor’s office,” he said.

For those hoping for more guidance, Dr. Morren noted that he is the chairman of the professional practice committee of AANEM, and the group will be putting out a position statement within the next couple of months. “It will be a little bit of a blueprint for the path going forward. There are specific things that need to be done. In research, for example, you have to ensure that datasets are diverse enough. To do that we need to have inter-institutional collaboration. We have to ensure patient privacy. Consent for this needs to be a little more explicit because this is a novel area. Those are things that need to be stipulated and ratified through a task force.”

Dr. Morren has no relevant financial disclosures.

PHOENIX – Artificial intelligence (AI) is poised to dramatically alter health care, and it presents opportunities for increased production and automation of some tasks. However, it is prone to error and ‘hallucinations’ despite an authoritative tone, so its conclusions must be verified.

Those were some of the messages from a talk by John Morren, MD, an associate professor of neurology at Case Western Reserve University, Cleveland, who spoke about AI at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

He encouraged attendees to get involved in the conversation of AI, because it is here to stay and will have a big impact on health care. “If we’re not around the table making decisions, decisions will be made for us in our absence and won’t be in our favor,” said Dr. Morren.

He started out his talk by asking if anyone in the room had used AI. After about half raised their hands, he countered that nearly everyone likely had. Voice assistants like SIRI and Alexa, social media with curated feeds, online shopping tools that provide product suggestions, and content recommendations from streaming services like Netflix all rely on AI technology.

Within medicine, AI is already playing a role in various fields, including medical imaging, disease diagnosis, drug discovery and development, predictive analytics, personalized medicine, telemedicine, and health care management.

It also has potential to be used on the job. For example, ChatGPT can generate and refine conversations towards a specific length, format, style, and level of detail. Alternatives include Bing AI from Microsoft, Bard AI from Google, Writesonic, Copy.ai, SpinBot, HIX.AI, and Chatsonic.

Specific to medicine, Consensus is a search engine that uses AI to search for, summarize, and synthesize studies from peer-reviewed literature.
 

Trust, but verify

Dr. Morren presented some specific use cases, including patient education and responses to patient inquiries, as well as generating letters to insurance companies appealing denial of coverage claims. He also showed an example where he asked Bing AI to explain to a patient, at a sixth- to seventh-grade reading level, the red-flag symptoms of myasthenic crisis.

AI can generate summaries of clinical evidence of previous studies. Asked by this reporter how to trust the accuracies of the summaries if the user hasn’t thoroughly read the papers, he acknowledged the imperfection of AI. “I would say that if you’re going to make a decision that you would not have made normally based on the summary that it’s giving, if you can find the fact that you’re anchoring the decision on, go into the article yourself and make sure that it’s well vetted. The AI is just good to tap you on your shoulder and say, ‘hey, just consider this.’ That’s all it is. You should always trust, but verify. If the AI is forcing you to say something new that you would not say, maybe don’t do it – or at least research it to know that it’s the truth and then you elevate yourself and get yourself to the next level.”
 

Limitations

The need to verify can create its own burden, according to one attendee. “I often find I end up spending more time verifying [what ChatGPT has provided]. This seems to take more time than a traditional way of going to PubMed or UpToDate or any of the other human generated consensus way,” he said.

Dr. Morren replied that he wouldn’t recommend using ChatGPT to query medical literature. Instead he recommended Consensus, which only searches the peer-reviewed medical literature.

Another key limitation is that most AI programs are date limited: For example, ChatGPT doesn’t include information after September 2021, though this may change with paid subscriptions. He also starkly warned the audience to never enter sensitive information, including patient identifiers.

There are legal and ethical considerations to AI. Dr. Morren warned against overreliance on AI, as this could undermine compassion and lead to erosion of trust, which makes it important to disclose any use of AI-generated content.

Another attendee raised concerns that AI may be generating research content, including slides for presentations, abstracts, titles, or article text. Dr. Morren said that some organizations, such as the International Committee of Medical Journal Editors, have incorporated AI in their recommendations, stating that authors should disclose any contributions of AI to their publications. However, there is little that can be done to identify AI-generated content, leaving it up to the honor code.

Asked to make predictions about how AI will evolve in the clinic over the next 2-3 years, Dr. Morren suggested that it will likely be embedded in electronic medical records. He anticipated that it will save physicians time so that they can spend more time interacting directly with patients. He quoted Eric Topol, MD, professor of medicine at Scripps Research Translational Institute, La Jolla, Calif., as saying that AI could save 20% of a physician’s time, which could be spent with patients. Dr. Morren saw it differently. “I know where that 20% of time liberated is going to go. I’m going to see 20% more patients. I’m a realist,” he said, to audience laughter.

He also predicted that AI will be found in wearables and devices, allowing health care to expand into the patient’s home in real time. “A lot of what we’re wearing is going to be an extension of the doctor’s office,” he said.

For those hoping for more guidance, Dr. Morren noted that he is the chairman of the professional practice committee of AANEM, and the group will be putting out a position statement within the next couple of months. “It will be a little bit of a blueprint for the path going forward. There are specific things that need to be done. In research, for example, you have to ensure that datasets are diverse enough. To do that we need to have inter-institutional collaboration. We have to ensure patient privacy. Consent for this needs to be a little more explicit because this is a novel area. Those are things that need to be stipulated and ratified through a task force.”

Dr. Morren has no relevant financial disclosures.

PHOENIX – Artificial intelligence (AI) is poised to dramatically alter health care, and it presents opportunities for increased production and automation of some tasks. However, it is prone to error and ‘hallucinations’ despite an authoritative tone, so its conclusions must be verified.

Those were some of the messages from a talk by John Morren, MD, an associate professor of neurology at Case Western Reserve University, Cleveland, who spoke about AI at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

He encouraged attendees to get involved in the conversation of AI, because it is here to stay and will have a big impact on health care. “If we’re not around the table making decisions, decisions will be made for us in our absence and won’t be in our favor,” said Dr. Morren.

He started out his talk by asking if anyone in the room had used AI. After about half raised their hands, he countered that nearly everyone likely had. Voice assistants like SIRI and Alexa, social media with curated feeds, online shopping tools that provide product suggestions, and content recommendations from streaming services like Netflix all rely on AI technology.

Within medicine, AI is already playing a role in various fields, including medical imaging, disease diagnosis, drug discovery and development, predictive analytics, personalized medicine, telemedicine, and health care management.

It also has potential to be used on the job. For example, ChatGPT can generate and refine conversations towards a specific length, format, style, and level of detail. Alternatives include Bing AI from Microsoft, Bard AI from Google, Writesonic, Copy.ai, SpinBot, HIX.AI, and Chatsonic.

Specific to medicine, Consensus is a search engine that uses AI to search for, summarize, and synthesize studies from peer-reviewed literature.
 

Trust, but verify

Dr. Morren presented some specific use cases, including patient education and responses to patient inquiries, as well as generating letters to insurance companies appealing denial of coverage claims. He also showed an example where he asked Bing AI to explain to a patient, at a sixth- to seventh-grade reading level, the red-flag symptoms of myasthenic crisis.

AI can generate summaries of clinical evidence of previous studies. Asked by this reporter how to trust the accuracies of the summaries if the user hasn’t thoroughly read the papers, he acknowledged the imperfection of AI. “I would say that if you’re going to make a decision that you would not have made normally based on the summary that it’s giving, if you can find the fact that you’re anchoring the decision on, go into the article yourself and make sure that it’s well vetted. The AI is just good to tap you on your shoulder and say, ‘hey, just consider this.’ That’s all it is. You should always trust, but verify. If the AI is forcing you to say something new that you would not say, maybe don’t do it – or at least research it to know that it’s the truth and then you elevate yourself and get yourself to the next level.”
 

Limitations

The need to verify can create its own burden, according to one attendee. “I often find I end up spending more time verifying [what ChatGPT has provided]. This seems to take more time than a traditional way of going to PubMed or UpToDate or any of the other human generated consensus way,” he said.

Dr. Morren replied that he wouldn’t recommend using ChatGPT to query medical literature. Instead he recommended Consensus, which only searches the peer-reviewed medical literature.

Another key limitation is that most AI programs are date limited: For example, ChatGPT doesn’t include information after September 2021, though this may change with paid subscriptions. He also starkly warned the audience to never enter sensitive information, including patient identifiers.

There are legal and ethical considerations to AI. Dr. Morren warned against overreliance on AI, as this could undermine compassion and lead to erosion of trust, which makes it important to disclose any use of AI-generated content.

Another attendee raised concerns that AI may be generating research content, including slides for presentations, abstracts, titles, or article text. Dr. Morren said that some organizations, such as the International Committee of Medical Journal Editors, have incorporated AI in their recommendations, stating that authors should disclose any contributions of AI to their publications. However, there is little that can be done to identify AI-generated content, leaving it up to the honor code.

Asked to make predictions about how AI will evolve in the clinic over the next 2-3 years, Dr. Morren suggested that it will likely be embedded in electronic medical records. He anticipated that it will save physicians time so that they can spend more time interacting directly with patients. He quoted Eric Topol, MD, professor of medicine at Scripps Research Translational Institute, La Jolla, Calif., as saying that AI could save 20% of a physician’s time, which could be spent with patients. Dr. Morren saw it differently. “I know where that 20% of time liberated is going to go. I’m going to see 20% more patients. I’m a realist,” he said, to audience laughter.

He also predicted that AI will be found in wearables and devices, allowing health care to expand into the patient’s home in real time. “A lot of what we’re wearing is going to be an extension of the doctor’s office,” he said.

For those hoping for more guidance, Dr. Morren noted that he is the chairman of the professional practice committee of AANEM, and the group will be putting out a position statement within the next couple of months. “It will be a little bit of a blueprint for the path going forward. There are specific things that need to be done. In research, for example, you have to ensure that datasets are diverse enough. To do that we need to have inter-institutional collaboration. We have to ensure patient privacy. Consent for this needs to be a little more explicit because this is a novel area. Those are things that need to be stipulated and ratified through a task force.”

Dr. Morren has no relevant financial disclosures.

PHOENIX – The prevalence of myasthenia gravis is about 0.13% among U.S. adults, and the condition is more common in Whites than in African Americans, according to a new analysis of the National Institutes of Health All of Us database. The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.

Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.

However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
 

True incidence or artifact?

The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.

However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
 

Understanding the true prevalence

Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.

He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.

It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.

The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.

The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.

The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).

Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.

PHOENIX – The prevalence of myasthenia gravis is about 0.13% among U.S. adults, and the condition is more common in Whites than in African Americans, according to a new analysis of the National Institutes of Health All of Us database. The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.

Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.

However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
 

True incidence or artifact?

The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.

However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
 

Understanding the true prevalence

Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.

He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.

It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.

The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.

The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.

The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).

Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.

PHOENIX – The prevalence of myasthenia gravis is about 0.13% among U.S. adults, and the condition is more common in Whites than in African Americans, according to a new analysis of the National Institutes of Health All of Us database. The prevalence is higher than what has been seen in other studies, which could represent a true difference in prevalence, or reflect limitations of the database.

Worldwide estimates suggest that myasthenia gravis affects 700,000 people globally, with incidence rates ranging between 6.3 and 29 per 1,000,000 person-years in Europe and a prevalence between 111.7 and 361 per 1,000,000. Data from Australia, Taiwan, and South Korea also show evidence of increased prevalence in recent years.

However, there is little data about the prevalence of myasthenia gravis in the United States, or about differences between racial groups, according to Bhaskar Roy, MBBS, who presented the study at the 2023 annual meeting of the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). He noted that most studies are outdated, and the most recent study focused on ocular myasthenia gravis.
 

True incidence or artifact?

The finding is surprising and may be an artifact of the immature nature of the All of Us database, according to Srikanth Muppidi, MD, who asked about the limitation during the Q&A session following the talk. “The incidence of 0.13 is definitely higher than what we would think would be the true incidence of myasthenia gravis from [clinical experience]. It’s possible that our understanding of true incidence is wrong and this is the actual incidence. What I would like them to do, and I think they’re trying to do, is to look at this finding [and compare it with] other more mature databases and other regional databases. One of the current challenges of All of Us is that our patients are basically being recruited from some parts of the country, and the middle of the country has hardly any presence in the database, so it becomes really challenging to understand it,” Dr. Muppidi said in an interview.

However, Dr. Muppidi, who is a clinical professor of neurology at Stanford (Calif.) Medicine, noted that the All of Us database is still growing. When it has recruited more patients with a diverse population, “it [will be a] valuable source for rare diseases to try to understand true incidence of those diseases,” he said.
 

Understanding the true prevalence

Dr. Roy recognized the geographic limitations of the database. “Some states, particularly Massachusetts, New York, and California, had a lot of patients in the database, where there were no patients from many states,” said Dr. Roy, associate professor of neurology at Yale University, New Haven, Conn.

He said that the group is working with other databases, including UK Biobank. “The goal is to incorporate all of these databases together [to determine the true incidence],” said Dr. Roy.

It’s critical to understand the true prevalence of myasthenia gravis since new therapies are in development and coming to market. “I worry that myasthenia gravis might be considered less common than it truly is, and that will limit growth of the field if the feeling is that there are not that many [myasthenia gravis patients] in the country,” said Dr. Muppidi.

The study included data from 369,297 adult patients, using Systematized Nomenclature of Medicine (SNOMED) and International Classification of Diseases (ICD) codes to identify patients with myasthenia gravis. There were 479 cases of myasthenia gravis, for a prevalence of 0.13 (95% confidence interval [CI], 0.12-0.14). Of myasthenia gravis patients, 65% were female and the mean age was 64 years. The prevalence of myasthenia gravis in White individuals was 0.16 (95% CI, 0.15-0.18), of which 63% were female, and the mean age was 66 years. The prevalence among Black individuals was 0.078 (95% CI, 0.060-0.10), with 77% of the population female and a mean age of 58 years. The prevalence in Hispanics was 0.091 (95% CI, 0.070-0.12), with 80% female and a mean age of 58 years. Among Asians, the prevalence was 0.056 (95% CI, 0.025-0.12) and 57% were female, with a mean age of 58 years.

The researchers also looked at the EXPLORE-MG database drawn from Yale (n = 3,269,000), which showed a much lower overall myasthenia gravis prevalence of 0.019 (95% CI, 0.017-0.020), a female proportion of 46.8%, and a mean age of 56.6 years. Notably, EXPLORE-MG had a lower proportion of women and a younger population than All of Us.

The researchers compared data from All of Us with other databases for other conditions. The prevalence of ALS was the same as in other conditions, while diabetic neuropathy was significantly lower (2.7 versus 28.5-50 among diabetic patients) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was higher (0.084 versus 0.028).

Dr. Muppidi has been on advisory boards for Alexion, Argenx, UBC, and Immunovant. Dr. Roy has consulted for Alexion, Takeda Pharmaceuticals, and Argenx and owns stock in Cabaletta Bio. He has received research support from Takeda, Abcuro, and Argenx.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.

“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

Children’s Hospital of Richmond at Virginia Commonwealth University

A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.

Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.

A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
 

A tool for continuous cognitive assessment

The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.

Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.

She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.

Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.

She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.

Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.

She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.

Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
 

Overcoming a significant barrier

The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.

Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”

Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.

“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

Children’s Hospital of Richmond at Virginia Commonwealth University

A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.

Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.

A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
 

A tool for continuous cognitive assessment

The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.

Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.

She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.

Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.

She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.

Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.

She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.

Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
 

Overcoming a significant barrier

The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.

Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”

Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.

Cognitive issues in children with Duchenne muscular dystrophy (DMD) are linked to worse outcomes, but limited access to specialists and limited resources make this problem difficult to address. A new tool from the National Institutes of Health, called NIH Toolbox, could improve that outcome, according to Mathula Thangarajh, MD, PhD, who has conducted research in the field.

“When we talk to families and parents, they are able to identify that even during infancy that [children with DMD] have delayed cognitive function. This includes speech delay, but also language and adaptive skills. We also know that those children with speech delay, which is really a very commonly reported phenotype in up to 50%, go on to have school-based needs. They may repeat [grades] in elementary years, but they also use more resources at school,” said Dr. Thangarajh, who is an assistant professor of neurology at the Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, during a talk at the 2023 annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine (AANEM).

Children’s Hospital of Richmond at Virginia Commonwealth University

A previous natural history study that utilized the Pediatric Quality of Life assessment also showed that DMD patients reported the lowest scores in brain health, including emotional health and school performance.

Other research has shown a correlation between cognitive function and survival in DMD. “This suggests that health maintenance may play an important role [in outcomes],” said Dr. Thangarajh. Another study found a correlation between psychomotor delay that required school-based interventions and earlier loss of ambulation, lower cardiac ejection fraction, and worse pulmonary function. The researchers also found that boys with cognitive delay were diagnosed at an earlier age, and yet had delays in diagnosis and worse motor function, pulmonary health, and cardiac health outcomes. On average, they lost ambulatory ability 2 years earlier.

A study by Dr. Thangarajh’s group showed that patients with speech delay and lower IQ had lower performance in timed tests, including 6-minute walk test distance and scored an average of 2 points lower on the North Star Ambulatory Assessment.
 

A tool for continuous cognitive assessment

The Centers for Disease Control and Prevention–supported DMD CARE guidelines only say that neuropsychological evaluations should be considered at diagnosis, but is essential if concerns arise about developmental progress. However, the Muscular Dystrophy Association has found barriers both in access to specialists, with an average wait time of 1-2 years, and burdensome out-of-pocket costs.

Those issues prompted Dr. Thangarajh to look for an alternative solution. At the time that she embarked on this work, the NIH was interested in technologies to assess neurobehavioral issues across different diseases. The resulting NIH Toolbox iPad app was driven largely by failed clinical trials in dementia, and the aim was to be able to provide continuous assessment over time. “It will allow for assessments across the lifespan, so you can use the same construct from age 3 to 80-plus,” said Dr. Thangarajh. It can also normalize population factors, such as annual household income and mother’s IQ.

She set out to validate the NIH Toolbox in children with DMD. The toolbox includes measures of crystalized cognition and fluid cognition. The former encompasses vocabulary and reading ability, which are strongly predicted by socioeconomic status and maternal IQ. On the other hand, fluid cognition includes cognitive features that develop across the lifespan and is directly related to academic underperformance in DMD patients.

Dr. Thangarajh’s group assessed 30 boys with DMD and found that crystallized cognition was normal, but they had a deficit in fluid cognition. They found deficits within several subdomains of fluid cognition. “This tells us that the NIH Toolbox was able to replicate what we had known in the literature, that these boys really have lower intellectual capacity, but they also have significant weakness in fluid cognition,” she said.

She also wanted to examine changes over time by testing the boys at a 1-year interview. “What we found was that they are not making as much gain in fluid cognition as we would like. They are just making marginal improvements over time. This has implications on how often we should screen them, but also not be over reliant on using school-based resources for them to get tested,” said Dr. Thangarajh.

Her group’s analysis of a dataset of 55 boys provided by PTC Therapeutics revealed a difference by age in a test of working memory. “What we found was that boys who are actually greater than 9 years, compared with those who are less than 9 years, they actually had a reversal of development-based improvement. The older they get, they were not making as much gains as you would expect,” said Dr. Thangarajh.

She went on to discuss psychosocial determinants of cognitive health in DMD. It is known that women who are carriers of the dystrophin mutation can underperform in cognitively stressful tasks, leading her to wonder if this could lead to transgenerational risk to offspring with DMD. Her group tested women who were carriers of the mutation with the NIH Toolbox and found that they had lower fluid cognition than noncarriers. They then tested 65 dyads of mothers and children, and found a correlation, but only when it came to inhibitory control, which required the individual to note the direction of an arrow while ignoring surrounding arrows pointing in various directions.

Next, the researchers examined neighborhoods and their impact on cognitive health, which can be affected by the presence of green spaces, access to public transportation and good nutrition, and other factors. There were significant deficits associated with residence zip codes. “We were pretty shocked. Someone who is not in a socially vulnerable region is scoring slightly below average, but someone who is in a very socially vulnerable neighborhood is only scoring 75 [age-adjusted score] on the NIH toolbox. So with this, we can conclude that carrier women are vulnerable in certain cognitive domains, but also children who come from socially vulnerable [situations] have poor cognitive control. This, again, has implications on how often we should screen and how much we should overly rely on school-based resources for these individuals,” said Dr. Thangarajh.
 

Overcoming a significant barrier

The NIH Toolbox has a lot of potential to improve DMD care, according to Dianna Quan, MD, who is the incoming president of AANEM, and professor of neurology at the University of Colorado at Denver, Aurora. “There’s this huge problem in terms of getting people in to see neuropsychologists and having formal evaluations. I think that’s a huge barrier. If we have people able to access this toolkit, which is simple and easily and universally accessible, how wonderful is that? I think that will be a really great improvement on what’s going on right now. It allows people to easily screen for these cognitive disabilities and make sure that we address them,” Dr. Quan said in an interview.

Asked how the tool could specifically improve care, Dr. Quan suggested that the first step is to understand the contributing factors to cognitive issues, whether they are biological, social, or a combination. “Some of them we can modify, potentially, through addressing the social environment. Some of those biologic factors may also be modifiable with many of the new drug studies that are coming.”

Dr. Thangarajh has received speaker honoraria from NS Pharma and PTC Therapeutics. Dr. Quan has received funding from Alnylam, Pfizer, Cytokinetics, Momenta, and Argenx.