Patients with migraines and patients classified as Caucasian had higher odds of being diagnosed with transient global amnesia (TGA), according to a recent study. All minority populations, however, showed a lower rate of diagnosis that fell short of statistical significance.  Data were obtained from the Nationwide Inpatient Sample using ICD-9 and procedure codes. Descriptive and survey logistic regression analyses were conducted and adjusted for influence of comorbidities, demographic characteristics, and hospitalization-related factors. Researchers found:

• Patients with migraines were 5.98 times more likely to also have a diagnosis of TGA compared with patients without migraines.
• Similarly, patients with TGA were more likely to have hypertension, precerebral disease, and hyperlipidemia.
• The odds of being diagnosed with TGA was lower among African Americans and Hispanics as well as among patients classified as Asian/other, compared with Caucasians.
• TGA was associated with lower hospital charges ($14,242 vs $21,319), shorter hospital stays (mean days: 2.49 [SE=0.036] vs 4.72 [SE=0.025]), and routine hospital discharges (91.4% vs 74.5%).

Yi M, Sherzai AZ, Ani C, et al. Strong association between migraine and transient global amnesia: A National Inpatient Sample analysis. [Published online ahead of print October 11, 2018]. J Neuropsychiatry Clin Neurosci. doi:10.1176/appi.neuropsych.17120353.

Patients with migraines and patients classified as Caucasian had higher odds of being diagnosed with transient global amnesia (TGA), according to a recent study. All minority populations, however, showed a lower rate of diagnosis that fell short of statistical significance.  Data were obtained from the Nationwide Inpatient Sample using ICD-9 and procedure codes. Descriptive and survey logistic regression analyses were conducted and adjusted for influence of comorbidities, demographic characteristics, and hospitalization-related factors. Researchers found:

• Patients with migraines were 5.98 times more likely to also have a diagnosis of TGA compared with patients without migraines.
• Similarly, patients with TGA were more likely to have hypertension, precerebral disease, and hyperlipidemia.
• The odds of being diagnosed with TGA was lower among African Americans and Hispanics as well as among patients classified as Asian/other, compared with Caucasians.
• TGA was associated with lower hospital charges ($14,242 vs $21,319), shorter hospital stays (mean days: 2.49 [SE=0.036] vs 4.72 [SE=0.025]), and routine hospital discharges (91.4% vs 74.5%).

Yi M, Sherzai AZ, Ani C, et al. Strong association between migraine and transient global amnesia: A National Inpatient Sample analysis. [Published online ahead of print October 11, 2018]. J Neuropsychiatry Clin Neurosci. doi:10.1176/appi.neuropsych.17120353.

Patients with migraines and patients classified as Caucasian had higher odds of being diagnosed with transient global amnesia (TGA), according to a recent study. All minority populations, however, showed a lower rate of diagnosis that fell short of statistical significance.  Data were obtained from the Nationwide Inpatient Sample using ICD-9 and procedure codes. Descriptive and survey logistic regression analyses were conducted and adjusted for influence of comorbidities, demographic characteristics, and hospitalization-related factors. Researchers found:

• Patients with migraines were 5.98 times more likely to also have a diagnosis of TGA compared with patients without migraines.
• Similarly, patients with TGA were more likely to have hypertension, precerebral disease, and hyperlipidemia.
• The odds of being diagnosed with TGA was lower among African Americans and Hispanics as well as among patients classified as Asian/other, compared with Caucasians.
• TGA was associated with lower hospital charges ($14,242 vs $21,319), shorter hospital stays (mean days: 2.49 [SE=0.036] vs 4.72 [SE=0.025]), and routine hospital discharges (91.4% vs 74.5%).

Yi M, Sherzai AZ, Ani C, et al. Strong association between migraine and transient global amnesia: A National Inpatient Sample analysis. [Published online ahead of print October 11, 2018]. J Neuropsychiatry Clin Neurosci. doi:10.1176/appi.neuropsych.17120353.

ORLANDO – Less than half of children could identify a real gun from a toy gun in photos, regardless of whether their parents owned a gun or had talked to them about firearm safety, according to a new study.

Tara Haelle/MDedge News

“That is very concerning to us because a large percentage of these parents are actually storing their firearms insecurely and then their children cannot tell the difference,” study investigator Kiesha Fraser Doh, MD, reported at the annual conference of the American Academy of Pediatrics.

Dr. Fraser Doh, assistant professor of pediatrics and emergency medicine physician at Emory University School of Medicine and Children’s Healthcare of Atlanta said she was inspired to conduct this study after she noticed she was seeing approximately one firearm injury in children about every 2½ weeks in her institution. She also realized that her own child frequently went on play dates, but she did not always think to ask about firearms in the home of the friends her child visited.

An estimated one in three U.S. children live in homes with a firearm, she explained, and many of these guns are left loaded and/or unlocked.

The researchers enrolled a convenience sample of 297 English-speaking caregivers who presented at one of three pediatrics EDs over 3 months. Two were suburban departments, and one was urban.

Overall, most respondents (79%) were female and 56% were black, while 33% were white. Most of the caregivers responding had some college education (72%), and just over half (51%) had an income greater than $50,000.

The researchers asked caregivers whether they had guns in their own home and whether their child had access to firearms in their own or other homes. They also asked if their child played with toy guns and whether they believed their child could tell the difference between a real gun and a toy one.

Compared with those who did not own guns, gun owners were significantly more likely to be white and have both an income over $50,000 and some college education.

Meanwhile, researchers showed the children, aged 7-17 years, photos of a toy gun and a real gun and asked which was which.

A quarter of the caregivers (25%) owned guns, and half of them (50%) allowed their children to play with guns, compared with 26% of the non-gun owners.

In addition, 86% of the gun owners had discussed gun safety with their children, and the same proportion believed their children could correctly distinguish between a real gun and a toy gun.

By comparison, 58% of the non-gun owners had discussed gun safety with their children, and the same percentage believed their children could tell the difference between real and fake guns.

The children’s confidence in being able to tell the difference was similar regardless of whether their parents owned guns (79%) or didn’t (76%).

Yet less than half of all children correctly identified the real gun in the photos: 39% of the gun owners’ children and 42% of the non-gun owners’ children correctly pointed out the real gun, a nonsignificant difference.

Throughout the entire sample, more than 8 in 10 respondents, both gun owners (86%) and not (84%), believed there should be a law that requires caregivers to store their guns safely. A similar proportion (85% of gun owners and 80% of non-gun owners) believed legal penalties should exist for caregivers “if a child encounters an unsecured firearm.”

Overall, 5% of the respondents (14% of gun owners and 4% of non-gun owners) believed their child could get a gun within 24 hours if desired.

“So what does this mean to us as clinicians? It behooves [pediatricians] to actually continue to educate families at well-child visits on the guidelines about how to store firearms safely, locked up, unloaded, separate from ammunition,” Dr. Fraser Doh said. “On the flip side, parents need to be asking about the presence of firearms in the homes their children visit and also make sure that they’re storing their weapons safety.”

Dr. Fraser Doh said she had no relevant conflicts of interest.

ORLANDO – Less than half of children could identify a real gun from a toy gun in photos, regardless of whether their parents owned a gun or had talked to them about firearm safety, according to a new study.

Tara Haelle/MDedge News

“That is very concerning to us because a large percentage of these parents are actually storing their firearms insecurely and then their children cannot tell the difference,” study investigator Kiesha Fraser Doh, MD, reported at the annual conference of the American Academy of Pediatrics.

Dr. Fraser Doh, assistant professor of pediatrics and emergency medicine physician at Emory University School of Medicine and Children’s Healthcare of Atlanta said she was inspired to conduct this study after she noticed she was seeing approximately one firearm injury in children about every 2½ weeks in her institution. She also realized that her own child frequently went on play dates, but she did not always think to ask about firearms in the home of the friends her child visited.

An estimated one in three U.S. children live in homes with a firearm, she explained, and many of these guns are left loaded and/or unlocked.

The researchers enrolled a convenience sample of 297 English-speaking caregivers who presented at one of three pediatrics EDs over 3 months. Two were suburban departments, and one was urban.

Overall, most respondents (79%) were female and 56% were black, while 33% were white. Most of the caregivers responding had some college education (72%), and just over half (51%) had an income greater than $50,000.

The researchers asked caregivers whether they had guns in their own home and whether their child had access to firearms in their own or other homes. They also asked if their child played with toy guns and whether they believed their child could tell the difference between a real gun and a toy one.

Compared with those who did not own guns, gun owners were significantly more likely to be white and have both an income over $50,000 and some college education.

Meanwhile, researchers showed the children, aged 7-17 years, photos of a toy gun and a real gun and asked which was which.

A quarter of the caregivers (25%) owned guns, and half of them (50%) allowed their children to play with guns, compared with 26% of the non-gun owners.

In addition, 86% of the gun owners had discussed gun safety with their children, and the same proportion believed their children could correctly distinguish between a real gun and a toy gun.

By comparison, 58% of the non-gun owners had discussed gun safety with their children, and the same percentage believed their children could tell the difference between real and fake guns.

The children’s confidence in being able to tell the difference was similar regardless of whether their parents owned guns (79%) or didn’t (76%).

Yet less than half of all children correctly identified the real gun in the photos: 39% of the gun owners’ children and 42% of the non-gun owners’ children correctly pointed out the real gun, a nonsignificant difference.

Throughout the entire sample, more than 8 in 10 respondents, both gun owners (86%) and not (84%), believed there should be a law that requires caregivers to store their guns safely. A similar proportion (85% of gun owners and 80% of non-gun owners) believed legal penalties should exist for caregivers “if a child encounters an unsecured firearm.”

Overall, 5% of the respondents (14% of gun owners and 4% of non-gun owners) believed their child could get a gun within 24 hours if desired.

“So what does this mean to us as clinicians? It behooves [pediatricians] to actually continue to educate families at well-child visits on the guidelines about how to store firearms safely, locked up, unloaded, separate from ammunition,” Dr. Fraser Doh said. “On the flip side, parents need to be asking about the presence of firearms in the homes their children visit and also make sure that they’re storing their weapons safety.”

Dr. Fraser Doh said she had no relevant conflicts of interest.

ORLANDO – Less than half of children could identify a real gun from a toy gun in photos, regardless of whether their parents owned a gun or had talked to them about firearm safety, according to a new study.

Tara Haelle/MDedge News

“That is very concerning to us because a large percentage of these parents are actually storing their firearms insecurely and then their children cannot tell the difference,” study investigator Kiesha Fraser Doh, MD, reported at the annual conference of the American Academy of Pediatrics.

Dr. Fraser Doh, assistant professor of pediatrics and emergency medicine physician at Emory University School of Medicine and Children’s Healthcare of Atlanta said she was inspired to conduct this study after she noticed she was seeing approximately one firearm injury in children about every 2½ weeks in her institution. She also realized that her own child frequently went on play dates, but she did not always think to ask about firearms in the home of the friends her child visited.

An estimated one in three U.S. children live in homes with a firearm, she explained, and many of these guns are left loaded and/or unlocked.

The researchers enrolled a convenience sample of 297 English-speaking caregivers who presented at one of three pediatrics EDs over 3 months. Two were suburban departments, and one was urban.

Overall, most respondents (79%) were female and 56% were black, while 33% were white. Most of the caregivers responding had some college education (72%), and just over half (51%) had an income greater than $50,000.

The researchers asked caregivers whether they had guns in their own home and whether their child had access to firearms in their own or other homes. They also asked if their child played with toy guns and whether they believed their child could tell the difference between a real gun and a toy one.

Compared with those who did not own guns, gun owners were significantly more likely to be white and have both an income over $50,000 and some college education.

Meanwhile, researchers showed the children, aged 7-17 years, photos of a toy gun and a real gun and asked which was which.

A quarter of the caregivers (25%) owned guns, and half of them (50%) allowed their children to play with guns, compared with 26% of the non-gun owners.

In addition, 86% of the gun owners had discussed gun safety with their children, and the same proportion believed their children could correctly distinguish between a real gun and a toy gun.

By comparison, 58% of the non-gun owners had discussed gun safety with their children, and the same percentage believed their children could tell the difference between real and fake guns.

The children’s confidence in being able to tell the difference was similar regardless of whether their parents owned guns (79%) or didn’t (76%).

Yet less than half of all children correctly identified the real gun in the photos: 39% of the gun owners’ children and 42% of the non-gun owners’ children correctly pointed out the real gun, a nonsignificant difference.

Throughout the entire sample, more than 8 in 10 respondents, both gun owners (86%) and not (84%), believed there should be a law that requires caregivers to store their guns safely. A similar proportion (85% of gun owners and 80% of non-gun owners) believed legal penalties should exist for caregivers “if a child encounters an unsecured firearm.”

Overall, 5% of the respondents (14% of gun owners and 4% of non-gun owners) believed their child could get a gun within 24 hours if desired.

“So what does this mean to us as clinicians? It behooves [pediatricians] to actually continue to educate families at well-child visits on the guidelines about how to store firearms safely, locked up, unloaded, separate from ammunition,” Dr. Fraser Doh said. “On the flip side, parents need to be asking about the presence of firearms in the homes their children visit and also make sure that they’re storing their weapons safety.”

Dr. Fraser Doh said she had no relevant conflicts of interest.

SAN DIEGO – “Working at the top of your license,” focusing only on those tasks that cannot be performed by anyone else but you, is a key strategy when handling mass casualties, according to Dr. Toree McGowan, an emergency physician who works in a critical care facility in rural Oregon.

Vidyard Video

In our video interview at the annual meeting of the American College of Emergency Physicians, she outlined key strategies for obtaining resources and delegating care when managing mass casualties from disasters.

Dr. McGowan of the St. Charles Medical Group, Culver, Ore., said that, although she is the only physician at her rural critical care center about 70% of the time, she has established plans in place for obtaining additional staff and resources in the event of disasters. During her time in the military, she was among a team that implemented a disaster plan after a toxic chemical release at a nearby factory. The response was effective because the threat had been anticipated and a plan was in place. To develop the skills and strategies she describes in this interview, Dr. McGowan recommends free training that is available from the nonprofit National Disaster Life Support Foundation.
 

SAN DIEGO – “Working at the top of your license,” focusing only on those tasks that cannot be performed by anyone else but you, is a key strategy when handling mass casualties, according to Dr. Toree McGowan, an emergency physician who works in a critical care facility in rural Oregon.

Vidyard Video

In our video interview at the annual meeting of the American College of Emergency Physicians, she outlined key strategies for obtaining resources and delegating care when managing mass casualties from disasters.

Dr. McGowan of the St. Charles Medical Group, Culver, Ore., said that, although she is the only physician at her rural critical care center about 70% of the time, she has established plans in place for obtaining additional staff and resources in the event of disasters. During her time in the military, she was among a team that implemented a disaster plan after a toxic chemical release at a nearby factory. The response was effective because the threat had been anticipated and a plan was in place. To develop the skills and strategies she describes in this interview, Dr. McGowan recommends free training that is available from the nonprofit National Disaster Life Support Foundation.
 

SAN DIEGO – “Working at the top of your license,” focusing only on those tasks that cannot be performed by anyone else but you, is a key strategy when handling mass casualties, according to Dr. Toree McGowan, an emergency physician who works in a critical care facility in rural Oregon.

Vidyard Video

In our video interview at the annual meeting of the American College of Emergency Physicians, she outlined key strategies for obtaining resources and delegating care when managing mass casualties from disasters.

Dr. McGowan of the St. Charles Medical Group, Culver, Ore., said that, although she is the only physician at her rural critical care center about 70% of the time, she has established plans in place for obtaining additional staff and resources in the event of disasters. During her time in the military, she was among a team that implemented a disaster plan after a toxic chemical release at a nearby factory. The response was effective because the threat had been anticipated and a plan was in place. To develop the skills and strategies she describes in this interview, Dr. McGowan recommends free training that is available from the nonprofit National Disaster Life Support Foundation.
 

Cognitive deficits and behavioral symptoms that are specific to amyotrophic lateral sclerosis (ALS) occur more frequently as the disease progresses, according to research published online ahead of print September 12 in Neurology. Few patients are free of neuropsychologic impairment when they reach the final stage of the disease. It might be appropriate to include cognitive and behavioral change in the diagnostic criteria and future staging systems for ALS, said the authors.

In 2013, Elamin et al suggested that cognitive change in ALS may be associated with indirect measures of disease progression, such as total score on the ALS Functional Rating Scale-Revised. Christopher Crockford, PhD, a researcher at the University of Edinburgh, and colleagues sought to determine whether the cognitive and behavioral symptoms in ALS were more prevalent at more advanced stages of disease.

The Role of Letter Fluency Impairment

They conducted a multicenter, cross-sectional, observational study that included 161 patients from Edinburgh, Dublin, and London with possible, probable, or definite ALS, according to revised El Escorial diagnostic criteria. The researchers also recruited 80 healthy, matched controls. Through interviews, Dr. Crockford and colleagues elicited demographic and clinical data. They measured participants’ clinical staging with the King’s Clinical Staging System and neuropsychologic status with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS).

The investigators did not observe significant differences between the patient and control groups in background variables. Approximately 67% of patients with ALS were male, compared with 60% of controls. Mean age at testing was approximately 61 in both groups. Among patients with ALS, 40 were in Stage 1, 45 were in Stage 2, 22 were in Stage 3, and 54 were in Stage 4.

Compared with controls, patients with ALS had significantly worse cognitive performance on all domains of the ECAS except visuospatial functioning. Dr. Crockford’s group found a significant cross-sectional effect across disease stages for ALS-specific functions (eg, executive, language, and letter fluency) and ECAS total score. They did not find a similar effect for ALS-nonspecific functions (eg, memory and visuospatial). In addition, rates of ALS-specific impairment and behavioral change increased with increasing disease stage.

Letter fluency impairment may explain the relationship between cognitive function and disease stage, said the authors. They observed higher rates of all behavioral problems in later King’s stages. Bulbar signs were significantly related to ALS-specific scores, ECAS total score, and behavioral scores. Site of onset was not related to these scores, however.

Intervention programs to alleviate the effect of patients’ neuropsychologic impairment on caregivers may be appropriate, said the authors. “Furthermore, clinicians should be cognizant of current neuropsychologic status when prescribing life-prolonging interventions to patients and implement support structures for those with a neuropsychologic impairment,” they added.

Informing Patients and Caregivers

Although Dr. Crockford and colleagues focused on the behavioral and cognitive effects of ALS, the disease may affect mental health as well, said Paul Wicks, PhD, Vice President of Innovation at PatientsLikeMe in Cambridge, Massachusetts, and Steven M. Albert, PhD, Professor and Chair of Behavioral and Community Health Sciences at the University of Pittsburgh, in an accompanying editorial. The data show that the rates of major depression and depressed mood increase with increasing disease stage.

Drs. Wicks and Albert cited a survey in which 90% of patients and caregivers reported that their doctors had not told them that cognitive or psychologic symptoms can arise in ALS. “In our experience, colleagues report keeping the information from patients in order to spare them further distress,” they said. Yet most respondents to this survey reported that they would have liked to have been informed about these symptoms.

“Educating patients and caregivers that cognitive change is a part of ALS should be no different from similar discussions to be had in multiple sclerosis, Parkinson disease, and a range of other conditions,” said Drs. Wicks and Albert. “Keeping the truth from patients and caregivers is not protective; it is paternalistic, and it is time to stop. Only by facing up to the hard truth that one of the most dreaded conditions in medicine is even worse than we previously acknowledged can we take stock, marshal our resources, and make renewed plans to defeat our common enemy.”

Suggested Reading

Crockford C, Newton J, Lonergan K, et al. ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].

Wicks P, Albert SM. It’s time to stop saying “the mind is unaffected” in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].

Cognitive deficits and behavioral symptoms that are specific to amyotrophic lateral sclerosis (ALS) occur more frequently as the disease progresses, according to research published online ahead of print September 12 in Neurology. Few patients are free of neuropsychologic impairment when they reach the final stage of the disease. It might be appropriate to include cognitive and behavioral change in the diagnostic criteria and future staging systems for ALS, said the authors.

In 2013, Elamin et al suggested that cognitive change in ALS may be associated with indirect measures of disease progression, such as total score on the ALS Functional Rating Scale-Revised. Christopher Crockford, PhD, a researcher at the University of Edinburgh, and colleagues sought to determine whether the cognitive and behavioral symptoms in ALS were more prevalent at more advanced stages of disease.

The Role of Letter Fluency Impairment

They conducted a multicenter, cross-sectional, observational study that included 161 patients from Edinburgh, Dublin, and London with possible, probable, or definite ALS, according to revised El Escorial diagnostic criteria. The researchers also recruited 80 healthy, matched controls. Through interviews, Dr. Crockford and colleagues elicited demographic and clinical data. They measured participants’ clinical staging with the King’s Clinical Staging System and neuropsychologic status with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS).

The investigators did not observe significant differences between the patient and control groups in background variables. Approximately 67% of patients with ALS were male, compared with 60% of controls. Mean age at testing was approximately 61 in both groups. Among patients with ALS, 40 were in Stage 1, 45 were in Stage 2, 22 were in Stage 3, and 54 were in Stage 4.

Compared with controls, patients with ALS had significantly worse cognitive performance on all domains of the ECAS except visuospatial functioning. Dr. Crockford’s group found a significant cross-sectional effect across disease stages for ALS-specific functions (eg, executive, language, and letter fluency) and ECAS total score. They did not find a similar effect for ALS-nonspecific functions (eg, memory and visuospatial). In addition, rates of ALS-specific impairment and behavioral change increased with increasing disease stage.

Letter fluency impairment may explain the relationship between cognitive function and disease stage, said the authors. They observed higher rates of all behavioral problems in later King’s stages. Bulbar signs were significantly related to ALS-specific scores, ECAS total score, and behavioral scores. Site of onset was not related to these scores, however.

Intervention programs to alleviate the effect of patients’ neuropsychologic impairment on caregivers may be appropriate, said the authors. “Furthermore, clinicians should be cognizant of current neuropsychologic status when prescribing life-prolonging interventions to patients and implement support structures for those with a neuropsychologic impairment,” they added.

Informing Patients and Caregivers

Although Dr. Crockford and colleagues focused on the behavioral and cognitive effects of ALS, the disease may affect mental health as well, said Paul Wicks, PhD, Vice President of Innovation at PatientsLikeMe in Cambridge, Massachusetts, and Steven M. Albert, PhD, Professor and Chair of Behavioral and Community Health Sciences at the University of Pittsburgh, in an accompanying editorial. The data show that the rates of major depression and depressed mood increase with increasing disease stage.

Drs. Wicks and Albert cited a survey in which 90% of patients and caregivers reported that their doctors had not told them that cognitive or psychologic symptoms can arise in ALS. “In our experience, colleagues report keeping the information from patients in order to spare them further distress,” they said. Yet most respondents to this survey reported that they would have liked to have been informed about these symptoms.

“Educating patients and caregivers that cognitive change is a part of ALS should be no different from similar discussions to be had in multiple sclerosis, Parkinson disease, and a range of other conditions,” said Drs. Wicks and Albert. “Keeping the truth from patients and caregivers is not protective; it is paternalistic, and it is time to stop. Only by facing up to the hard truth that one of the most dreaded conditions in medicine is even worse than we previously acknowledged can we take stock, marshal our resources, and make renewed plans to defeat our common enemy.”

Suggested Reading

Crockford C, Newton J, Lonergan K, et al. ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].

Wicks P, Albert SM. It’s time to stop saying “the mind is unaffected” in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].

Cognitive deficits and behavioral symptoms that are specific to amyotrophic lateral sclerosis (ALS) occur more frequently as the disease progresses, according to research published online ahead of print September 12 in Neurology. Few patients are free of neuropsychologic impairment when they reach the final stage of the disease. It might be appropriate to include cognitive and behavioral change in the diagnostic criteria and future staging systems for ALS, said the authors.

In 2013, Elamin et al suggested that cognitive change in ALS may be associated with indirect measures of disease progression, such as total score on the ALS Functional Rating Scale-Revised. Christopher Crockford, PhD, a researcher at the University of Edinburgh, and colleagues sought to determine whether the cognitive and behavioral symptoms in ALS were more prevalent at more advanced stages of disease.

The Role of Letter Fluency Impairment

They conducted a multicenter, cross-sectional, observational study that included 161 patients from Edinburgh, Dublin, and London with possible, probable, or definite ALS, according to revised El Escorial diagnostic criteria. The researchers also recruited 80 healthy, matched controls. Through interviews, Dr. Crockford and colleagues elicited demographic and clinical data. They measured participants’ clinical staging with the King’s Clinical Staging System and neuropsychologic status with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS).

The investigators did not observe significant differences between the patient and control groups in background variables. Approximately 67% of patients with ALS were male, compared with 60% of controls. Mean age at testing was approximately 61 in both groups. Among patients with ALS, 40 were in Stage 1, 45 were in Stage 2, 22 were in Stage 3, and 54 were in Stage 4.

Compared with controls, patients with ALS had significantly worse cognitive performance on all domains of the ECAS except visuospatial functioning. Dr. Crockford’s group found a significant cross-sectional effect across disease stages for ALS-specific functions (eg, executive, language, and letter fluency) and ECAS total score. They did not find a similar effect for ALS-nonspecific functions (eg, memory and visuospatial). In addition, rates of ALS-specific impairment and behavioral change increased with increasing disease stage.

Letter fluency impairment may explain the relationship between cognitive function and disease stage, said the authors. They observed higher rates of all behavioral problems in later King’s stages. Bulbar signs were significantly related to ALS-specific scores, ECAS total score, and behavioral scores. Site of onset was not related to these scores, however.

Intervention programs to alleviate the effect of patients’ neuropsychologic impairment on caregivers may be appropriate, said the authors. “Furthermore, clinicians should be cognizant of current neuropsychologic status when prescribing life-prolonging interventions to patients and implement support structures for those with a neuropsychologic impairment,” they added.

Informing Patients and Caregivers

Although Dr. Crockford and colleagues focused on the behavioral and cognitive effects of ALS, the disease may affect mental health as well, said Paul Wicks, PhD, Vice President of Innovation at PatientsLikeMe in Cambridge, Massachusetts, and Steven M. Albert, PhD, Professor and Chair of Behavioral and Community Health Sciences at the University of Pittsburgh, in an accompanying editorial. The data show that the rates of major depression and depressed mood increase with increasing disease stage.

Drs. Wicks and Albert cited a survey in which 90% of patients and caregivers reported that their doctors had not told them that cognitive or psychologic symptoms can arise in ALS. “In our experience, colleagues report keeping the information from patients in order to spare them further distress,” they said. Yet most respondents to this survey reported that they would have liked to have been informed about these symptoms.

“Educating patients and caregivers that cognitive change is a part of ALS should be no different from similar discussions to be had in multiple sclerosis, Parkinson disease, and a range of other conditions,” said Drs. Wicks and Albert. “Keeping the truth from patients and caregivers is not protective; it is paternalistic, and it is time to stop. Only by facing up to the hard truth that one of the most dreaded conditions in medicine is even worse than we previously acknowledged can we take stock, marshal our resources, and make renewed plans to defeat our common enemy.”

Suggested Reading

Crockford C, Newton J, Lonergan K, et al. ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].

Wicks P, Albert SM. It’s time to stop saying “the mind is unaffected” in ALS. Neurology. 2018 Sep 12 [Epub ahead of print].

The Food and Drug Administration has approved Sympazan (clobazam) oral film for adjunctive treatment of Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older, according to a release from its developer. Final approval came after the orphan drug designation period for the previously marketed formulation, Onfi, came to an end in October.

LGS is a severe form of epilepsy; it can present with multiple types of seizures, as well as intellectual disabilities. Patients with LGS can have difficulty swallowing tablets or large volumes of oral suspension – which was previously the only way clobazam was delivered – because of physical limitations or behavioral or compliance issues. According to the press release from Aquestive Therapeutics, the Sympazan oral film might be able to get around those difficulties and reduce care burdens, especially with patients who are resistant to or even combative about treatment.

The approval is based on multiple pharmacokinetic studies that altogether showed that the oral film is bioequivalent to clobazam tablets and has a similar safety profile.

In a phase 3 study of 238 patients with LGS, clobazam tablets were shown to reduce drop seizures (those that involved falls) by 41% at low doses and by 68% at high doses versus a reduction of 12% seen with placebo (P less than .05 for all doses vs. placebo).

There is a risk of profound sedation when clobazam is used alongside benzodiazepines; there is also a risk of sedation and somnolence if it is used concomitantly with alcohol or other CNS depressants. Other risks associated with clobazam include suicidal ideation and behavior, serious dermatologic reactions, and physical and psychological dependence. The most common adverse reactions included constipation, pyrexia, lethargy, and drooling.

Full prescribing information can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved Sympazan (clobazam) oral film for adjunctive treatment of Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older, according to a release from its developer. Final approval came after the orphan drug designation period for the previously marketed formulation, Onfi, came to an end in October.

LGS is a severe form of epilepsy; it can present with multiple types of seizures, as well as intellectual disabilities. Patients with LGS can have difficulty swallowing tablets or large volumes of oral suspension – which was previously the only way clobazam was delivered – because of physical limitations or behavioral or compliance issues. According to the press release from Aquestive Therapeutics, the Sympazan oral film might be able to get around those difficulties and reduce care burdens, especially with patients who are resistant to or even combative about treatment.

The approval is based on multiple pharmacokinetic studies that altogether showed that the oral film is bioequivalent to clobazam tablets and has a similar safety profile.

In a phase 3 study of 238 patients with LGS, clobazam tablets were shown to reduce drop seizures (those that involved falls) by 41% at low doses and by 68% at high doses versus a reduction of 12% seen with placebo (P less than .05 for all doses vs. placebo).

There is a risk of profound sedation when clobazam is used alongside benzodiazepines; there is also a risk of sedation and somnolence if it is used concomitantly with alcohol or other CNS depressants. Other risks associated with clobazam include suicidal ideation and behavior, serious dermatologic reactions, and physical and psychological dependence. The most common adverse reactions included constipation, pyrexia, lethargy, and drooling.

Full prescribing information can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved Sympazan (clobazam) oral film for adjunctive treatment of Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older, according to a release from its developer. Final approval came after the orphan drug designation period for the previously marketed formulation, Onfi, came to an end in October.

LGS is a severe form of epilepsy; it can present with multiple types of seizures, as well as intellectual disabilities. Patients with LGS can have difficulty swallowing tablets or large volumes of oral suspension – which was previously the only way clobazam was delivered – because of physical limitations or behavioral or compliance issues. According to the press release from Aquestive Therapeutics, the Sympazan oral film might be able to get around those difficulties and reduce care burdens, especially with patients who are resistant to or even combative about treatment.

The approval is based on multiple pharmacokinetic studies that altogether showed that the oral film is bioequivalent to clobazam tablets and has a similar safety profile.

In a phase 3 study of 238 patients with LGS, clobazam tablets were shown to reduce drop seizures (those that involved falls) by 41% at low doses and by 68% at high doses versus a reduction of 12% seen with placebo (P less than .05 for all doses vs. placebo).

There is a risk of profound sedation when clobazam is used alongside benzodiazepines; there is also a risk of sedation and somnolence if it is used concomitantly with alcohol or other CNS depressants. Other risks associated with clobazam include suicidal ideation and behavior, serious dermatologic reactions, and physical and psychological dependence. The most common adverse reactions included constipation, pyrexia, lethargy, and drooling.

Full prescribing information can be found on the FDA website.

[email protected]

BERLIN—Smoking and low vitamin D levels are key modifiable prognostic factors that show a significant interaction with risk of Expanded Disability Status Scale (EDSS) progression in patients with clinically isolated syndrome (CIS), according to a study presented at ECTRIMS 2018. This finding suggests potential preventive strategies for avoiding disability, said Susana Otero-Romero, MD, PhD, an epidemiologist at the Multiple Sclerosis Center of Catalonia (CEMCAT) at University Hospital Vall d’Hebron in Barcelona, and her research colleagues.

A dynamic model for predicting long-term prognosis incorporating age, sex, topography of CIS, oligoclonal bands, and number of T2 lesions was designed by Dr. Otero-Romero and colleagues. They then sought to include modifiable environmental factors such as vitamin D and cotinine serum levels (as a surrogate for smoking status) to their modeling strategy for predicting long-term prognosis.

From 1995 to 2016, the researchers prospectively recruited 1,088 patients with CIS for clinical assessment and brain MRI follow-up. Baseline hazard for EDSS 3.0 was calculated after fitting several parametric models (Weibull, generalized gamma) for a linear combination of baseline domains, including: age, sex, topography, oligoclonal bands, and baseline T2 lesions. A recursive partitioning regression tree (RPART) method was used to stratify patients in risk groups according to their predicted median time to EDSS 3.0. This prognostic model was further updated by adding vitamin D deficiency (n = 472; cutoff, 8 ng/mL), smoking (n = 435; cotinine cutoff, 14 ng/mL), and their interactions with risk groups. Harrell C statistic was used to evaluate the performance of these models.

The predictive model is based on 1,062 patients with more than one year of follow-up. After fitting several models, a final Weibull (proportional hazard) model was selected. RPART allowed patients to be stratified in three groups: low risk (n = 442; hazard ratio [HR], 1.0 reference), medium risk (n = 561; HR, 3.0), and high risk (n = 51; HR, 9.6) with a Harrell C of 0.65. An interaction was observed for vitamin D deficiency and risk group. Vitamin D deficiency increased the risk for EDSS progression. Patients with vitamin D deficiency with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. In patients with high risk at baseline, the impact of vitamin D deficiency was minor. Overall Harrell C increased from 0.65 to 0.69.

A similar interaction was observed for smoking and risk group. High cotinine levels increased the risk for EDSS progression. Patients with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. For the high-risk group, adding smoking status raised hazard ratios from 13.8 to 64.2. Harrell C improved from 0.68 to 0.73.

This study was financed with grants from the Spanish Ministry of Economy and Competitiveness, the Fondo de Investigación Sanitaria, and the Instituto de Salud Carlos III. It also was supported by a grant from Genzyme.

BERLIN—Smoking and low vitamin D levels are key modifiable prognostic factors that show a significant interaction with risk of Expanded Disability Status Scale (EDSS) progression in patients with clinically isolated syndrome (CIS), according to a study presented at ECTRIMS 2018. This finding suggests potential preventive strategies for avoiding disability, said Susana Otero-Romero, MD, PhD, an epidemiologist at the Multiple Sclerosis Center of Catalonia (CEMCAT) at University Hospital Vall d’Hebron in Barcelona, and her research colleagues.

A dynamic model for predicting long-term prognosis incorporating age, sex, topography of CIS, oligoclonal bands, and number of T2 lesions was designed by Dr. Otero-Romero and colleagues. They then sought to include modifiable environmental factors such as vitamin D and cotinine serum levels (as a surrogate for smoking status) to their modeling strategy for predicting long-term prognosis.

From 1995 to 2016, the researchers prospectively recruited 1,088 patients with CIS for clinical assessment and brain MRI follow-up. Baseline hazard for EDSS 3.0 was calculated after fitting several parametric models (Weibull, generalized gamma) for a linear combination of baseline domains, including: age, sex, topography, oligoclonal bands, and baseline T2 lesions. A recursive partitioning regression tree (RPART) method was used to stratify patients in risk groups according to their predicted median time to EDSS 3.0. This prognostic model was further updated by adding vitamin D deficiency (n = 472; cutoff, 8 ng/mL), smoking (n = 435; cotinine cutoff, 14 ng/mL), and their interactions with risk groups. Harrell C statistic was used to evaluate the performance of these models.

The predictive model is based on 1,062 patients with more than one year of follow-up. After fitting several models, a final Weibull (proportional hazard) model was selected. RPART allowed patients to be stratified in three groups: low risk (n = 442; hazard ratio [HR], 1.0 reference), medium risk (n = 561; HR, 3.0), and high risk (n = 51; HR, 9.6) with a Harrell C of 0.65. An interaction was observed for vitamin D deficiency and risk group. Vitamin D deficiency increased the risk for EDSS progression. Patients with vitamin D deficiency with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. In patients with high risk at baseline, the impact of vitamin D deficiency was minor. Overall Harrell C increased from 0.65 to 0.69.

A similar interaction was observed for smoking and risk group. High cotinine levels increased the risk for EDSS progression. Patients with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. For the high-risk group, adding smoking status raised hazard ratios from 13.8 to 64.2. Harrell C improved from 0.68 to 0.73.

This study was financed with grants from the Spanish Ministry of Economy and Competitiveness, the Fondo de Investigación Sanitaria, and the Instituto de Salud Carlos III. It also was supported by a grant from Genzyme.

BERLIN—Smoking and low vitamin D levels are key modifiable prognostic factors that show a significant interaction with risk of Expanded Disability Status Scale (EDSS) progression in patients with clinically isolated syndrome (CIS), according to a study presented at ECTRIMS 2018. This finding suggests potential preventive strategies for avoiding disability, said Susana Otero-Romero, MD, PhD, an epidemiologist at the Multiple Sclerosis Center of Catalonia (CEMCAT) at University Hospital Vall d’Hebron in Barcelona, and her research colleagues.

A dynamic model for predicting long-term prognosis incorporating age, sex, topography of CIS, oligoclonal bands, and number of T2 lesions was designed by Dr. Otero-Romero and colleagues. They then sought to include modifiable environmental factors such as vitamin D and cotinine serum levels (as a surrogate for smoking status) to their modeling strategy for predicting long-term prognosis.

From 1995 to 2016, the researchers prospectively recruited 1,088 patients with CIS for clinical assessment and brain MRI follow-up. Baseline hazard for EDSS 3.0 was calculated after fitting several parametric models (Weibull, generalized gamma) for a linear combination of baseline domains, including: age, sex, topography, oligoclonal bands, and baseline T2 lesions. A recursive partitioning regression tree (RPART) method was used to stratify patients in risk groups according to their predicted median time to EDSS 3.0. This prognostic model was further updated by adding vitamin D deficiency (n = 472; cutoff, 8 ng/mL), smoking (n = 435; cotinine cutoff, 14 ng/mL), and their interactions with risk groups. Harrell C statistic was used to evaluate the performance of these models.

The predictive model is based on 1,062 patients with more than one year of follow-up. After fitting several models, a final Weibull (proportional hazard) model was selected. RPART allowed patients to be stratified in three groups: low risk (n = 442; hazard ratio [HR], 1.0 reference), medium risk (n = 561; HR, 3.0), and high risk (n = 51; HR, 9.6) with a Harrell C of 0.65. An interaction was observed for vitamin D deficiency and risk group. Vitamin D deficiency increased the risk for EDSS progression. Patients with vitamin D deficiency with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. In patients with high risk at baseline, the impact of vitamin D deficiency was minor. Overall Harrell C increased from 0.65 to 0.69.

A similar interaction was observed for smoking and risk group. High cotinine levels increased the risk for EDSS progression. Patients with low risk moved to the medium-risk group, and patients with medium risk moved to the high-risk group. For the high-risk group, adding smoking status raised hazard ratios from 13.8 to 64.2. Harrell C improved from 0.68 to 0.73.

This study was financed with grants from the Spanish Ministry of Economy and Competitiveness, the Fondo de Investigación Sanitaria, and the Instituto de Salud Carlos III. It also was supported by a grant from Genzyme.

Sandoz has decided not to pursue U.S. approval for its rituximab product (GP2013), a proposed biosimilar of Rituxan.

Sandoz, a division of Novartis, was seeking Food and Drug Administration approval of GP2013 for all the same indications as the reference product – B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris.

GP2013 already is approved in the European Union and elsewhere.

The FDA had accepted the biologics license application (BLA) for GP2013 in September 2017. In May 2018, the agency issued a complete response letter saying it could not approve GP2013. The agency also requested additional information to complement the BLA submission.

At the time of the complete response letter, Sandoz said it was still committed to bringing GP2013 to the U.S. market.

“We appreciate the important conversations with the FDA, which have provided specific requirements for our potential U.S. biosimilar rituximab but believe the patient and marketplace needs in the U.S. will be satisfied before we can generate the data required,” Stefan Hendriks, global head of biopharmaceuticals at Sandoz, said in a statement.

“We are disappointed to have to make this decision and stand behind the safety, efficacy, and quality of our medicine, which met the stringent criteria for approval in the European Union, Switzerland, Japan, New Zealand, and Australia.”

The BLA for GP2013 was supported, in part, by results from the ASSIST-FL trial, in which researchers compared GP2013 with the reference product (Lancet Haematol. 2017 Aug;4[8]:e350-61).

The phase 3 trial included adults with previously untreated, advanced-stage follicular lymphoma. Patients received eight cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.

At a median follow-up of 11.6 months, the overall response rate was 87% in the GP2013 arm and 88% in the rituximab arm.

[email protected]

Sandoz has decided not to pursue U.S. approval for its rituximab product (GP2013), a proposed biosimilar of Rituxan.

Sandoz, a division of Novartis, was seeking Food and Drug Administration approval of GP2013 for all the same indications as the reference product – B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris.

GP2013 already is approved in the European Union and elsewhere.

The FDA had accepted the biologics license application (BLA) for GP2013 in September 2017. In May 2018, the agency issued a complete response letter saying it could not approve GP2013. The agency also requested additional information to complement the BLA submission.

At the time of the complete response letter, Sandoz said it was still committed to bringing GP2013 to the U.S. market.

“We appreciate the important conversations with the FDA, which have provided specific requirements for our potential U.S. biosimilar rituximab but believe the patient and marketplace needs in the U.S. will be satisfied before we can generate the data required,” Stefan Hendriks, global head of biopharmaceuticals at Sandoz, said in a statement.

“We are disappointed to have to make this decision and stand behind the safety, efficacy, and quality of our medicine, which met the stringent criteria for approval in the European Union, Switzerland, Japan, New Zealand, and Australia.”

The BLA for GP2013 was supported, in part, by results from the ASSIST-FL trial, in which researchers compared GP2013 with the reference product (Lancet Haematol. 2017 Aug;4[8]:e350-61).

The phase 3 trial included adults with previously untreated, advanced-stage follicular lymphoma. Patients received eight cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.

At a median follow-up of 11.6 months, the overall response rate was 87% in the GP2013 arm and 88% in the rituximab arm.

[email protected]

Sandoz has decided not to pursue U.S. approval for its rituximab product (GP2013), a proposed biosimilar of Rituxan.

Sandoz, a division of Novartis, was seeking Food and Drug Administration approval of GP2013 for all the same indications as the reference product – B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris.

GP2013 already is approved in the European Union and elsewhere.

The FDA had accepted the biologics license application (BLA) for GP2013 in September 2017. In May 2018, the agency issued a complete response letter saying it could not approve GP2013. The agency also requested additional information to complement the BLA submission.

At the time of the complete response letter, Sandoz said it was still committed to bringing GP2013 to the U.S. market.

“We appreciate the important conversations with the FDA, which have provided specific requirements for our potential U.S. biosimilar rituximab but believe the patient and marketplace needs in the U.S. will be satisfied before we can generate the data required,” Stefan Hendriks, global head of biopharmaceuticals at Sandoz, said in a statement.

“We are disappointed to have to make this decision and stand behind the safety, efficacy, and quality of our medicine, which met the stringent criteria for approval in the European Union, Switzerland, Japan, New Zealand, and Australia.”

The BLA for GP2013 was supported, in part, by results from the ASSIST-FL trial, in which researchers compared GP2013 with the reference product (Lancet Haematol. 2017 Aug;4[8]:e350-61).

The phase 3 trial included adults with previously untreated, advanced-stage follicular lymphoma. Patients received eight cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.

At a median follow-up of 11.6 months, the overall response rate was 87% in the GP2013 arm and 88% in the rituximab arm.

[email protected]

BERLIN—Switching from interferon beta-1a to ocrelizumab after two years at the start of the OPERA I and OPERA II open-label extension period was associated with a rapid reduction in annualized release rate, according to a report presented at ECTRIMS 2018. “Both patients who continued treatment with ocrelizumab as well as those who were switched from interferon beta-1a to ocrelizumab maintained their robust reduction in annualized relapse rate through the three-year follow-up of the open-label extension period,” said lead author Stephen L. Hauser, MD, Director of the UCSF Weill Institute for Neurosciences, University of California, San Francisco, and colleagues.

“After five years of follow-up, the proportion of patients with disability progression was lower in patients who initiated ocrelizumab treatment earlier, compared with patients who received initial interferon treatment before switching to ocrelizumab, showing that patients who initiated ocrelizumab two years earlier accrued significant and sustained reductions in disability progression compared with patients switching from interferon therapy.”

The efficacy and safety of ocrelizumab in relapsing multiple sclerosis (MS) were demonstrated in the 96-week double-blind control period of OPERA I and OPERA II, and results for the two-year follow-up of the pooled OPERA I and OPERA II open-label extension period have previously been reported. For this study, Dr. Hauser and colleagues sought to assess the efficacy of switching to or maintaining ocrelizumab therapy on clinical measures of disease activity and progression after three years of follow-up in the open-label extension period of the OPERA I and OPERA II phase III trials in relapsing MS.

At the start of the open-label extension period, patients continued ocrelizumab therapy or were switched from interferon beta-1a to ocrelizumab. The researchers analyzed adjusted annualized relapse rate (ARR), time to onset of 24-week confirmed disability progression, and change in adjusted mean Expanded Disability Status Scale (EDSS) score from baseline.

Overall, 88.6% of patients who entered the open-label extension completed year three of follow-up. Among patients who switched therapy, annualized release rate decreased from 0.20 in the year preswitch to 0.10, 0.08, and 0.07 at years one, two, and three postswitch. Those patients who continued on ocrelizumab maintained a low annualized relapse rate through the year prior to the open-label extension and the three years of the open-label extension period (0.13, 0.11, 0.08, and 0.07). In addition, those patients who continued on ocrelizumab versus those who switched therapy had lower proportions of patients with 24-week confirmed disability progression in the year preswitch and years one, two, and three of the open-label extension period (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1%, and 16.1%/21.3%).

This study was sponsored by F. Hoffmann-La Roche, and writing and editorial assistance was provided by Articulate Science, UK.

BERLIN—Switching from interferon beta-1a to ocrelizumab after two years at the start of the OPERA I and OPERA II open-label extension period was associated with a rapid reduction in annualized release rate, according to a report presented at ECTRIMS 2018. “Both patients who continued treatment with ocrelizumab as well as those who were switched from interferon beta-1a to ocrelizumab maintained their robust reduction in annualized relapse rate through the three-year follow-up of the open-label extension period,” said lead author Stephen L. Hauser, MD, Director of the UCSF Weill Institute for Neurosciences, University of California, San Francisco, and colleagues.

“After five years of follow-up, the proportion of patients with disability progression was lower in patients who initiated ocrelizumab treatment earlier, compared with patients who received initial interferon treatment before switching to ocrelizumab, showing that patients who initiated ocrelizumab two years earlier accrued significant and sustained reductions in disability progression compared with patients switching from interferon therapy.”

The efficacy and safety of ocrelizumab in relapsing multiple sclerosis (MS) were demonstrated in the 96-week double-blind control period of OPERA I and OPERA II, and results for the two-year follow-up of the pooled OPERA I and OPERA II open-label extension period have previously been reported. For this study, Dr. Hauser and colleagues sought to assess the efficacy of switching to or maintaining ocrelizumab therapy on clinical measures of disease activity and progression after three years of follow-up in the open-label extension period of the OPERA I and OPERA II phase III trials in relapsing MS.

At the start of the open-label extension period, patients continued ocrelizumab therapy or were switched from interferon beta-1a to ocrelizumab. The researchers analyzed adjusted annualized relapse rate (ARR), time to onset of 24-week confirmed disability progression, and change in adjusted mean Expanded Disability Status Scale (EDSS) score from baseline.

Overall, 88.6% of patients who entered the open-label extension completed year three of follow-up. Among patients who switched therapy, annualized release rate decreased from 0.20 in the year preswitch to 0.10, 0.08, and 0.07 at years one, two, and three postswitch. Those patients who continued on ocrelizumab maintained a low annualized relapse rate through the year prior to the open-label extension and the three years of the open-label extension period (0.13, 0.11, 0.08, and 0.07). In addition, those patients who continued on ocrelizumab versus those who switched therapy had lower proportions of patients with 24-week confirmed disability progression in the year preswitch and years one, two, and three of the open-label extension period (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1%, and 16.1%/21.3%).

This study was sponsored by F. Hoffmann-La Roche, and writing and editorial assistance was provided by Articulate Science, UK.

BERLIN—Switching from interferon beta-1a to ocrelizumab after two years at the start of the OPERA I and OPERA II open-label extension period was associated with a rapid reduction in annualized release rate, according to a report presented at ECTRIMS 2018. “Both patients who continued treatment with ocrelizumab as well as those who were switched from interferon beta-1a to ocrelizumab maintained their robust reduction in annualized relapse rate through the three-year follow-up of the open-label extension period,” said lead author Stephen L. Hauser, MD, Director of the UCSF Weill Institute for Neurosciences, University of California, San Francisco, and colleagues.

“After five years of follow-up, the proportion of patients with disability progression was lower in patients who initiated ocrelizumab treatment earlier, compared with patients who received initial interferon treatment before switching to ocrelizumab, showing that patients who initiated ocrelizumab two years earlier accrued significant and sustained reductions in disability progression compared with patients switching from interferon therapy.”

The efficacy and safety of ocrelizumab in relapsing multiple sclerosis (MS) were demonstrated in the 96-week double-blind control period of OPERA I and OPERA II, and results for the two-year follow-up of the pooled OPERA I and OPERA II open-label extension period have previously been reported. For this study, Dr. Hauser and colleagues sought to assess the efficacy of switching to or maintaining ocrelizumab therapy on clinical measures of disease activity and progression after three years of follow-up in the open-label extension period of the OPERA I and OPERA II phase III trials in relapsing MS.

At the start of the open-label extension period, patients continued ocrelizumab therapy or were switched from interferon beta-1a to ocrelizumab. The researchers analyzed adjusted annualized relapse rate (ARR), time to onset of 24-week confirmed disability progression, and change in adjusted mean Expanded Disability Status Scale (EDSS) score from baseline.

Overall, 88.6% of patients who entered the open-label extension completed year three of follow-up. Among patients who switched therapy, annualized release rate decreased from 0.20 in the year preswitch to 0.10, 0.08, and 0.07 at years one, two, and three postswitch. Those patients who continued on ocrelizumab maintained a low annualized relapse rate through the year prior to the open-label extension and the three years of the open-label extension period (0.13, 0.11, 0.08, and 0.07). In addition, those patients who continued on ocrelizumab versus those who switched therapy had lower proportions of patients with 24-week confirmed disability progression in the year preswitch and years one, two, and three of the open-label extension period (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1%, and 16.1%/21.3%).

This study was sponsored by F. Hoffmann-La Roche, and writing and editorial assistance was provided by Articulate Science, UK.

BERLIN—Levels of neurofilament light chain (NfL) indicate that patients with secondary progressive multiple sclerosis (MS) have more ongoing neuronal loss than patients with primary progressive MS of comparable age, both in the presence and in absence of gadolinium enhancing lesions, according to research presented at ECTRIMS 2018. In secondary progressive MS and primary progressive MS, NfL may serve as a prognostic marker of brain atrophy, said the investigators.

NfL is considered a blood biomarker for monitoring neuronal damage, disease activity, and treatment response in MS. Most studies of blood NfL have focused on patients with relapsing-remitting MS, and little is known about blood NfL levels in patients with progressive MS.

BERLIN—Levels of neurofilament light chain (NfL) indicate that patients with secondary progressive multiple sclerosis (MS) have more ongoing neuronal loss than patients with primary progressive MS of comparable age, both in the presence and in absence of gadolinium enhancing lesions, according to research presented at ECTRIMS 2018. In secondary progressive MS and primary progressive MS, NfL may serve as a prognostic marker of brain atrophy, said the investigators.

NfL is considered a blood biomarker for monitoring neuronal damage, disease activity, and treatment response in MS. Most studies of blood NfL have focused on patients with relapsing-remitting MS, and little is known about blood NfL levels in patients with progressive MS.

BERLIN—Levels of neurofilament light chain (NfL) indicate that patients with secondary progressive multiple sclerosis (MS) have more ongoing neuronal loss than patients with primary progressive MS of comparable age, both in the presence and in absence of gadolinium enhancing lesions, according to research presented at ECTRIMS 2018. In secondary progressive MS and primary progressive MS, NfL may serve as a prognostic marker of brain atrophy, said the investigators.

NfL is considered a blood biomarker for monitoring neuronal damage, disease activity, and treatment response in MS. Most studies of blood NfL have focused on patients with relapsing-remitting MS, and little is known about blood NfL levels in patients with progressive MS.

BERLIN—Vitamin D increases the therapeutic effects of glucocorticoids via an mTORc1–dependent upregulation of the glucocorticoid receptor, according to a report at ECTRIMS 2018. “These data suggest that efficacy of glucocorticoids in the treatment of multiple sclerosis (MS) relapses could be improved by mTORc1 inhibition,” said lead author Maud Bagnoud, a doctoral candidate from the Department for Biomedical Research at the University of Bern in Switzerland, and colleagues.

Glucocorticoids are the mainstay in the treatment of acute MS relapses. Still, disability increases in more than 40% of patients. Ms. Bagnoud and colleagues investigated the potential of vitamin D to enhance steroid efficacy for MS relapse therapy and the mechanisms involved.

The researchers analyzed vitamin D levels using an immunoassay in patients with stable MS (n = 56), patients with relapsing glucocorticoid-responsive MS (n = 30), and patients with relapsing glucocorticoid-resistant MS (n = 24). Gene expression of human T cells (microarrays, n = 112) were correlated with 25(OH)D₃ levels. Glucocorticoid receptor protein was measured using ELISA. T cell apoptosis was analyzed by FACS. Myelin oligodendrocyte glycoprotein (MOG_35-55) experimental autoimmune encephalomyelitis (EAE) was performed in wild type and knockout mice with T cell specific deficiency for glucocorticoid receptor/mTORc1. The investigators analyzed the relevance of the JNK-pathway in human T cells using a competitive JNK-inhibitor (SP600125).

Patients with glucocorticoid-resistant MS had a decreased vitamin D serum level, compared with patients with glucocorticoid-responsive MS or stable MS. This decreased level of vitamin D was associated with reduced expression of the glucocorticoid receptor in T cells. In vitro, vitamin D increased the concentration of glucocorticoid receptor protein in T cells in a dose-dependent manner. Focusing on T cells donated from patients with MS during glucocorticoid-resistant relapse, this glucocorticoid receptor upregulation by vitamin D increased T cell apoptosis by approximately 10%, if treated with vitamin D and glucocorticoids, compared with glucocorticoid monotherapy. Combination therapy ameliorated EAE disease course more efficiently than monotherapies did. This effect was dependent on the presence of the glucocorticoid receptor in T cells.

On a molecular level, vitamin D inhibited mTORc1 signal transduction in murine T cells in vitro. Furthermore, hypovitaminosis D was associated with reduced expression of the archetype mTORc1 inhibitor tuberous sclerosis complex 1 in human T cells. The upregulation of the glucocorticoid receptor by vitamin D as well as the functional vitamin D/glucocorticoid synergism observed in vitro and in vivo were absent in mice with mTORc1-deficient T cells. Pharmacologic inhibition of mTORc1 by everolimus augmented the effects of glucocorticoid treatment in wild type mice during EAE even more potently than vitamin D co-administration did.

No significant changes of proliferation or apoptosis by JNK-inhibition and MP co-incubation were observed in human T cells.

BERLIN—Vitamin D increases the therapeutic effects of glucocorticoids via an mTORc1–dependent upregulation of the glucocorticoid receptor, according to a report at ECTRIMS 2018. “These data suggest that efficacy of glucocorticoids in the treatment of multiple sclerosis (MS) relapses could be improved by mTORc1 inhibition,” said lead author Maud Bagnoud, a doctoral candidate from the Department for Biomedical Research at the University of Bern in Switzerland, and colleagues.

Glucocorticoids are the mainstay in the treatment of acute MS relapses. Still, disability increases in more than 40% of patients. Ms. Bagnoud and colleagues investigated the potential of vitamin D to enhance steroid efficacy for MS relapse therapy and the mechanisms involved.

The researchers analyzed vitamin D levels using an immunoassay in patients with stable MS (n = 56), patients with relapsing glucocorticoid-responsive MS (n = 30), and patients with relapsing glucocorticoid-resistant MS (n = 24). Gene expression of human T cells (microarrays, n = 112) were correlated with 25(OH)D₃ levels. Glucocorticoid receptor protein was measured using ELISA. T cell apoptosis was analyzed by FACS. Myelin oligodendrocyte glycoprotein (MOG_35-55) experimental autoimmune encephalomyelitis (EAE) was performed in wild type and knockout mice with T cell specific deficiency for glucocorticoid receptor/mTORc1. The investigators analyzed the relevance of the JNK-pathway in human T cells using a competitive JNK-inhibitor (SP600125).

Patients with glucocorticoid-resistant MS had a decreased vitamin D serum level, compared with patients with glucocorticoid-responsive MS or stable MS. This decreased level of vitamin D was associated with reduced expression of the glucocorticoid receptor in T cells. In vitro, vitamin D increased the concentration of glucocorticoid receptor protein in T cells in a dose-dependent manner. Focusing on T cells donated from patients with MS during glucocorticoid-resistant relapse, this glucocorticoid receptor upregulation by vitamin D increased T cell apoptosis by approximately 10%, if treated with vitamin D and glucocorticoids, compared with glucocorticoid monotherapy. Combination therapy ameliorated EAE disease course more efficiently than monotherapies did. This effect was dependent on the presence of the glucocorticoid receptor in T cells.

On a molecular level, vitamin D inhibited mTORc1 signal transduction in murine T cells in vitro. Furthermore, hypovitaminosis D was associated with reduced expression of the archetype mTORc1 inhibitor tuberous sclerosis complex 1 in human T cells. The upregulation of the glucocorticoid receptor by vitamin D as well as the functional vitamin D/glucocorticoid synergism observed in vitro and in vivo were absent in mice with mTORc1-deficient T cells. Pharmacologic inhibition of mTORc1 by everolimus augmented the effects of glucocorticoid treatment in wild type mice during EAE even more potently than vitamin D co-administration did.

No significant changes of proliferation or apoptosis by JNK-inhibition and MP co-incubation were observed in human T cells.

BERLIN—Vitamin D increases the therapeutic effects of glucocorticoids via an mTORc1–dependent upregulation of the glucocorticoid receptor, according to a report at ECTRIMS 2018. “These data suggest that efficacy of glucocorticoids in the treatment of multiple sclerosis (MS) relapses could be improved by mTORc1 inhibition,” said lead author Maud Bagnoud, a doctoral candidate from the Department for Biomedical Research at the University of Bern in Switzerland, and colleagues.

Glucocorticoids are the mainstay in the treatment of acute MS relapses. Still, disability increases in more than 40% of patients. Ms. Bagnoud and colleagues investigated the potential of vitamin D to enhance steroid efficacy for MS relapse therapy and the mechanisms involved.

The researchers analyzed vitamin D levels using an immunoassay in patients with stable MS (n = 56), patients with relapsing glucocorticoid-responsive MS (n = 30), and patients with relapsing glucocorticoid-resistant MS (n = 24). Gene expression of human T cells (microarrays, n = 112) were correlated with 25(OH)D₃ levels. Glucocorticoid receptor protein was measured using ELISA. T cell apoptosis was analyzed by FACS. Myelin oligodendrocyte glycoprotein (MOG_35-55) experimental autoimmune encephalomyelitis (EAE) was performed in wild type and knockout mice with T cell specific deficiency for glucocorticoid receptor/mTORc1. The investigators analyzed the relevance of the JNK-pathway in human T cells using a competitive JNK-inhibitor (SP600125).

Patients with glucocorticoid-resistant MS had a decreased vitamin D serum level, compared with patients with glucocorticoid-responsive MS or stable MS. This decreased level of vitamin D was associated with reduced expression of the glucocorticoid receptor in T cells. In vitro, vitamin D increased the concentration of glucocorticoid receptor protein in T cells in a dose-dependent manner. Focusing on T cells donated from patients with MS during glucocorticoid-resistant relapse, this glucocorticoid receptor upregulation by vitamin D increased T cell apoptosis by approximately 10%, if treated with vitamin D and glucocorticoids, compared with glucocorticoid monotherapy. Combination therapy ameliorated EAE disease course more efficiently than monotherapies did. This effect was dependent on the presence of the glucocorticoid receptor in T cells.

On a molecular level, vitamin D inhibited mTORc1 signal transduction in murine T cells in vitro. Furthermore, hypovitaminosis D was associated with reduced expression of the archetype mTORc1 inhibitor tuberous sclerosis complex 1 in human T cells. The upregulation of the glucocorticoid receptor by vitamin D as well as the functional vitamin D/glucocorticoid synergism observed in vitro and in vivo were absent in mice with mTORc1-deficient T cells. Pharmacologic inhibition of mTORc1 by everolimus augmented the effects of glucocorticoid treatment in wild type mice during EAE even more potently than vitamin D co-administration did.

No significant changes of proliferation or apoptosis by JNK-inhibition and MP co-incubation were observed in human T cells.