Neurology

BALTIMORE – Older patients may have better outcomes at 1 year after resective surgery for epilepsy than the general population does, according to research presented at the annual meeting of the American Epilepsy Society. A tendency toward greater prevalence of lesional epilepsy and temporal lobe epilepsy (TLE) in the older patients in the study population could explain this difference in outcomes. Although surgery might entail greater risks in older patients, the decision to operate should be based on the patient’s inherent risk, and not on his or her age, said Juan S. Bottan, MD, neurosurgery resident at Hospital Pedro De Elizalde in Buenos Aires, and colleagues.

Zerbor/Thinkstock

Epilepsy surgery as a treatment for elderly patients is controversial. These patients generally are not considered to be surgical candidates because of concerns about long disease duration and increased surgical risk. Recent literature, however, suggests that elderly patients can benefit from surgery. Lang et al. found that epilepsy surgery success rates can be higher in selected older patients than in younger patients, although older patients may be at greater risk for postoperative hygroma and memory deficits.

Dr. Bottan and colleagues sought to analyze the role of resective surgery in patients older than age 60 years by evaluating surgical outcomes and safety. The investigators retrospectively analyzed 595 patients who underwent resective epilepsy surgery at Western University in London, Ontario, during 1999-2019. Eligible participants had drug-resistant epilepsy that had failed the best medical management. The researchers identified 31 patients aged 60 years or older and randomly selected 60 patients aged 59 years or younger as a control group. Dr. Bottan and colleagues analyzed the population’s characteristics, presurgical evaluations, postoperative outcome, and complications.

The investigators found no significant differences between groups in terms of hemisphere dominance, side of surgery, the ratio of patients with lesional epilepsy to patients with nonlesional epilepsy, and incidence of TLE over extratemporal epilepsy.

Nevertheless, extratemporal epilepsy was more frequent in older patients. Age and duration of epilepsy were significantly greater in older patients, and invasive recording was significantly more common in younger patients.

The most common pathology results in older patients were mesial temporal sclerosis (39%), gliosis (19%), and other (19%). Among younger patients, the most common pathology results were mesial temporal sclerosis (25%), gliosis (25%), and focal cortical dysplasia (15%).

The rates of Engel Class I outcome at 6 months, 1 year, and 2 years were 92.9%, 88.5%, and 94.7% among older patients and 75%, 63.5%, and 75.8% among younger patients, respectively. The difference between groups in Engel Class I outcome at 1 year was statistically significant. Patients with TLE had a better seizure outcome, regardless of age group, but the rate of good outcome was higher among older patients. The rate of complications was higher among older patients, but the difference was not statistically significant.

The study was not supported by external funding, and the investigators had no disclosures.

egreb@mdedge.com

SOURCE: Bottan JS et al. AES 2019, Abstract 1.343.

BALTIMORE – Older patients may have better outcomes at 1 year after resective surgery for epilepsy than the general population does, according to research presented at the annual meeting of the American Epilepsy Society. A tendency toward greater prevalence of lesional epilepsy and temporal lobe epilepsy (TLE) in the older patients in the study population could explain this difference in outcomes. Although surgery might entail greater risks in older patients, the decision to operate should be based on the patient’s inherent risk, and not on his or her age, said Juan S. Bottan, MD, neurosurgery resident at Hospital Pedro De Elizalde in Buenos Aires, and colleagues.

Zerbor/Thinkstock

Epilepsy surgery as a treatment for elderly patients is controversial. These patients generally are not considered to be surgical candidates because of concerns about long disease duration and increased surgical risk. Recent literature, however, suggests that elderly patients can benefit from surgery. Lang et al. found that epilepsy surgery success rates can be higher in selected older patients than in younger patients, although older patients may be at greater risk for postoperative hygroma and memory deficits.

Dr. Bottan and colleagues sought to analyze the role of resective surgery in patients older than age 60 years by evaluating surgical outcomes and safety. The investigators retrospectively analyzed 595 patients who underwent resective epilepsy surgery at Western University in London, Ontario, during 1999-2019. Eligible participants had drug-resistant epilepsy that had failed the best medical management. The researchers identified 31 patients aged 60 years or older and randomly selected 60 patients aged 59 years or younger as a control group. Dr. Bottan and colleagues analyzed the population’s characteristics, presurgical evaluations, postoperative outcome, and complications.

The investigators found no significant differences between groups in terms of hemisphere dominance, side of surgery, the ratio of patients with lesional epilepsy to patients with nonlesional epilepsy, and incidence of TLE over extratemporal epilepsy.

Nevertheless, extratemporal epilepsy was more frequent in older patients. Age and duration of epilepsy were significantly greater in older patients, and invasive recording was significantly more common in younger patients.

The most common pathology results in older patients were mesial temporal sclerosis (39%), gliosis (19%), and other (19%). Among younger patients, the most common pathology results were mesial temporal sclerosis (25%), gliosis (25%), and focal cortical dysplasia (15%).

The rates of Engel Class I outcome at 6 months, 1 year, and 2 years were 92.9%, 88.5%, and 94.7% among older patients and 75%, 63.5%, and 75.8% among younger patients, respectively. The difference between groups in Engel Class I outcome at 1 year was statistically significant. Patients with TLE had a better seizure outcome, regardless of age group, but the rate of good outcome was higher among older patients. The rate of complications was higher among older patients, but the difference was not statistically significant.

The study was not supported by external funding, and the investigators had no disclosures.

egreb@mdedge.com

SOURCE: Bottan JS et al. AES 2019, Abstract 1.343.

BALTIMORE – Older patients may have better outcomes at 1 year after resective surgery for epilepsy than the general population does, according to research presented at the annual meeting of the American Epilepsy Society. A tendency toward greater prevalence of lesional epilepsy and temporal lobe epilepsy (TLE) in the older patients in the study population could explain this difference in outcomes. Although surgery might entail greater risks in older patients, the decision to operate should be based on the patient’s inherent risk, and not on his or her age, said Juan S. Bottan, MD, neurosurgery resident at Hospital Pedro De Elizalde in Buenos Aires, and colleagues.

Zerbor/Thinkstock

Epilepsy surgery as a treatment for elderly patients is controversial. These patients generally are not considered to be surgical candidates because of concerns about long disease duration and increased surgical risk. Recent literature, however, suggests that elderly patients can benefit from surgery. Lang et al. found that epilepsy surgery success rates can be higher in selected older patients than in younger patients, although older patients may be at greater risk for postoperative hygroma and memory deficits.

Dr. Bottan and colleagues sought to analyze the role of resective surgery in patients older than age 60 years by evaluating surgical outcomes and safety. The investigators retrospectively analyzed 595 patients who underwent resective epilepsy surgery at Western University in London, Ontario, during 1999-2019. Eligible participants had drug-resistant epilepsy that had failed the best medical management. The researchers identified 31 patients aged 60 years or older and randomly selected 60 patients aged 59 years or younger as a control group. Dr. Bottan and colleagues analyzed the population’s characteristics, presurgical evaluations, postoperative outcome, and complications.

The investigators found no significant differences between groups in terms of hemisphere dominance, side of surgery, the ratio of patients with lesional epilepsy to patients with nonlesional epilepsy, and incidence of TLE over extratemporal epilepsy.

Nevertheless, extratemporal epilepsy was more frequent in older patients. Age and duration of epilepsy were significantly greater in older patients, and invasive recording was significantly more common in younger patients.

The most common pathology results in older patients were mesial temporal sclerosis (39%), gliosis (19%), and other (19%). Among younger patients, the most common pathology results were mesial temporal sclerosis (25%), gliosis (25%), and focal cortical dysplasia (15%).

The rates of Engel Class I outcome at 6 months, 1 year, and 2 years were 92.9%, 88.5%, and 94.7% among older patients and 75%, 63.5%, and 75.8% among younger patients, respectively. The difference between groups in Engel Class I outcome at 1 year was statistically significant. Patients with TLE had a better seizure outcome, regardless of age group, but the rate of good outcome was higher among older patients. The rate of complications was higher among older patients, but the difference was not statistically significant.

The study was not supported by external funding, and the investigators had no disclosures.

egreb@mdedge.com

SOURCE: Bottan JS et al. AES 2019, Abstract 1.343.

BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.

Jake Remaly/MDedge News

To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.

“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.

Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.

An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.

“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.

Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:

• Massive ongoing cluster with about 20% apneic events.
• My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
• Started feeling like I was having an aura and pulled over.
• Thought about suicide for the first time in a while.

Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.

UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.

jremaly@mdedge.com

SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.

BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.

Jake Remaly/MDedge News

To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.

“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.

Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.

An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.

“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.

Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:

• Massive ongoing cluster with about 20% apneic events.
• My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
• Started feeling like I was having an aura and pulled over.
• Thought about suicide for the first time in a while.

Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.

UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.

jremaly@mdedge.com

SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.

BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.

Jake Remaly/MDedge News

To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.

“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.

Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.

An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.

“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.

Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:

• Massive ongoing cluster with about 20% apneic events.
• My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
• Started feeling like I was having an aura and pulled over.
• Thought about suicide for the first time in a while.

Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.

UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.

jremaly@mdedge.com

SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.

BALTIMORE – Head CTs for breakthrough seizures in chronic epilepsy are useful for known structural triggers such as brain tumors, but they don’t change management for most patients, according to a review from the SUNY Upstate Medical University, Syracuse, N.Y., emergency department.

gorodenkoff/Getty Images

“Nonselective use of ED neuroimaging in patients with no new neurological findings” and no known structural problem, is “very low yield, and increases the use of hospital resources and radiation exposure without impacting the immediate care,” concluded investigators led by Shahram Izadyar, MD, an epileptologist and associate professor of neurology at the university.

In short, CTs for breakthrough seizures – routine in many EDs – usually are a waste of time and money. Absent a known structural cause, “there really isn’t a reason to do imaging,” he said at the American Epilepsy Society annual meeting.

Dr. Izadyar wanted to look into the issue after noticing how common CTs were among his breakthrough patients. He and his team reviewed 90 adults with an established diagnosis of epilepsy and on at least one antiepileptic who presented to the university ED for breakthrough seizures during 2017-2018; 39 (43.3%) had head CTs, 51 (56.7%) did not.

CT changed management in three of the four patients (4.4%) who had a known brain tumor, leading, for instance, to steroids for increased tumor edema. The rest of the patients had nonfocal exams, and imaging had no impact on management.

There was no rhyme or reason why some people got CTs and others didn’t; it seemed to be dependent on the provider. Defensive medicine probably had something to do with it, as well as saving time by ordering a CT instead of doing a neurologic exam, Dr. Izadyar said.

People aren’t going to stop doing defensive medicine, but even a small reduction in unnecessary CTs would “be a positive change.” There’s the cost issue, but also the radiation exposure, which is considerable when people end up in the ED every few months for breakthrough seizures, he said.

There were no differences between the CT and no-CT groups in the suspected causes of breakthroughs (P = .93). About half the cases were probably because of noncompliance, about a quarter from sleep deprivation, and the rest from a change in seizure medication or some other issue.

Dr. Izadyar said the next step is taking the findings to his ED colleagues, and perhaps calculating how much money the university would save by skipping CTs in chronic epilepsy patients with no known structural problem.

There were slightly more men than women in the study, and the mean age was 38 years.

There was no industry funding, and the investigators didn’t have any relevant disclosures.

aotto@mdedge.com

SOURCE: Ali S et al. AES 2019. Abstract 1.213.

BALTIMORE – Head CTs for breakthrough seizures in chronic epilepsy are useful for known structural triggers such as brain tumors, but they don’t change management for most patients, according to a review from the SUNY Upstate Medical University, Syracuse, N.Y., emergency department.

gorodenkoff/Getty Images

“Nonselective use of ED neuroimaging in patients with no new neurological findings” and no known structural problem, is “very low yield, and increases the use of hospital resources and radiation exposure without impacting the immediate care,” concluded investigators led by Shahram Izadyar, MD, an epileptologist and associate professor of neurology at the university.

In short, CTs for breakthrough seizures – routine in many EDs – usually are a waste of time and money. Absent a known structural cause, “there really isn’t a reason to do imaging,” he said at the American Epilepsy Society annual meeting.

Dr. Izadyar wanted to look into the issue after noticing how common CTs were among his breakthrough patients. He and his team reviewed 90 adults with an established diagnosis of epilepsy and on at least one antiepileptic who presented to the university ED for breakthrough seizures during 2017-2018; 39 (43.3%) had head CTs, 51 (56.7%) did not.

CT changed management in three of the four patients (4.4%) who had a known brain tumor, leading, for instance, to steroids for increased tumor edema. The rest of the patients had nonfocal exams, and imaging had no impact on management.

There was no rhyme or reason why some people got CTs and others didn’t; it seemed to be dependent on the provider. Defensive medicine probably had something to do with it, as well as saving time by ordering a CT instead of doing a neurologic exam, Dr. Izadyar said.

People aren’t going to stop doing defensive medicine, but even a small reduction in unnecessary CTs would “be a positive change.” There’s the cost issue, but also the radiation exposure, which is considerable when people end up in the ED every few months for breakthrough seizures, he said.

There were no differences between the CT and no-CT groups in the suspected causes of breakthroughs (P = .93). About half the cases were probably because of noncompliance, about a quarter from sleep deprivation, and the rest from a change in seizure medication or some other issue.

Dr. Izadyar said the next step is taking the findings to his ED colleagues, and perhaps calculating how much money the university would save by skipping CTs in chronic epilepsy patients with no known structural problem.

There were slightly more men than women in the study, and the mean age was 38 years.

There was no industry funding, and the investigators didn’t have any relevant disclosures.

aotto@mdedge.com

SOURCE: Ali S et al. AES 2019. Abstract 1.213.

BALTIMORE – Head CTs for breakthrough seizures in chronic epilepsy are useful for known structural triggers such as brain tumors, but they don’t change management for most patients, according to a review from the SUNY Upstate Medical University, Syracuse, N.Y., emergency department.

gorodenkoff/Getty Images

“Nonselective use of ED neuroimaging in patients with no new neurological findings” and no known structural problem, is “very low yield, and increases the use of hospital resources and radiation exposure without impacting the immediate care,” concluded investigators led by Shahram Izadyar, MD, an epileptologist and associate professor of neurology at the university.

In short, CTs for breakthrough seizures – routine in many EDs – usually are a waste of time and money. Absent a known structural cause, “there really isn’t a reason to do imaging,” he said at the American Epilepsy Society annual meeting.

Dr. Izadyar wanted to look into the issue after noticing how common CTs were among his breakthrough patients. He and his team reviewed 90 adults with an established diagnosis of epilepsy and on at least one antiepileptic who presented to the university ED for breakthrough seizures during 2017-2018; 39 (43.3%) had head CTs, 51 (56.7%) did not.

CT changed management in three of the four patients (4.4%) who had a known brain tumor, leading, for instance, to steroids for increased tumor edema. The rest of the patients had nonfocal exams, and imaging had no impact on management.

There was no rhyme or reason why some people got CTs and others didn’t; it seemed to be dependent on the provider. Defensive medicine probably had something to do with it, as well as saving time by ordering a CT instead of doing a neurologic exam, Dr. Izadyar said.

People aren’t going to stop doing defensive medicine, but even a small reduction in unnecessary CTs would “be a positive change.” There’s the cost issue, but also the radiation exposure, which is considerable when people end up in the ED every few months for breakthrough seizures, he said.

There were no differences between the CT and no-CT groups in the suspected causes of breakthroughs (P = .93). About half the cases were probably because of noncompliance, about a quarter from sleep deprivation, and the rest from a change in seizure medication or some other issue.

Dr. Izadyar said the next step is taking the findings to his ED colleagues, and perhaps calculating how much money the university would save by skipping CTs in chronic epilepsy patients with no known structural problem.

There were slightly more men than women in the study, and the mean age was 38 years.

There was no industry funding, and the investigators didn’t have any relevant disclosures.

aotto@mdedge.com

SOURCE: Ali S et al. AES 2019. Abstract 1.213.

BALTIMORE – The rates of breastfeeding initiation and adherence are lower in women with epilepsy, compared with the general population, according to data presented at the annual meeting of the American Epilepsy Society. Seizure control, education by the treating neurologist, and postpartum lactation consultative support are associated with adherence to breastfeeding, said the researchers.

©Lev Olkha/iStockphoto.com

“We need to understand and address the challenges that women with epilepsy face beyond seizure control and medication management when they are being seen by various health care providers to ensure the best quality of life for them and their babies,” Abrar Al-Faraj, MD, instructor of neurology at Boston University, said in a press release. “The strong efforts to advocate for breastfeeding in the general population should include women with chronic diseases such as epilepsy.”
 

A retrospective study of women who underwent pregnancy

Data have established the benefits of breastfeeding in the general population. Recent studies have confirmed that for women with epilepsy and their children, breastfeeding is safe and may provide neurodevelopmental benefits. Data also indicate, however, that rates of breastfeeding are significantly lower in women with epilepsy than in the general population. Dr. Al-Faraj and colleagues sought to compare the rates of initiation of and adherence to breastfeeding in women with epilepsy with those in healthy controls. They also intended to identify the factors that affect breastfeeding in women with epilepsy and assess the influence of support systems (e.g., lactation consult services) on breastfeeding.

The investigators retrospectively studied 102 women with epilepsy who were treated at the Beth Israel Deaconess Medical Center (BIDMC) Epilepsy Clinic and underwent pregnancies between 2009 and 2018. They compared these women to 113 healthy controls without epilepsy who were treated at the obstetrical service at BIDMC during the same period. Dr. Al-Faraj and colleagues reviewed patients’ medical records for demographic information, epilepsy type, degree of seizure control during pregnancy and post partum, number of antiepileptic medications (AEDs), breastfeeding education by providers (i.e., neurologists and epilepsy nurses), lactation consult, and rate of initiation of and adherence to breastfeeding at 6 weeks and 3 and 6 months. The investigators excluded from their analysis patients with other chronic medical conditions, those taking medications other than AEDs that may affect breastfeeding, and those with limited follow-up during pregnancy and post partum.
 

Education and support were correlated with breastfeeding

Participants’ ages ranged from 20 years to 40 years. The rate of breastfeeding initiation was significantly lower in women with epilepsy (51%) than in controls (87%). The rate declined significantly to 38.2% at 6 weeks in women with epilepsy, compared to 76% in controls. The rate of adherence at 3 months was 36.2% in women with epilepsy, and adherence at 6 months was 18.6%.

The reasons for not breastfeeding were known for 17.6% of women with epilepsy. These reasons included fear of AED exposure through breast milk, recommendations by providers (e.g., pediatricians and obstetricians) not to breastfeed, failed breastfeeding attempts because of technical difficulties (e.g., the baby’s inability to latch), and lack of milk supply. Treating neurologists discussed breastfeeding with 52.9% of women with epilepsy, and epilepsy nurses discussed it with 91% of women with epilepsy. Among the 66% of patients who received obstetrical care at BIDMC, 13% of women with epilepsy had lactation consultation post partum, compared with 58% of controls. Breastfeeding education by the treating neurologist was significantly and positively correlated with decision to breastfeed and initiation of breastfeeding. Postpartum lactation consult support was also associated with a significantly higher rate of breastfeeding initiation, adherence at 6 weeks, adherence at 3 months, and adherence at 6 months. Women with well-controlled seizures were more likely to continue breastfeeding at 6 weeks, compared with women with uncontrolled seizures. The researchers found no statistically significant difference in the breastfeeding initiation rate, however, between women with controlled seizures and those with uncontrolled seizures.

“Women with poor seizure control are a particularly vulnerable group and have the greatest need for intervention to improve breastfeeding rates,” said Dr. Al-Faraj and colleagues. Focused physician education and support measures such as lactation consultation may be potential interventions to improve the treatment of women with epilepsy, they added. “Further prospective investigations are needed to identify other factors that prevent the decision to initiate or adhere to breastfeeding in women with epilepsy and evaluate interventions that may be implemented as a public health measure to support this vulnerable population.”

The study did not have external funding, and the investigators reported no disclosures.

egreb@mdedge.com

SOURCE: Al-Faraj AO et al. AES 2019, Abstract 1.246.

BALTIMORE – The rates of breastfeeding initiation and adherence are lower in women with epilepsy, compared with the general population, according to data presented at the annual meeting of the American Epilepsy Society. Seizure control, education by the treating neurologist, and postpartum lactation consultative support are associated with adherence to breastfeeding, said the researchers.

©Lev Olkha/iStockphoto.com

“We need to understand and address the challenges that women with epilepsy face beyond seizure control and medication management when they are being seen by various health care providers to ensure the best quality of life for them and their babies,” Abrar Al-Faraj, MD, instructor of neurology at Boston University, said in a press release. “The strong efforts to advocate for breastfeeding in the general population should include women with chronic diseases such as epilepsy.”
 

A retrospective study of women who underwent pregnancy

Data have established the benefits of breastfeeding in the general population. Recent studies have confirmed that for women with epilepsy and their children, breastfeeding is safe and may provide neurodevelopmental benefits. Data also indicate, however, that rates of breastfeeding are significantly lower in women with epilepsy than in the general population. Dr. Al-Faraj and colleagues sought to compare the rates of initiation of and adherence to breastfeeding in women with epilepsy with those in healthy controls. They also intended to identify the factors that affect breastfeeding in women with epilepsy and assess the influence of support systems (e.g., lactation consult services) on breastfeeding.

The investigators retrospectively studied 102 women with epilepsy who were treated at the Beth Israel Deaconess Medical Center (BIDMC) Epilepsy Clinic and underwent pregnancies between 2009 and 2018. They compared these women to 113 healthy controls without epilepsy who were treated at the obstetrical service at BIDMC during the same period. Dr. Al-Faraj and colleagues reviewed patients’ medical records for demographic information, epilepsy type, degree of seizure control during pregnancy and post partum, number of antiepileptic medications (AEDs), breastfeeding education by providers (i.e., neurologists and epilepsy nurses), lactation consult, and rate of initiation of and adherence to breastfeeding at 6 weeks and 3 and 6 months. The investigators excluded from their analysis patients with other chronic medical conditions, those taking medications other than AEDs that may affect breastfeeding, and those with limited follow-up during pregnancy and post partum.
 

Education and support were correlated with breastfeeding

Participants’ ages ranged from 20 years to 40 years. The rate of breastfeeding initiation was significantly lower in women with epilepsy (51%) than in controls (87%). The rate declined significantly to 38.2% at 6 weeks in women with epilepsy, compared to 76% in controls. The rate of adherence at 3 months was 36.2% in women with epilepsy, and adherence at 6 months was 18.6%.

The reasons for not breastfeeding were known for 17.6% of women with epilepsy. These reasons included fear of AED exposure through breast milk, recommendations by providers (e.g., pediatricians and obstetricians) not to breastfeed, failed breastfeeding attempts because of technical difficulties (e.g., the baby’s inability to latch), and lack of milk supply. Treating neurologists discussed breastfeeding with 52.9% of women with epilepsy, and epilepsy nurses discussed it with 91% of women with epilepsy. Among the 66% of patients who received obstetrical care at BIDMC, 13% of women with epilepsy had lactation consultation post partum, compared with 58% of controls. Breastfeeding education by the treating neurologist was significantly and positively correlated with decision to breastfeed and initiation of breastfeeding. Postpartum lactation consult support was also associated with a significantly higher rate of breastfeeding initiation, adherence at 6 weeks, adherence at 3 months, and adherence at 6 months. Women with well-controlled seizures were more likely to continue breastfeeding at 6 weeks, compared with women with uncontrolled seizures. The researchers found no statistically significant difference in the breastfeeding initiation rate, however, between women with controlled seizures and those with uncontrolled seizures.

“Women with poor seizure control are a particularly vulnerable group and have the greatest need for intervention to improve breastfeeding rates,” said Dr. Al-Faraj and colleagues. Focused physician education and support measures such as lactation consultation may be potential interventions to improve the treatment of women with epilepsy, they added. “Further prospective investigations are needed to identify other factors that prevent the decision to initiate or adhere to breastfeeding in women with epilepsy and evaluate interventions that may be implemented as a public health measure to support this vulnerable population.”

The study did not have external funding, and the investigators reported no disclosures.

egreb@mdedge.com

SOURCE: Al-Faraj AO et al. AES 2019, Abstract 1.246.

BALTIMORE – The rates of breastfeeding initiation and adherence are lower in women with epilepsy, compared with the general population, according to data presented at the annual meeting of the American Epilepsy Society. Seizure control, education by the treating neurologist, and postpartum lactation consultative support are associated with adherence to breastfeeding, said the researchers.

©Lev Olkha/iStockphoto.com

“We need to understand and address the challenges that women with epilepsy face beyond seizure control and medication management when they are being seen by various health care providers to ensure the best quality of life for them and their babies,” Abrar Al-Faraj, MD, instructor of neurology at Boston University, said in a press release. “The strong efforts to advocate for breastfeeding in the general population should include women with chronic diseases such as epilepsy.”
 

A retrospective study of women who underwent pregnancy

Data have established the benefits of breastfeeding in the general population. Recent studies have confirmed that for women with epilepsy and their children, breastfeeding is safe and may provide neurodevelopmental benefits. Data also indicate, however, that rates of breastfeeding are significantly lower in women with epilepsy than in the general population. Dr. Al-Faraj and colleagues sought to compare the rates of initiation of and adherence to breastfeeding in women with epilepsy with those in healthy controls. They also intended to identify the factors that affect breastfeeding in women with epilepsy and assess the influence of support systems (e.g., lactation consult services) on breastfeeding.

The investigators retrospectively studied 102 women with epilepsy who were treated at the Beth Israel Deaconess Medical Center (BIDMC) Epilepsy Clinic and underwent pregnancies between 2009 and 2018. They compared these women to 113 healthy controls without epilepsy who were treated at the obstetrical service at BIDMC during the same period. Dr. Al-Faraj and colleagues reviewed patients’ medical records for demographic information, epilepsy type, degree of seizure control during pregnancy and post partum, number of antiepileptic medications (AEDs), breastfeeding education by providers (i.e., neurologists and epilepsy nurses), lactation consult, and rate of initiation of and adherence to breastfeeding at 6 weeks and 3 and 6 months. The investigators excluded from their analysis patients with other chronic medical conditions, those taking medications other than AEDs that may affect breastfeeding, and those with limited follow-up during pregnancy and post partum.
 

Education and support were correlated with breastfeeding

Participants’ ages ranged from 20 years to 40 years. The rate of breastfeeding initiation was significantly lower in women with epilepsy (51%) than in controls (87%). The rate declined significantly to 38.2% at 6 weeks in women with epilepsy, compared to 76% in controls. The rate of adherence at 3 months was 36.2% in women with epilepsy, and adherence at 6 months was 18.6%.

The reasons for not breastfeeding were known for 17.6% of women with epilepsy. These reasons included fear of AED exposure through breast milk, recommendations by providers (e.g., pediatricians and obstetricians) not to breastfeed, failed breastfeeding attempts because of technical difficulties (e.g., the baby’s inability to latch), and lack of milk supply. Treating neurologists discussed breastfeeding with 52.9% of women with epilepsy, and epilepsy nurses discussed it with 91% of women with epilepsy. Among the 66% of patients who received obstetrical care at BIDMC, 13% of women with epilepsy had lactation consultation post partum, compared with 58% of controls. Breastfeeding education by the treating neurologist was significantly and positively correlated with decision to breastfeed and initiation of breastfeeding. Postpartum lactation consult support was also associated with a significantly higher rate of breastfeeding initiation, adherence at 6 weeks, adherence at 3 months, and adherence at 6 months. Women with well-controlled seizures were more likely to continue breastfeeding at 6 weeks, compared with women with uncontrolled seizures. The researchers found no statistically significant difference in the breastfeeding initiation rate, however, between women with controlled seizures and those with uncontrolled seizures.

“Women with poor seizure control are a particularly vulnerable group and have the greatest need for intervention to improve breastfeeding rates,” said Dr. Al-Faraj and colleagues. Focused physician education and support measures such as lactation consultation may be potential interventions to improve the treatment of women with epilepsy, they added. “Further prospective investigations are needed to identify other factors that prevent the decision to initiate or adhere to breastfeeding in women with epilepsy and evaluate interventions that may be implemented as a public health measure to support this vulnerable population.”

The study did not have external funding, and the investigators reported no disclosures.

egreb@mdedge.com

SOURCE: Al-Faraj AO et al. AES 2019, Abstract 1.246.

SAN DIEGO – Positive findings from a post hoc subanalysis of two unsuccessful studies represent “a major step forward in Alzheimer’s disease research” and could set the antiamyloid antibody up as a “foothold” in slowing disease progression, study investigators said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

After full follow-up of 78 weeks, patients with mild Alzheimer’s disease (AD) who took the highest 10-mg/kg dose for a full 14 doses experienced up to a 53% slowing of functional decline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) in one study and a 48% slowing in the other study – relative to placebo – a result that might give them “an extra year or 2” of independence; they might perhaps retain the ability to drive and even stay employed, said Sharon Cohen, MD, a panelist at the meeting’s aducanumab presentation session and a clinical investigator in EMERGE, one of two phase 3 studies from which the data were derived.

Samantha Budd Haeberlein, PhD, Biogen’s vice president and head of late-stage clinical development in Alzheimer’s disease, presented the new data. They “are complex” and require much more study before investigators, clinicians, and federal regulators can fully embrace them, said the panelists who discussed the results. Nevertheless, Biogen, which is codeveloping the antibody with partner Eisai, said in October it will put aducanumab forward to the Food and Drug Administration in a new drug application for the first-ever AD disease-modifying agent. FDA regulators have said they will review the data.

The new subanalysis comprised 570 of 3,285 patients in two identical studies with negative primary endpoint results. One, ENGAGE, failed to reach both its primary and secondary endpoints; the other, EMERGE, was halted last spring after a futility analysis determined that aducanumab was unlikely to confer significant benefit. The post hoc subanalysis looked at a combined subset of those who received the highest 10-mg/kg dose for the full 78 weeks of each trial. The statistically significant functional endpoints occurred in this group, comprised largely of apolipoprotein E epsilon-4 (APOE4) allele carriers.

“The futility analysis of EMERGE was highly unfortunate,” said panelist Paul Aisen, MD, founding director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles. “Clearly in the final analysis, EMERGE was positive in the primary endpoints, and now the secondary analysis of both studies is positive and consistent.” The diverging trajectory of placebo and treatment groups continued to the end of follow-up in both studies, a finding that at least suggests continuing improvement, he added.

Biogen undertook the pooled analysis after ENGAGE’s futility analysis. Early in the development program, concern about amyloid-related imaging abnormalities (ARIA) in APOE4 carriers led Biogen to stratify doses in that group.

“When we started [creating aducanumab trials], we stratified the dose so that e4 carriers had the lowest dose, but in PRIME [the phase 1b study], we saw the best result from the 10-mg/kg dose, so we believed that was important for efficacy. However, we didn’t have sufficient evidence to believe that it was safe to put carriers on that dose. In EMERGE, we saw that carriers could safely take it until the end of the study.”

Since the trials were running almost synchronously, a new version of randomization ensued. This allowed more e4 carriers to go forward on the 10-mg/kg dose.

“I would not normally recommend changing dose in the middle of a phase 3 trial, but it did have a real impact in the high-dose group,” Dr. Haeberlein said. Additionally, by the time of data lock after the futility analysis, more patients had completed the entire 78 weeks at the 10-mg/kg dose. Cumulative dosing ended up being quite different in the APOE4 carriers after this new version ensued. Before, the median cumulative dose for both carriers and noncarriers was 116 mg/kg. After the change, the median cumulative dose was 153 mg/kg. And before the alteration, 21% in EMERGE and 15% in ENGAGE received the full 14 possible 10-mg/kg doses. After the change, 51% in EMERGE and 47% in ENGAGE received the full 14 doses of 10 mg/kg.

The pooled analysis comprised this combined group, which was then largely composed of APOE4 carriers.

Imaging confirmed such dose-driven reductions in both brain amyloid plaques and phosphorylated tau. Although amyloid reduction has never been tied to cognitive or functional benefits, tau reduction has been associated with nonsignificant cognitive benefits in prior studies.

In the primary analysis of ENGAGE, aducanumab conferred no cognitive or functional benefit. In EMERGE, there were significant cognitive improvements on both the Mini Mental State Exam score (an 18% slowing of decline relative to placebo) and the Alzheimer’s Disease Assessment Scale cognitive portion (a 27% slowing).

However, the functional improvements seen in the pooled post hoc data “are a big deal,” and probably more meaningful to patients and families than the memory improvements, Dr. Cohen said.

“Those of us who know this disease well know what it means to lose yourself slice by slice, and anything you can hang onto is a triumph,” said Dr. Cohen, medical director and principal investigator of the Toronto Memory Program, an independent medical facility for dementia care and research. “I am pleased with a 27% slowing of cognitive decline, but a 40% slowing of functional decline is what will be really meaningful to patients. This is a long, slow disease, and if we can slow it at all, we’re winning out.”

Safety endpoints, especially ARIA, were not unexpected considering past studies. ARIA occurred in 41% of patients treated with the high aducanumab dose in EMERGE and in 40% in ENGAGE. It was largely asymptomatic (80% in EMERGE and 71% in ENGAGE). Headache was the next most common adverse event, followed by dizziness, visual disturbance, and nausea and vomiting. ARIA generally resolved within 4-6 weeks, and most patients continued their 10-mg/kg dose.

Biogen intends to begin a new study, an open-label nonrandomized trial that will offer the 10-mg/kg dose to all patients in both trials, including those who took placebo. This may provide interesting data regarding redosing patients who were off their successful 10-mg/kg dose for an extended period of time, said Laurie Ryan, PhD, chief of the Dementias of Aging Branch in the Division of Neuroscience at the National Institute on Aging.

“If those in the high-dose group had a regression of their improvements and then improved again when restarted, that would certainly tell us something,” she said in an interview. Likewise, researchers will be carefully looking at any placebo group response. “But we have to remember that this will not be a randomized study,” and will bring with it all the issues that such a study typically carries.

“I agree it’s unfortunate that they had to stop the EMERGE trial,” she said. “It really did complicate the results, even though they are certainly trending in the right way. But we have had a number of post hoc analyses that show APOE4-positive benefiting, or e4-negative benefiting, and these haven’t panned out.”

msullivan@medege.com

SAN DIEGO – Positive findings from a post hoc subanalysis of two unsuccessful studies represent “a major step forward in Alzheimer’s disease research” and could set the antiamyloid antibody up as a “foothold” in slowing disease progression, study investigators said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

After full follow-up of 78 weeks, patients with mild Alzheimer’s disease (AD) who took the highest 10-mg/kg dose for a full 14 doses experienced up to a 53% slowing of functional decline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) in one study and a 48% slowing in the other study – relative to placebo – a result that might give them “an extra year or 2” of independence; they might perhaps retain the ability to drive and even stay employed, said Sharon Cohen, MD, a panelist at the meeting’s aducanumab presentation session and a clinical investigator in EMERGE, one of two phase 3 studies from which the data were derived.

Samantha Budd Haeberlein, PhD, Biogen’s vice president and head of late-stage clinical development in Alzheimer’s disease, presented the new data. They “are complex” and require much more study before investigators, clinicians, and federal regulators can fully embrace them, said the panelists who discussed the results. Nevertheless, Biogen, which is codeveloping the antibody with partner Eisai, said in October it will put aducanumab forward to the Food and Drug Administration in a new drug application for the first-ever AD disease-modifying agent. FDA regulators have said they will review the data.

The new subanalysis comprised 570 of 3,285 patients in two identical studies with negative primary endpoint results. One, ENGAGE, failed to reach both its primary and secondary endpoints; the other, EMERGE, was halted last spring after a futility analysis determined that aducanumab was unlikely to confer significant benefit. The post hoc subanalysis looked at a combined subset of those who received the highest 10-mg/kg dose for the full 78 weeks of each trial. The statistically significant functional endpoints occurred in this group, comprised largely of apolipoprotein E epsilon-4 (APOE4) allele carriers.

“The futility analysis of EMERGE was highly unfortunate,” said panelist Paul Aisen, MD, founding director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles. “Clearly in the final analysis, EMERGE was positive in the primary endpoints, and now the secondary analysis of both studies is positive and consistent.” The diverging trajectory of placebo and treatment groups continued to the end of follow-up in both studies, a finding that at least suggests continuing improvement, he added.

Biogen undertook the pooled analysis after ENGAGE’s futility analysis. Early in the development program, concern about amyloid-related imaging abnormalities (ARIA) in APOE4 carriers led Biogen to stratify doses in that group.

“When we started [creating aducanumab trials], we stratified the dose so that e4 carriers had the lowest dose, but in PRIME [the phase 1b study], we saw the best result from the 10-mg/kg dose, so we believed that was important for efficacy. However, we didn’t have sufficient evidence to believe that it was safe to put carriers on that dose. In EMERGE, we saw that carriers could safely take it until the end of the study.”

Since the trials were running almost synchronously, a new version of randomization ensued. This allowed more e4 carriers to go forward on the 10-mg/kg dose.

“I would not normally recommend changing dose in the middle of a phase 3 trial, but it did have a real impact in the high-dose group,” Dr. Haeberlein said. Additionally, by the time of data lock after the futility analysis, more patients had completed the entire 78 weeks at the 10-mg/kg dose. Cumulative dosing ended up being quite different in the APOE4 carriers after this new version ensued. Before, the median cumulative dose for both carriers and noncarriers was 116 mg/kg. After the change, the median cumulative dose was 153 mg/kg. And before the alteration, 21% in EMERGE and 15% in ENGAGE received the full 14 possible 10-mg/kg doses. After the change, 51% in EMERGE and 47% in ENGAGE received the full 14 doses of 10 mg/kg.

The pooled analysis comprised this combined group, which was then largely composed of APOE4 carriers.

Imaging confirmed such dose-driven reductions in both brain amyloid plaques and phosphorylated tau. Although amyloid reduction has never been tied to cognitive or functional benefits, tau reduction has been associated with nonsignificant cognitive benefits in prior studies.

In the primary analysis of ENGAGE, aducanumab conferred no cognitive or functional benefit. In EMERGE, there were significant cognitive improvements on both the Mini Mental State Exam score (an 18% slowing of decline relative to placebo) and the Alzheimer’s Disease Assessment Scale cognitive portion (a 27% slowing).

However, the functional improvements seen in the pooled post hoc data “are a big deal,” and probably more meaningful to patients and families than the memory improvements, Dr. Cohen said.

“Those of us who know this disease well know what it means to lose yourself slice by slice, and anything you can hang onto is a triumph,” said Dr. Cohen, medical director and principal investigator of the Toronto Memory Program, an independent medical facility for dementia care and research. “I am pleased with a 27% slowing of cognitive decline, but a 40% slowing of functional decline is what will be really meaningful to patients. This is a long, slow disease, and if we can slow it at all, we’re winning out.”

Safety endpoints, especially ARIA, were not unexpected considering past studies. ARIA occurred in 41% of patients treated with the high aducanumab dose in EMERGE and in 40% in ENGAGE. It was largely asymptomatic (80% in EMERGE and 71% in ENGAGE). Headache was the next most common adverse event, followed by dizziness, visual disturbance, and nausea and vomiting. ARIA generally resolved within 4-6 weeks, and most patients continued their 10-mg/kg dose.

Biogen intends to begin a new study, an open-label nonrandomized trial that will offer the 10-mg/kg dose to all patients in both trials, including those who took placebo. This may provide interesting data regarding redosing patients who were off their successful 10-mg/kg dose for an extended period of time, said Laurie Ryan, PhD, chief of the Dementias of Aging Branch in the Division of Neuroscience at the National Institute on Aging.

“If those in the high-dose group had a regression of their improvements and then improved again when restarted, that would certainly tell us something,” she said in an interview. Likewise, researchers will be carefully looking at any placebo group response. “But we have to remember that this will not be a randomized study,” and will bring with it all the issues that such a study typically carries.

“I agree it’s unfortunate that they had to stop the EMERGE trial,” she said. “It really did complicate the results, even though they are certainly trending in the right way. But we have had a number of post hoc analyses that show APOE4-positive benefiting, or e4-negative benefiting, and these haven’t panned out.”

msullivan@medege.com

SAN DIEGO – Positive findings from a post hoc subanalysis of two unsuccessful studies represent “a major step forward in Alzheimer’s disease research” and could set the antiamyloid antibody up as a “foothold” in slowing disease progression, study investigators said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

After full follow-up of 78 weeks, patients with mild Alzheimer’s disease (AD) who took the highest 10-mg/kg dose for a full 14 doses experienced up to a 53% slowing of functional decline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) in one study and a 48% slowing in the other study – relative to placebo – a result that might give them “an extra year or 2” of independence; they might perhaps retain the ability to drive and even stay employed, said Sharon Cohen, MD, a panelist at the meeting’s aducanumab presentation session and a clinical investigator in EMERGE, one of two phase 3 studies from which the data were derived.

Samantha Budd Haeberlein, PhD, Biogen’s vice president and head of late-stage clinical development in Alzheimer’s disease, presented the new data. They “are complex” and require much more study before investigators, clinicians, and federal regulators can fully embrace them, said the panelists who discussed the results. Nevertheless, Biogen, which is codeveloping the antibody with partner Eisai, said in October it will put aducanumab forward to the Food and Drug Administration in a new drug application for the first-ever AD disease-modifying agent. FDA regulators have said they will review the data.

The new subanalysis comprised 570 of 3,285 patients in two identical studies with negative primary endpoint results. One, ENGAGE, failed to reach both its primary and secondary endpoints; the other, EMERGE, was halted last spring after a futility analysis determined that aducanumab was unlikely to confer significant benefit. The post hoc subanalysis looked at a combined subset of those who received the highest 10-mg/kg dose for the full 78 weeks of each trial. The statistically significant functional endpoints occurred in this group, comprised largely of apolipoprotein E epsilon-4 (APOE4) allele carriers.

“The futility analysis of EMERGE was highly unfortunate,” said panelist Paul Aisen, MD, founding director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles. “Clearly in the final analysis, EMERGE was positive in the primary endpoints, and now the secondary analysis of both studies is positive and consistent.” The diverging trajectory of placebo and treatment groups continued to the end of follow-up in both studies, a finding that at least suggests continuing improvement, he added.

Biogen undertook the pooled analysis after ENGAGE’s futility analysis. Early in the development program, concern about amyloid-related imaging abnormalities (ARIA) in APOE4 carriers led Biogen to stratify doses in that group.

“When we started [creating aducanumab trials], we stratified the dose so that e4 carriers had the lowest dose, but in PRIME [the phase 1b study], we saw the best result from the 10-mg/kg dose, so we believed that was important for efficacy. However, we didn’t have sufficient evidence to believe that it was safe to put carriers on that dose. In EMERGE, we saw that carriers could safely take it until the end of the study.”

Since the trials were running almost synchronously, a new version of randomization ensued. This allowed more e4 carriers to go forward on the 10-mg/kg dose.

“I would not normally recommend changing dose in the middle of a phase 3 trial, but it did have a real impact in the high-dose group,” Dr. Haeberlein said. Additionally, by the time of data lock after the futility analysis, more patients had completed the entire 78 weeks at the 10-mg/kg dose. Cumulative dosing ended up being quite different in the APOE4 carriers after this new version ensued. Before, the median cumulative dose for both carriers and noncarriers was 116 mg/kg. After the change, the median cumulative dose was 153 mg/kg. And before the alteration, 21% in EMERGE and 15% in ENGAGE received the full 14 possible 10-mg/kg doses. After the change, 51% in EMERGE and 47% in ENGAGE received the full 14 doses of 10 mg/kg.

The pooled analysis comprised this combined group, which was then largely composed of APOE4 carriers.

Imaging confirmed such dose-driven reductions in both brain amyloid plaques and phosphorylated tau. Although amyloid reduction has never been tied to cognitive or functional benefits, tau reduction has been associated with nonsignificant cognitive benefits in prior studies.

In the primary analysis of ENGAGE, aducanumab conferred no cognitive or functional benefit. In EMERGE, there were significant cognitive improvements on both the Mini Mental State Exam score (an 18% slowing of decline relative to placebo) and the Alzheimer’s Disease Assessment Scale cognitive portion (a 27% slowing).

However, the functional improvements seen in the pooled post hoc data “are a big deal,” and probably more meaningful to patients and families than the memory improvements, Dr. Cohen said.

“Those of us who know this disease well know what it means to lose yourself slice by slice, and anything you can hang onto is a triumph,” said Dr. Cohen, medical director and principal investigator of the Toronto Memory Program, an independent medical facility for dementia care and research. “I am pleased with a 27% slowing of cognitive decline, but a 40% slowing of functional decline is what will be really meaningful to patients. This is a long, slow disease, and if we can slow it at all, we’re winning out.”

Safety endpoints, especially ARIA, were not unexpected considering past studies. ARIA occurred in 41% of patients treated with the high aducanumab dose in EMERGE and in 40% in ENGAGE. It was largely asymptomatic (80% in EMERGE and 71% in ENGAGE). Headache was the next most common adverse event, followed by dizziness, visual disturbance, and nausea and vomiting. ARIA generally resolved within 4-6 weeks, and most patients continued their 10-mg/kg dose.

Biogen intends to begin a new study, an open-label nonrandomized trial that will offer the 10-mg/kg dose to all patients in both trials, including those who took placebo. This may provide interesting data regarding redosing patients who were off their successful 10-mg/kg dose for an extended period of time, said Laurie Ryan, PhD, chief of the Dementias of Aging Branch in the Division of Neuroscience at the National Institute on Aging.

“If those in the high-dose group had a regression of their improvements and then improved again when restarted, that would certainly tell us something,” she said in an interview. Likewise, researchers will be carefully looking at any placebo group response. “But we have to remember that this will not be a randomized study,” and will bring with it all the issues that such a study typically carries.

“I agree it’s unfortunate that they had to stop the EMERGE trial,” she said. “It really did complicate the results, even though they are certainly trending in the right way. But we have had a number of post hoc analyses that show APOE4-positive benefiting, or e4-negative benefiting, and these haven’t panned out.”

msullivan@medege.com

SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.

“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”

The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.

SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.

At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.

Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.

After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.

Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.

Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.

The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.

There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.

“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”

The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.

Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.

The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm³ vs. 0.92 cm³). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm^3, compared with a loss of 26.9 cm³ in the standard-treatment group.

“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.

Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.

However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.

SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.

msullivan@mdedge.com

SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.

“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”

The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.

SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.

At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.

Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.

After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.

Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.

Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.

The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.

There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.

“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”

The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.

Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.

The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm³ vs. 0.92 cm³). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm^3, compared with a loss of 26.9 cm³ in the standard-treatment group.

“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.

Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.

However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.

SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.

msullivan@mdedge.com

SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.

“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”

The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.

SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.

At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.

Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.

After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.

Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.

Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.

The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.

There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.

“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”

The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.

Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.

The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm³ vs. 0.92 cm³). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm^3, compared with a loss of 26.9 cm³ in the standard-treatment group.

“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.

Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.

However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.

SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.

msullivan@mdedge.com

About 20% of patients who receive tablets containing 50 mg or 100 mg of ubrogepant for the acute treatment of migraine are pain free 2 hours later, compared with 12% of patients who receive placebo, according to phase 3 trial results published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.

Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.

Assessing a gepant for acute migraine treatment

Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.

To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.

In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.

The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.

The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”

“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”

The CGRP therapeutic landscape

“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.

Ubrogepant stands to join other treatments targeting CGRP.

“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”

Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.

jremaly@mdedge.com

SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.

About 20% of patients who receive tablets containing 50 mg or 100 mg of ubrogepant for the acute treatment of migraine are pain free 2 hours later, compared with 12% of patients who receive placebo, according to phase 3 trial results published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.

Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.

Assessing a gepant for acute migraine treatment

Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.

To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.

In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.

The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.

The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”

“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”

The CGRP therapeutic landscape

“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.

Ubrogepant stands to join other treatments targeting CGRP.

“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”

Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.

jremaly@mdedge.com

SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.

About 20% of patients who receive tablets containing 50 mg or 100 mg of ubrogepant for the acute treatment of migraine are pain free 2 hours later, compared with 12% of patients who receive placebo, according to phase 3 trial results published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.

Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.

Assessing a gepant for acute migraine treatment

Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.

To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.

In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.

The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.

The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”

“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”

The CGRP therapeutic landscape

“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.

Ubrogepant stands to join other treatments targeting CGRP.

“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”

Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.

jremaly@mdedge.com

SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.

CHICAGO – Individuals who sustain gunshot wounds have an increased risk for rehospitalization years, and even decades, after their initial injury.

Kateywhat/ThinkStock

A study of individuals at a single institution who were hospitalized and had a prior history of gunshot wound found some patterns of injury that set patients up for a greater likelihood of readmission.

In particular, patients who sustained visceral gunshot wounds were over six times more likely to be readmitted to the hospital, Corbin Pomeranz, MD, a radiology resident at Thomas Jefferson University, Philadelphia, said in an interview at the annual meeting of the Radiological Society of North America. Dr. Pomeranz led the retrospective study that begins to fill a knowledge gap about what happens over the long term to those who sustain gunshot wounds.

“There continues to be profound lack of substantial information related to gun violence, particularly in predicting long-term outcomes,” Dr. Pomeranz and coauthors wrote in the abstract accompanying the presentation.

The researchers performed a single-site retrospective analysis over 3 months in 2018, tapping into an imaging database and looking for inpatient imaging exams that were nonacute, but related to gunshot wounds. From this information, the researchers went back to the original gunshot wound injury imaging, and recorded the pattern of injury, classifying wounds as neurologic, vascular, visceral, musculoskeletal, or involving multiple systems.

The investigators were able to glean additional information including the initial admitting hospital unit, information about interval admissions or surgeries, and demographic data. Regarding the nature of the gunshot injury itself, Dr. Pomeranz and coauthors went back to the earlier imaging studies to note bullet morphology, recording whether the bullet was intact, deformed, or had splintered into shrapnel within injured tissues.

In all, 174 imaging studies involving 110 patients were examined. Men made up 92% of the study population; the average age was 49.7 years. Neurologic and visceral gunshot wounds were moderately correlated with subsequent readmission (r = .436; P less than .001). However, some of this effect was blunted when patient age was controlled for in the statistical analysis.

Patients who were initially admitted to the intensive care unit, and who presumably had more severe injuries, were also more likely to be readmitted (r = .494, P less than .001). Here, “controlling for age had very little effect on the strength of the relationship between these two variables,” noted Dr. Pomeranz and coauthors.

A more elaborate statistical model incorporated several independent variables including age, type of injury, and body region involved, as well as bullet morphology. In this model, visceral injury was the strongest predictor for readmission, with an odds ratio of 6.44.

Dr. Pomeranz said that both the initial gunshot wound and subsequent gaps in care can contribute to readmissions. A patient who has a spinal cord injury may not be reimbursed adequately for supportive cushioning, or an appropriate wheelchair, and so may require admission for decubitus ulcers.

The number of admissions for osteomyelitis, which made up more than half of the subsequent admissions, initially surprised Dr. Pomeranz, until he realized that lack of mobility and sensory losses from gunshot-induced spinal cord injuries could easily lead to nonhealing lower extremity wounds, with osteomyelitis as a sequela.

Several patients were admitted for small bowel obstructions with no interval surgery since treatment for the gunshot wound. These readmissions, said Dr. Pomeranz, were assessed as related to the gunshot wound since it’s extremely rare for a patient with no history of abdominal surgery and no malignancy to have a small bowel obstruction. Exploratory laparotomies are common in the context of abdominal trauma caused by gunshot wounds, and either the gunshot itself or the laparotomy was the likely cause of adhesions.

Dr. Pomeranz acknowledged the many limitations of the study, but pointed out that some will be addressed when he and his coauthors conduct a larger study they have planned to look at readmissions from gunshot wounds at multiple hospitals in the Philadelphia area. The small sample size in the current study meant that the impact of socioeconomic status and other lifestyle and social variables and comorbidities couldn’t be adequately addressed in the statistical analysis. By casting a wider net within the greater Philadelphia area, the investigators should be able to track patients who receive care in more than one hospital system, increasing participant numbers, he said.

“Morbidity and outcomes from gun violence can only be assessed after a firm understanding of injury patterns on imaging,” noted Dr. Pomeranz. He said that interdisciplinary research investigating individual and societal short- and long-term costs of gun violence is sorely needed to inform public policy.

Dr. Pomeranz reported no outside sources of funding and reported that he had no conflicts of interest.

koakes@mdedge.com

SOURCE: Pomeranz C et al. RSNA 2019, Presentation HP226-SD-THA3.

CHICAGO – Individuals who sustain gunshot wounds have an increased risk for rehospitalization years, and even decades, after their initial injury.

Kateywhat/ThinkStock

A study of individuals at a single institution who were hospitalized and had a prior history of gunshot wound found some patterns of injury that set patients up for a greater likelihood of readmission.

In particular, patients who sustained visceral gunshot wounds were over six times more likely to be readmitted to the hospital, Corbin Pomeranz, MD, a radiology resident at Thomas Jefferson University, Philadelphia, said in an interview at the annual meeting of the Radiological Society of North America. Dr. Pomeranz led the retrospective study that begins to fill a knowledge gap about what happens over the long term to those who sustain gunshot wounds.

“There continues to be profound lack of substantial information related to gun violence, particularly in predicting long-term outcomes,” Dr. Pomeranz and coauthors wrote in the abstract accompanying the presentation.

The researchers performed a single-site retrospective analysis over 3 months in 2018, tapping into an imaging database and looking for inpatient imaging exams that were nonacute, but related to gunshot wounds. From this information, the researchers went back to the original gunshot wound injury imaging, and recorded the pattern of injury, classifying wounds as neurologic, vascular, visceral, musculoskeletal, or involving multiple systems.

The investigators were able to glean additional information including the initial admitting hospital unit, information about interval admissions or surgeries, and demographic data. Regarding the nature of the gunshot injury itself, Dr. Pomeranz and coauthors went back to the earlier imaging studies to note bullet morphology, recording whether the bullet was intact, deformed, or had splintered into shrapnel within injured tissues.

In all, 174 imaging studies involving 110 patients were examined. Men made up 92% of the study population; the average age was 49.7 years. Neurologic and visceral gunshot wounds were moderately correlated with subsequent readmission (r = .436; P less than .001). However, some of this effect was blunted when patient age was controlled for in the statistical analysis.

Patients who were initially admitted to the intensive care unit, and who presumably had more severe injuries, were also more likely to be readmitted (r = .494, P less than .001). Here, “controlling for age had very little effect on the strength of the relationship between these two variables,” noted Dr. Pomeranz and coauthors.

A more elaborate statistical model incorporated several independent variables including age, type of injury, and body region involved, as well as bullet morphology. In this model, visceral injury was the strongest predictor for readmission, with an odds ratio of 6.44.

Dr. Pomeranz said that both the initial gunshot wound and subsequent gaps in care can contribute to readmissions. A patient who has a spinal cord injury may not be reimbursed adequately for supportive cushioning, or an appropriate wheelchair, and so may require admission for decubitus ulcers.

The number of admissions for osteomyelitis, which made up more than half of the subsequent admissions, initially surprised Dr. Pomeranz, until he realized that lack of mobility and sensory losses from gunshot-induced spinal cord injuries could easily lead to nonhealing lower extremity wounds, with osteomyelitis as a sequela.

Several patients were admitted for small bowel obstructions with no interval surgery since treatment for the gunshot wound. These readmissions, said Dr. Pomeranz, were assessed as related to the gunshot wound since it’s extremely rare for a patient with no history of abdominal surgery and no malignancy to have a small bowel obstruction. Exploratory laparotomies are common in the context of abdominal trauma caused by gunshot wounds, and either the gunshot itself or the laparotomy was the likely cause of adhesions.

Dr. Pomeranz acknowledged the many limitations of the study, but pointed out that some will be addressed when he and his coauthors conduct a larger study they have planned to look at readmissions from gunshot wounds at multiple hospitals in the Philadelphia area. The small sample size in the current study meant that the impact of socioeconomic status and other lifestyle and social variables and comorbidities couldn’t be adequately addressed in the statistical analysis. By casting a wider net within the greater Philadelphia area, the investigators should be able to track patients who receive care in more than one hospital system, increasing participant numbers, he said.

“Morbidity and outcomes from gun violence can only be assessed after a firm understanding of injury patterns on imaging,” noted Dr. Pomeranz. He said that interdisciplinary research investigating individual and societal short- and long-term costs of gun violence is sorely needed to inform public policy.

Dr. Pomeranz reported no outside sources of funding and reported that he had no conflicts of interest.

koakes@mdedge.com

SOURCE: Pomeranz C et al. RSNA 2019, Presentation HP226-SD-THA3.

CHICAGO – Individuals who sustain gunshot wounds have an increased risk for rehospitalization years, and even decades, after their initial injury.

Kateywhat/ThinkStock

A study of individuals at a single institution who were hospitalized and had a prior history of gunshot wound found some patterns of injury that set patients up for a greater likelihood of readmission.

In particular, patients who sustained visceral gunshot wounds were over six times more likely to be readmitted to the hospital, Corbin Pomeranz, MD, a radiology resident at Thomas Jefferson University, Philadelphia, said in an interview at the annual meeting of the Radiological Society of North America. Dr. Pomeranz led the retrospective study that begins to fill a knowledge gap about what happens over the long term to those who sustain gunshot wounds.

“There continues to be profound lack of substantial information related to gun violence, particularly in predicting long-term outcomes,” Dr. Pomeranz and coauthors wrote in the abstract accompanying the presentation.

The researchers performed a single-site retrospective analysis over 3 months in 2018, tapping into an imaging database and looking for inpatient imaging exams that were nonacute, but related to gunshot wounds. From this information, the researchers went back to the original gunshot wound injury imaging, and recorded the pattern of injury, classifying wounds as neurologic, vascular, visceral, musculoskeletal, or involving multiple systems.

The investigators were able to glean additional information including the initial admitting hospital unit, information about interval admissions or surgeries, and demographic data. Regarding the nature of the gunshot injury itself, Dr. Pomeranz and coauthors went back to the earlier imaging studies to note bullet morphology, recording whether the bullet was intact, deformed, or had splintered into shrapnel within injured tissues.

In all, 174 imaging studies involving 110 patients were examined. Men made up 92% of the study population; the average age was 49.7 years. Neurologic and visceral gunshot wounds were moderately correlated with subsequent readmission (r = .436; P less than .001). However, some of this effect was blunted when patient age was controlled for in the statistical analysis.

Patients who were initially admitted to the intensive care unit, and who presumably had more severe injuries, were also more likely to be readmitted (r = .494, P less than .001). Here, “controlling for age had very little effect on the strength of the relationship between these two variables,” noted Dr. Pomeranz and coauthors.

A more elaborate statistical model incorporated several independent variables including age, type of injury, and body region involved, as well as bullet morphology. In this model, visceral injury was the strongest predictor for readmission, with an odds ratio of 6.44.

Dr. Pomeranz said that both the initial gunshot wound and subsequent gaps in care can contribute to readmissions. A patient who has a spinal cord injury may not be reimbursed adequately for supportive cushioning, or an appropriate wheelchair, and so may require admission for decubitus ulcers.

The number of admissions for osteomyelitis, which made up more than half of the subsequent admissions, initially surprised Dr. Pomeranz, until he realized that lack of mobility and sensory losses from gunshot-induced spinal cord injuries could easily lead to nonhealing lower extremity wounds, with osteomyelitis as a sequela.

Several patients were admitted for small bowel obstructions with no interval surgery since treatment for the gunshot wound. These readmissions, said Dr. Pomeranz, were assessed as related to the gunshot wound since it’s extremely rare for a patient with no history of abdominal surgery and no malignancy to have a small bowel obstruction. Exploratory laparotomies are common in the context of abdominal trauma caused by gunshot wounds, and either the gunshot itself or the laparotomy was the likely cause of adhesions.

Dr. Pomeranz acknowledged the many limitations of the study, but pointed out that some will be addressed when he and his coauthors conduct a larger study they have planned to look at readmissions from gunshot wounds at multiple hospitals in the Philadelphia area. The small sample size in the current study meant that the impact of socioeconomic status and other lifestyle and social variables and comorbidities couldn’t be adequately addressed in the statistical analysis. By casting a wider net within the greater Philadelphia area, the investigators should be able to track patients who receive care in more than one hospital system, increasing participant numbers, he said.

“Morbidity and outcomes from gun violence can only be assessed after a firm understanding of injury patterns on imaging,” noted Dr. Pomeranz. He said that interdisciplinary research investigating individual and societal short- and long-term costs of gun violence is sorely needed to inform public policy.

Dr. Pomeranz reported no outside sources of funding and reported that he had no conflicts of interest.

koakes@mdedge.com

SOURCE: Pomeranz C et al. RSNA 2019, Presentation HP226-SD-THA3.

From the Dartmouth Institute for Health Policy & Clinical Practice, Geisel School of Medicine, Hanover, NH (Ms. Manohar and Dr. Oliver), the Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH (Ms. Perkins, Ms. Laurion, and Dr. Oliver), and the Multiple Sclerosis Specialty Care Program, Concord Hospital, Concord, NH (Dr. Oliver).

Abstract

• Background: Patient-reported outcomes (PROs), including patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs), can be used to assess perceived health status, functioning, quality of life, and experience of care. Complex chronic illnesses such as multiple sclerosis (MS) affect multiple aspects of health, and PROs can be applied in assessment and decision-making in MS care as well as in research pertaining to MS.
• Objective: To provide a general review of PROs, with a specific focus on implications for MS care.
• Methods: Evidence synthesis of available literature on PROs in MS care.
• Results: PROs (including PROMs and PREMs) have historically been utilized in research and are now being applied in clinical, improvement, and population health settings using learning health system approaches in many disease populations, including MS. Many challenges complicate the use of PROs in MS care, including reliability, validity, and interpretability of PROMs, as well as feasibility barriers due to time and financial constraints in clinical settings.
• Conclusion: PROs have the potential to better inform clinical care, empower patient-centered care, inform health care improvement efforts, and create the conditions for coproduction of health care services.

Keywords: PRO; PROM; patient-reported outcome measure; patient-reported experience measure; quality of life; patient-centered care.

Multiple sclerosis (MS) is a disabling, complex, chronic, immune-mediated disorder of the central nervous system (CNS). MS causes inflammatory and degenerative damage in the CNS, which disrupts signaling pathways.¹ It is most commonly diagnosed in young adults and affects 2.3 million people worldwide.² People with MS experience very different disease courses and a wide range of neurological symptoms, including visual, somatic, mental health, sensory, motor, and cognitive problems.^1-3 Relapsing-remitting MS, the most common form, affects 85% of those with MS and is characterized by periods of relapse (exacerbation) and remission.¹ Other forms of MS (primary progressive and secondary progressive MS) are characterized by progressive deterioration and worsening symptom severity without exacerbations. Disease-modifying therapies (DMTs) can reduce the frequency of exacerbations and disability progression, but unfortunately there is no cure for MS. Treatment is focused on increasing quality of life, minimizing disability, and maximizing wellness.

Patient-reported outcomes (PROs) describe the perceived health status, function, and/or experience of a person as obtained by direct self-report. Patient-reported outcome measures (PROMs) are validated PROs that can be used to inform clinical care,⁴ and have demonstrated effectiveness in improving patient-provider communication and decision-making.^5-7 PROMs are currently used in some MS clinical trials to determine the impact of experimental interventions,^8-10 and are also being used to inform and improve clinical care in some settings. Especially for persons with MS, they can provide individualized perspectives about health experience and outcomes.¹¹ In more advanced applications, PROMs can be used to improve face-to-face collaborations between clinicians and patients and to inform patient-centered systems of care.^12-14 PROMs can also be used to inform systems-level improvement for entire patient populations.^15,16

In this article, we review current applications of PROs and PROMs in the care of persons with MS, as well as current limitations and barriers to their use.

CASE STUDY

Marion is a 26-year-old woman who first developed MS symptoms at age 16, including increased sensitivity to heat, blurry vision, and numbness in her legs (note: this case was developed based on interviews with persons with MS, obtained with appropriate consents, and does not represent a specific patient). At that time, her clinician attributed her symptoms to a car accident she had been in a few months before. Later, at age 20, she developed abdominal paresthesia, which her clinician attributed to an episode of shingles. At age 23, she developed double vision. She was evaluated by a neurologist and was diagnosed with MS. Marion started care with an MS specialists, who worked with her towards her goals of having a family, working, and exercising. In addition to appropriate medical care, she started martial arts training and biking for exercise and transitioned to a consulting position with flexible hours and the ability to work from home. Her daughter was born a year later.

At a recent visit to her neurologist, Marion reviews her health diary, in which she has been tracking her fatigue levels throughout the day and when she has to visit the bathroom. The PRO diary also helps her remember details that she might not otherwise be able to recall at the time of her clinic visit. They review the diary entrees together to develop a shared understanding of what Marion has been experiencing and identify trends in the PRO data. They discuss symptom management and use the PRO information from the diary to help guide adjustments to her physical therapy routine and medication regimen.

Part of Marion’s “PRO package” includes the Center for Epidemiologic Studies Depression Scale (CES-D), a validated depression screening and symptom severity questionnaire that she completes every 3 months. Although she denies being depressed, she has noticed that her CES-D scores in recent months have been consistently increasing. This prompts a discussion about mental health in MS and a referral to work on depression with the MS mental health specialist. Marion and the mental health specialist use CES-D measures at baseline and during treatment to set a remission target and to track progress during treatment. Marion finds this helpful because she says it is hard for her to “wrap my hands around depression… it’s not something that there is a blood test or a MRI for.” Marion is encouraged by being able to see her CES-D scores change as her depression severity decreases, and this helps motivate her to keep engaged in treatment.

PROs and PROMs: General Applications

PROs are measures obtained directly from an individual without a priori interpretation by a clinician.^9,17 PROs capture individual perspectives on symptoms, capability, disability, and health-related quality of life.⁹ With increasing emphasis on patient-centered care,¹⁸ individual perspectives and preferences elicited using PROMs may be able to inform better quality of care and patient-centered disease treatment and management.^19-21

PROMs are standardized, validated questionnaires used to assess PROs and can be generic or condition-specific. Generic PROMs can be used in any patient population. The SF-36²² is a set of quality of life measures that assess perceived ability to complete physical tasks and routine activities, general health status, fatigue, social functioning, pain, and emotional and mental health.²³ Condition-specific PROMs can be used for particular patient populations and are helpful in identifying changes in health status for a specific disease, disability, or surgery. For example, the PDQ-39 assesses 8 dimensions of daily living, functioning, and well-being for people with Parkinson’s disease.²⁴

PROMs have been used in some MS clinical trials and research studies to determine the effectiveness of experimental treatments from the viewpoint of study participants.^9,25,26 PROs can also be utilized in clinical care to facilitate communication of needs and track health outcomes,²⁷ and can inform improvement in outcomes for health systems and populations. They can also be used to assess experience of care,²⁸ encouraging a focus on high-quality outcomes through PRO-connected reimbursement mechanisms,²⁹ and provide aggregate data to evaluate clinical practice, population health outcomes, and the effectiveness of public policies.²⁷

Patient-reported experience measures (PREMs) assess patient satisfaction and experience of health care.^30,31 CollaboRATE³² is a PREM that assesses the degree of shared decision-making occurring between patients and clinicians during clinical care. PREMs are currently used for assessing self-efficacy and in shared decision-making and health care improvement applications. PREMs have yet to be developed specifically for persons with MS.

PROMs in MS Care

Generic PROMs have shown that persons with MS are disproportionately burdened by poor quality of life.^33-35 Other generic PROMs, like the SF-36,³⁶ the Sickness Impact Profile,³⁷ and versions of the Health Utilities Index,³⁸ can be used to gather information on dysfunction and to determine quality and duration of life modified by MS-related dysfunction and disability. MS-specific PROMs are used to assess MS impairments, including pain, fatigue, cognition, sexual dysfunction, and depression.^12,39-42 PROMs have also been used in MS clinical trials, including the Multiple Sclerosis Impact Scale-29 (MSIS-29),^43,44 the Leeds MS QoL (LMSQoL),^45,46 the Functional Assessment of MS (FAMS),⁴⁷ the Hamburg Quality of Life Questionnaire in MS (HAQUAMS),⁴⁸ the MS Quality of Life-54 (MSQoL-54),⁴⁹ the MS International QoL (MUSIQoL),⁵⁰ and the Patient-Reported Indices for MS Activity Limitations Scale (PRIMUS).⁵¹

Condition-specific PROMs are more sensitive to changes in health status and functioning for persons with MS compared to generic PROMs. They are also more reliable during MS remission and relapse periods.^44,52 For example, the SF-36 has floor and ceiling effects in MS populations—a high proportion of persons with MS are scored at the maximum or minimum levels of the scale, limiting discriminant capability.²² As a result, a “combined approach” using both generic and MS-specific measures is often recommended.⁵³ Some MS PROMs (eg, MSQoL-54) include generic questions found in the SF-36 as well as additional MS-specific questions or scales.

The variety of PROMs available (see Table for a selected listing) introduces a significant challenge to using them—limited generalizability and difficulty comparing PROs across MS studies. Efforts to establish common PROMs have been undertaken to address this problem.⁵⁴ The National Institute of Neurologicical Disorders and Stroke (NINDS) sponsored the development of a neurological quality of life battery, the Neuro-QOL.⁵⁵ Neuro-QOL measures the physical, mental, and social effects of neurological conditions in adults and children with neurological disorders and has the capability to facilitate comparisons across different neurological conditions. Additionally, the Patient-Reported Outcomes Measure Information System (PROMIS) has been developed to assess physical, mental, and social effects of chronic disease. PROMIS has a hybrid design that includes generic and MS-specific measures (such as PROMIS FatigueMS).⁵⁶ PROMIS can be used to assess persons with MS as well as to compare the MS population with other populations with chronic illness.

PROMs have varying levels of reliability and validity. The Evaluating the Measure of Patient-Reported Outcomes⁵⁷ study evaluated the development process of MS PROMs,⁴³ and found that the MSIS-29 and LMSQoL had the highest overall reliability among the most common MS PROMs. However, both scored poorly on validity due to lack of patient involvement during development. This questions the overall capability of existing MS PROMs to accurately and consistently assess PROs in persons with MS.

 

 

“Feed-Forward” PROMs

Oliver and colleagues¹⁶ have described “feed-forward” PROM applications in MS care in a community hospital setting using a learning health system approach. This MS clinic uses feed-forward PROs to inform clinical care—PRO data are gathered before the clinic visit and analyzed ahead of or during the clinic visit by the clinician. Patients are asked to arrive early and complete a questionnaire comprised of PROMs measuring disability, functioning, quality of life, cognitive ability, pain, fatigue, sleep quality, anxiety, and depression. Clinicians score the PROMs and input scores into the electronic health record before the clinical encounter. During the clinic visit, PROM data is visually displayed so that the clinician and patient can discuss results and use the data to better inform decision-making. The visual data display contains longitudinal information, displaying trends in health status across multiple domains, and includes specified thresholds for clinically active symptom levels (Figure).¹⁶ Longitudinal monitoring of PROM data allows for real-time assessment of goal-related progress throughout treatment. As illustrated previously by Marion’s case study, the use of real-time feed-forward PROM data can strengthen the partnership between patient and clinician as well as improve empowerment, engagement, self-monitoring, and adherence.

PRO Dashboards

Performance dashboards are increasingly used in health care to visually display clinical and PRO data for individual patients, systems, and populations over time. Dashboards display a parsimonious group of critically important measures to give clinicians and patients a longitudinal view of PRO status. They can inform decision-making in clinical care, operations, health care improvement efforts, and population health initiatives.⁵⁸ Effective dashboards allow for user customization with meaningful measures, knowledge discovery for analysis of health problems, accessibility of health information, clear visualization, alerts for unexpected data values, and system connectivity.^59,60 Appropriate development of PRO dashboards requires meaningful patient and clinician involvement via focus groups and key informant interviews, Delphi process approaches to prioritize and finalize selection of priority measures, iterative building of the interface with design input from key informants and stakeholders (co-design), and pilot testing to assess feasibility and acceptability of use.^61-63

Other Applications of PROs/PROMs in MS

Learning Health Systems

The National Quality Forum (NQF) and the Centers for Medicaid and Medicare Services have adopted PROs for use in quality measurement.^64-66 This includes a movement towards the use of LHS, defined as a health system in which information from patients and clinicians is systematically collected and synthesized with external evidence to inform clinical care, improvement, and research.^67-70 Often a LHS is undertaken as a collaborative effort between multiple health care centers to improve quality and outcomes of care.⁷⁰ The MS Continuous Quality Improvement Collaborative (MS-CQI), the first multi-center systems-level health care improvement research collaborative for MS,⁷¹ as well as IBD Qorus and the Cystic Fibrosis Care Center Network utilize LHS approaches.^72-77

IBD Qorus is a LHS developed by the Crohn’s and Colitis Foundation that uses performance dashboards to better inform clinical care for people with inflammatory bowel disease. It also employs system-level dashboards for performance benchmarking in quality improvement initiatives and aggregate-level dashboards to assess population health status.^78,79 MS-CQI uses a LHS approach to inform the improvement of MS care across multiple centers using a comprehensive dashboard, including PROMs, for benchmarking and to monitor system and population health status. MS-CQI collects PROMs using a secure online platform that can be accessed by persons with MS and their clinicians and also includes a journaling feature for collecting qualitative information and for reference and self-monitoring.⁷¹

MS Research

PROMs are used in clinical and epidemiological research to evaluate many aspects of MS, including the FAMS, the PDSS, the Fatigue Impact Scale (FIS), and others.^80-82 For example, the PROMIS FatigueMS and the Fatigue Performance Scale have been used to assess the impact of MS-related fatigue on social participation.⁸³ Generic and MS-specific PROMs have been used to assess pain levels for people with MS,^84-87 and multiple MS-specific PROMs, like PRIMUS and MSQoL-54,⁴³ as well as the SF-36³⁹ include pain assessment scales. PROMs have also been used to assess MS-related bladder, bowel, and sexual dysfunction. Urgency, frequency, and incontinence affect up to 75% of patients with MS,⁸⁸ and many PROMs, such as the LMSQoL, MUSIQoL, and the MSQoL-54, are able to evaluate bladder control and sexual functioning.^43,89

PROMs are employed in MS clinical trials to help assess the tolerability and effectiveness of DMTs.^90,91 PROs have been used as secondary endpoints to understand the global experience of a DMT from the patient perspective.^92-94 There are 15 FDA-approved DMTs for MS, and clinical trials for 6 of these have used PROMs as an effectiveness end point.^54,91,95,96 However, most DMT clinical trials are powered for MRI, relapse rate, or disease progression primary outcomes rather than PROMs, often resulting in underpowered PROM analyses.⁹⁷ In addition, many PROMs are not appropriate for use in DMT clinical trials.^98,99

In order to bridge the gap between clinical research and practice, some industry entities are championing “patient-focused drug development” approaches. The Accelerated Cure Project for MS has launched iConquerMS, which collects PROMs from persons with MS to further PRO research in MS and follows 4700 individuals with MS worldwide.¹⁰⁰ In 2018, the American College of Physicians announced a collaboration with an industry partner to share data to inform DMT clinical trials and develop and validate PROMs specifically designed for DMT clinical trials.¹⁰¹

Population Health

Registries following large cohorts of people with MS have the potential to develop knowledge about disease progression, treatment patterns, and outcomes.¹⁰² The Swedish EIMS study has identified associations between pre-disease body mass index and MS prognosis,¹⁰² alcohol and tobacco consumption affecting MS risk,^103,104 and exposure to shift work at a young age and increased MS risk.¹⁰⁵ The North American Research Committee on MS^83,106,107 and iConquerMS registries are “PROM-driven” and have been useful in identifying reductions in disease progression in people using DMTs.^107,108 The New York State MS Consortium has identified important demographic characteristics that influence MS progression.^109,110 PROs can also be used to determine risk of MS-related mortality¹¹¹ and decline in quality of life.^112,113 Limitations of these approaches include use of different PROMs, inconsistencies in data collection processes, and different follow-up intervals used across registries.¹⁰²

Patient-Centered Care

The Institute of Medicine defines patient-centeredness as “care that is respectful and responsive to individual patient preferences, needs, and values and ensures that patient values guide all clinical decisions.”¹¹⁴ PROs are useful for identifying a patient’s individual health concerns and preferences, something that is needed when treating a highly variable chronic health condition like MS. The use of PROs can help clinicicans visualize the lived experience of persons with MS and identify personal preferences,¹¹⁵ as well as improve self-monitoring, self-management, self-efficacy, adherence, wellness, and coping ability.¹¹⁶ At the system level, PROs can inform improvement initiatives and patient-centered care design efforts.^117-120

Selecting PROMs

Initiatives from groups like the COnsensus-based Standards for the Selection of health Measurement INstruments (COSMIN)¹²¹ and the International Society for Quality of Life Research (ISOQOL)¹⁰⁸ offer guidance on selecting PROs. The NINDS has promoted common data collection between clinical studies of the brain and nervous system.¹²² General guidance from these sources recommends first considering the outcome and target population, selecting PROMs to measure the outcome through a synthesis of the available evidence, assessing validity and reliability of selected PROMs, and using standard measures that can be compared across studies or populations.^108,121 Other factors include feasibility, acceptability, and burden of use for patients, clinicians, and systems, as well as literacy, cultural, and linguistic factors.¹²³

The NQF recommends that consideration be given to individual patient needs, insurance factors, clinical setting constraints, and available resources when selecting PROMs.¹²⁴ To maximize response rate, PROMs that are sensitive, reliable, valid, and developed in a comparative demographic of patients are advised.¹²⁵ ISOQOL has released a User’s Guide and several companion guides on implementing and utilizing PROMs.^108,126,127 Finally, PRO-Performance Measures (PRO-PMs) are sometimes used to assess whether PROMs are appropriately contributing to performance improvement and accountability.¹²⁴

The Cons of PROs

Time and Software Constraints

PROs can disrupt busy clinical care environments and overextend clinical staff.¹²⁵ Online collection of PROs outside of clinical encounters can relieve PRO-related burden, but this requires finding and funding appropriate secure online networks to effectively collect PROs.¹²⁸ In 2015, only 60% of people seen for primary care visits could access or view their records online, and of those, only 57% used messaging for medical questions or concerns.¹²⁹ Ideally, online patient portal or mobile health apps could synchronize directly to electronic health records or virtual scribes to transfer patient communications into clinical documentation.¹³⁰ There has been limited success with this approach in European countries¹³¹ and with some chronic illness conditions in the United States.⁷⁴

Electronic health technologies, including mobile health (mHealth) solutions, have improved the self-monitoring and self-management capability of patients with MS via information sharing in patient networks, assistive technologies, smartphone applications, and wearable devices.^132,133 A recent study found that communication modes included secure online patient portal use (29%) and email use (21%), and among those who owned tablets or smartphones, 46% used mHealth apps.¹³⁴ Social media use has been associated with increased peer/social/emotional support and increased access to health information, as well as clinical monitoring and behavior change.^134,135 Individuals using mHealth apps are younger, have comorbidities, and have higher socioeconomic and education levels,^135,136 suggesting that inequities in mHealth access exist.

Burden on People with MS

Questionnaires can be time-consuming and cause mental distress if not appropriately facilitated.¹³⁷ Decreasing questionnaire length and providing the option for PROMs to be delivered and completed online or outside of the clinic context can reduce burden.¹³⁸ Additionally, while some people are consistent in sharing their PROs, others struggle with using computers, especially while experiencing severe symptoms, forget to complete PROMs, or simply do not have internet access due to financial or geographic constraints.¹³⁹ A group of disabled and elderly persons with MS reported barriers to internet use due to visual deficits, small website font sizes, and distracting color schemes.¹⁴⁰

Interpretability

Interpreting PROMs and displays of longitudinal PROM data can be a challenge for persons with MS and their clinicians. There is little standardization in how PROMs are scored and presented, and there is often confusion about thresholds for clinical significance and how PROM scores can be compared to other PROMs.^141,142 While guidelines exist for implementing PRO scores in clinical settings,^126,143 there are few that aid PROM interpretation. As a result, clinicians often seek research evidence for PROMs used in other similar patient populations as a benchmark,^142-144 or compare them to other patients seen in their clinical practice.

Longitudinal PRO data are usually displayed in simple line graphs.^145,146 Overall, line graphs have been found to have the highest ease of understanding by both patients and clinicians, but sometimes can be confusing.¹⁴⁷ For example, upward trending lines are usually viewed as improvement and downward trending lines as decline; however, upward trending scores on a PROM can indicate decline, such as increasing fatigue severity. Annotation of visual displays can help. Patients and clinicians find that employing thresholds and color coding is useful, and better than “stoplight” red-yellow-green shading schemes or red-circle formats to indicate data that warrant attention.¹⁴²

Error Risks

PROs are not free of risk for error, especially if they are used independently of other information sources, such as clinical interview, examination, and diagnostic testing, or if they are utilized too frequently, too infrequently, or are duplicated in practice. If a PRO instrument is employed too frequently, score changes may reflect learning effects rather than actual clinical status. Conversely, if used too infrequently, PRO information will not be timely enough to inform real-time clinical practice. Duplication of PRO assessments (eg, multiple measures of the same PRO for the same patient on the same day) or use of multiple PRO measures to assess the same aspect (eg, 2 measures used to assess fatigue) could introduce unnecessary complexity and confusion to interpretation of PRO results.

PRO measures also can be biased or modified by clinical status and/or perceptions of people with MS at the time of assessment. For example, cognitive impairment, whether at baseline state or due to a cognitive MS relapse event, could impact patients’ ability to understand and respond to PRO assessments, producing erroneous results. However, when used appropriately, PROs targeting cognitive dysfunction may be able to detect onset of cognitive events or help to measure recovery from them. Finally, PROs measure perceived (self-reported) status, which may not be an accurate depiction of actual status.

All of these potential pitfalls support the argument that PROs should be utilized to augment the clinical interview, examination, and diagnostic (objective) testing aspects of comprehensive MS care. In this way, PROs can be correlated with other information sources to deepen the shared understanding of health status between a person with MS and her clinician, increasing the potential to make better treatment decisions and care plans together in partnership.

Value and Cost

National groups such as the Patient-Centered Outcomes Research Institute (PCORI) are working with regulatory bodies, funding agencies, insurance providers, patient advocacy groups, researchers, providers, and specialty groups to investigate how PROMs can be implemented into value-based health care reforms, including value-based reimbursement.¹⁴⁸ However, practical PRO implementation requires considerable time and resources, and many methodological and operational questions must be addressed before widespread adoption and reimbursement for PROMs will be feasible.^148,149

 

 

Summary

PROs can generate valuable information about perceived health status, function, quality of life, and experience of care using self-reported sources. Validated PRO assessment tools include PROMs and PREMs. PROs are currently utilized in research settings (especially PROMs) but are also being used in clinical practice, quality improvement initiatives, and population health applications using LHS approaches. PROs have the advantages of empowering and informing persons with MS and clinicians to optimize patient-centered care, improve systems of care, and study population health outcomes. Barriers include PROM validity, reliability, comparability, specificity, interpretability, equity, time, and cost. Generic PROMs and PREMs, and some MS-specific PROMs, can be used for persons with MS. Unfortunately, no PREMs have been developed specifically for persons with MS, and this is an area for future research. With appropriate development and utilization in LHS applications, PROs can inform patient-centered clinical care, system-level improvement initiatives, and population health research, and have the potential to help facilitate coproduction of health care services.

Acknowledgments: The authors thank Ann Cabot, DO, of the MS Specialty Care Program at Concord Hospital and (especially) peer mentors from a peer outreach wellness program for people with MS (who have asked to remain anonymous) for interviews conducted with their permission to inform the case study described in this article. The case study used in this manuscript has been de-identified, with some aspects modified from actual, and the person in the case study is fictitiously named.

Corresponding author: Brant Oliver, PhD, MS, MPH, APRN-BC, Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756; brant.j.oliver@dartmouth.edu.

Financial disclosures: None.

From the Dartmouth Institute for Health Policy & Clinical Practice, Geisel School of Medicine, Hanover, NH (Ms. Manohar and Dr. Oliver), the Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH (Ms. Perkins, Ms. Laurion, and Dr. Oliver), and the Multiple Sclerosis Specialty Care Program, Concord Hospital, Concord, NH (Dr. Oliver).

Abstract

• Background: Patient-reported outcomes (PROs), including patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs), can be used to assess perceived health status, functioning, quality of life, and experience of care. Complex chronic illnesses such as multiple sclerosis (MS) affect multiple aspects of health, and PROs can be applied in assessment and decision-making in MS care as well as in research pertaining to MS.
• Objective: To provide a general review of PROs, with a specific focus on implications for MS care.
• Methods: Evidence synthesis of available literature on PROs in MS care.
• Results: PROs (including PROMs and PREMs) have historically been utilized in research and are now being applied in clinical, improvement, and population health settings using learning health system approaches in many disease populations, including MS. Many challenges complicate the use of PROs in MS care, including reliability, validity, and interpretability of PROMs, as well as feasibility barriers due to time and financial constraints in clinical settings.
• Conclusion: PROs have the potential to better inform clinical care, empower patient-centered care, inform health care improvement efforts, and create the conditions for coproduction of health care services.

Keywords: PRO; PROM; patient-reported outcome measure; patient-reported experience measure; quality of life; patient-centered care.

Multiple sclerosis (MS) is a disabling, complex, chronic, immune-mediated disorder of the central nervous system (CNS). MS causes inflammatory and degenerative damage in the CNS, which disrupts signaling pathways.¹ It is most commonly diagnosed in young adults and affects 2.3 million people worldwide.² People with MS experience very different disease courses and a wide range of neurological symptoms, including visual, somatic, mental health, sensory, motor, and cognitive problems.^1-3 Relapsing-remitting MS, the most common form, affects 85% of those with MS and is characterized by periods of relapse (exacerbation) and remission.¹ Other forms of MS (primary progressive and secondary progressive MS) are characterized by progressive deterioration and worsening symptom severity without exacerbations. Disease-modifying therapies (DMTs) can reduce the frequency of exacerbations and disability progression, but unfortunately there is no cure for MS. Treatment is focused on increasing quality of life, minimizing disability, and maximizing wellness.

Patient-reported outcomes (PROs) describe the perceived health status, function, and/or experience of a person as obtained by direct self-report. Patient-reported outcome measures (PROMs) are validated PROs that can be used to inform clinical care,⁴ and have demonstrated effectiveness in improving patient-provider communication and decision-making.^5-7 PROMs are currently used in some MS clinical trials to determine the impact of experimental interventions,^8-10 and are also being used to inform and improve clinical care in some settings. Especially for persons with MS, they can provide individualized perspectives about health experience and outcomes.¹¹ In more advanced applications, PROMs can be used to improve face-to-face collaborations between clinicians and patients and to inform patient-centered systems of care.^12-14 PROMs can also be used to inform systems-level improvement for entire patient populations.^15,16

In this article, we review current applications of PROs and PROMs in the care of persons with MS, as well as current limitations and barriers to their use.

CASE STUDY

Marion is a 26-year-old woman who first developed MS symptoms at age 16, including increased sensitivity to heat, blurry vision, and numbness in her legs (note: this case was developed based on interviews with persons with MS, obtained with appropriate consents, and does not represent a specific patient). At that time, her clinician attributed her symptoms to a car accident she had been in a few months before. Later, at age 20, she developed abdominal paresthesia, which her clinician attributed to an episode of shingles. At age 23, she developed double vision. She was evaluated by a neurologist and was diagnosed with MS. Marion started care with an MS specialists, who worked with her towards her goals of having a family, working, and exercising. In addition to appropriate medical care, she started martial arts training and biking for exercise and transitioned to a consulting position with flexible hours and the ability to work from home. Her daughter was born a year later.

At a recent visit to her neurologist, Marion reviews her health diary, in which she has been tracking her fatigue levels throughout the day and when she has to visit the bathroom. The PRO diary also helps her remember details that she might not otherwise be able to recall at the time of her clinic visit. They review the diary entrees together to develop a shared understanding of what Marion has been experiencing and identify trends in the PRO data. They discuss symptom management and use the PRO information from the diary to help guide adjustments to her physical therapy routine and medication regimen.

Part of Marion’s “PRO package” includes the Center for Epidemiologic Studies Depression Scale (CES-D), a validated depression screening and symptom severity questionnaire that she completes every 3 months. Although she denies being depressed, she has noticed that her CES-D scores in recent months have been consistently increasing. This prompts a discussion about mental health in MS and a referral to work on depression with the MS mental health specialist. Marion and the mental health specialist use CES-D measures at baseline and during treatment to set a remission target and to track progress during treatment. Marion finds this helpful because she says it is hard for her to “wrap my hands around depression… it’s not something that there is a blood test or a MRI for.” Marion is encouraged by being able to see her CES-D scores change as her depression severity decreases, and this helps motivate her to keep engaged in treatment.

PROs and PROMs: General Applications

PROs are measures obtained directly from an individual without a priori interpretation by a clinician.^9,17 PROs capture individual perspectives on symptoms, capability, disability, and health-related quality of life.⁹ With increasing emphasis on patient-centered care,¹⁸ individual perspectives and preferences elicited using PROMs may be able to inform better quality of care and patient-centered disease treatment and management.^19-21

PROMs are standardized, validated questionnaires used to assess PROs and can be generic or condition-specific. Generic PROMs can be used in any patient population. The SF-36²² is a set of quality of life measures that assess perceived ability to complete physical tasks and routine activities, general health status, fatigue, social functioning, pain, and emotional and mental health.²³ Condition-specific PROMs can be used for particular patient populations and are helpful in identifying changes in health status for a specific disease, disability, or surgery. For example, the PDQ-39 assesses 8 dimensions of daily living, functioning, and well-being for people with Parkinson’s disease.²⁴

PROMs have been used in some MS clinical trials and research studies to determine the effectiveness of experimental treatments from the viewpoint of study participants.^9,25,26 PROs can also be utilized in clinical care to facilitate communication of needs and track health outcomes,²⁷ and can inform improvement in outcomes for health systems and populations. They can also be used to assess experience of care,²⁸ encouraging a focus on high-quality outcomes through PRO-connected reimbursement mechanisms,²⁹ and provide aggregate data to evaluate clinical practice, population health outcomes, and the effectiveness of public policies.²⁷

Patient-reported experience measures (PREMs) assess patient satisfaction and experience of health care.^30,31 CollaboRATE³² is a PREM that assesses the degree of shared decision-making occurring between patients and clinicians during clinical care. PREMs are currently used for assessing self-efficacy and in shared decision-making and health care improvement applications. PREMs have yet to be developed specifically for persons with MS.

PROMs in MS Care

Generic PROMs have shown that persons with MS are disproportionately burdened by poor quality of life.^33-35 Other generic PROMs, like the SF-36,³⁶ the Sickness Impact Profile,³⁷ and versions of the Health Utilities Index,³⁸ can be used to gather information on dysfunction and to determine quality and duration of life modified by MS-related dysfunction and disability. MS-specific PROMs are used to assess MS impairments, including pain, fatigue, cognition, sexual dysfunction, and depression.^12,39-42 PROMs have also been used in MS clinical trials, including the Multiple Sclerosis Impact Scale-29 (MSIS-29),^43,44 the Leeds MS QoL (LMSQoL),^45,46 the Functional Assessment of MS (FAMS),⁴⁷ the Hamburg Quality of Life Questionnaire in MS (HAQUAMS),⁴⁸ the MS Quality of Life-54 (MSQoL-54),⁴⁹ the MS International QoL (MUSIQoL),⁵⁰ and the Patient-Reported Indices for MS Activity Limitations Scale (PRIMUS).⁵¹

Condition-specific PROMs are more sensitive to changes in health status and functioning for persons with MS compared to generic PROMs. They are also more reliable during MS remission and relapse periods.^44,52 For example, the SF-36 has floor and ceiling effects in MS populations—a high proportion of persons with MS are scored at the maximum or minimum levels of the scale, limiting discriminant capability.²² As a result, a “combined approach” using both generic and MS-specific measures is often recommended.⁵³ Some MS PROMs (eg, MSQoL-54) include generic questions found in the SF-36 as well as additional MS-specific questions or scales.

The variety of PROMs available (see Table for a selected listing) introduces a significant challenge to using them—limited generalizability and difficulty comparing PROs across MS studies. Efforts to establish common PROMs have been undertaken to address this problem.⁵⁴ The National Institute of Neurologicical Disorders and Stroke (NINDS) sponsored the development of a neurological quality of life battery, the Neuro-QOL.⁵⁵ Neuro-QOL measures the physical, mental, and social effects of neurological conditions in adults and children with neurological disorders and has the capability to facilitate comparisons across different neurological conditions. Additionally, the Patient-Reported Outcomes Measure Information System (PROMIS) has been developed to assess physical, mental, and social effects of chronic disease. PROMIS has a hybrid design that includes generic and MS-specific measures (such as PROMIS FatigueMS).⁵⁶ PROMIS can be used to assess persons with MS as well as to compare the MS population with other populations with chronic illness.

PROMs have varying levels of reliability and validity. The Evaluating the Measure of Patient-Reported Outcomes⁵⁷ study evaluated the development process of MS PROMs,⁴³ and found that the MSIS-29 and LMSQoL had the highest overall reliability among the most common MS PROMs. However, both scored poorly on validity due to lack of patient involvement during development. This questions the overall capability of existing MS PROMs to accurately and consistently assess PROs in persons with MS.

 

 

“Feed-Forward” PROMs

Oliver and colleagues¹⁶ have described “feed-forward” PROM applications in MS care in a community hospital setting using a learning health system approach. This MS clinic uses feed-forward PROs to inform clinical care—PRO data are gathered before the clinic visit and analyzed ahead of or during the clinic visit by the clinician. Patients are asked to arrive early and complete a questionnaire comprised of PROMs measuring disability, functioning, quality of life, cognitive ability, pain, fatigue, sleep quality, anxiety, and depression. Clinicians score the PROMs and input scores into the electronic health record before the clinical encounter. During the clinic visit, PROM data is visually displayed so that the clinician and patient can discuss results and use the data to better inform decision-making. The visual data display contains longitudinal information, displaying trends in health status across multiple domains, and includes specified thresholds for clinically active symptom levels (Figure).¹⁶ Longitudinal monitoring of PROM data allows for real-time assessment of goal-related progress throughout treatment. As illustrated previously by Marion’s case study, the use of real-time feed-forward PROM data can strengthen the partnership between patient and clinician as well as improve empowerment, engagement, self-monitoring, and adherence.

PRO Dashboards

Performance dashboards are increasingly used in health care to visually display clinical and PRO data for individual patients, systems, and populations over time. Dashboards display a parsimonious group of critically important measures to give clinicians and patients a longitudinal view of PRO status. They can inform decision-making in clinical care, operations, health care improvement efforts, and population health initiatives.⁵⁸ Effective dashboards allow for user customization with meaningful measures, knowledge discovery for analysis of health problems, accessibility of health information, clear visualization, alerts for unexpected data values, and system connectivity.^59,60 Appropriate development of PRO dashboards requires meaningful patient and clinician involvement via focus groups and key informant interviews, Delphi process approaches to prioritize and finalize selection of priority measures, iterative building of the interface with design input from key informants and stakeholders (co-design), and pilot testing to assess feasibility and acceptability of use.^61-63

Other Applications of PROs/PROMs in MS

Learning Health Systems

The National Quality Forum (NQF) and the Centers for Medicaid and Medicare Services have adopted PROs for use in quality measurement.^64-66 This includes a movement towards the use of LHS, defined as a health system in which information from patients and clinicians is systematically collected and synthesized with external evidence to inform clinical care, improvement, and research.^67-70 Often a LHS is undertaken as a collaborative effort between multiple health care centers to improve quality and outcomes of care.⁷⁰ The MS Continuous Quality Improvement Collaborative (MS-CQI), the first multi-center systems-level health care improvement research collaborative for MS,⁷¹ as well as IBD Qorus and the Cystic Fibrosis Care Center Network utilize LHS approaches.^72-77

IBD Qorus is a LHS developed by the Crohn’s and Colitis Foundation that uses performance dashboards to better inform clinical care for people with inflammatory bowel disease. It also employs system-level dashboards for performance benchmarking in quality improvement initiatives and aggregate-level dashboards to assess population health status.^78,79 MS-CQI uses a LHS approach to inform the improvement of MS care across multiple centers using a comprehensive dashboard, including PROMs, for benchmarking and to monitor system and population health status. MS-CQI collects PROMs using a secure online platform that can be accessed by persons with MS and their clinicians and also includes a journaling feature for collecting qualitative information and for reference and self-monitoring.⁷¹

MS Research

PROMs are used in clinical and epidemiological research to evaluate many aspects of MS, including the FAMS, the PDSS, the Fatigue Impact Scale (FIS), and others.^80-82 For example, the PROMIS FatigueMS and the Fatigue Performance Scale have been used to assess the impact of MS-related fatigue on social participation.⁸³ Generic and MS-specific PROMs have been used to assess pain levels for people with MS,^84-87 and multiple MS-specific PROMs, like PRIMUS and MSQoL-54,⁴³ as well as the SF-36³⁹ include pain assessment scales. PROMs have also been used to assess MS-related bladder, bowel, and sexual dysfunction. Urgency, frequency, and incontinence affect up to 75% of patients with MS,⁸⁸ and many PROMs, such as the LMSQoL, MUSIQoL, and the MSQoL-54, are able to evaluate bladder control and sexual functioning.^43,89

PROMs are employed in MS clinical trials to help assess the tolerability and effectiveness of DMTs.^90,91 PROs have been used as secondary endpoints to understand the global experience of a DMT from the patient perspective.^92-94 There are 15 FDA-approved DMTs for MS, and clinical trials for 6 of these have used PROMs as an effectiveness end point.^54,91,95,96 However, most DMT clinical trials are powered for MRI, relapse rate, or disease progression primary outcomes rather than PROMs, often resulting in underpowered PROM analyses.⁹⁷ In addition, many PROMs are not appropriate for use in DMT clinical trials.^98,99

In order to bridge the gap between clinical research and practice, some industry entities are championing “patient-focused drug development” approaches. The Accelerated Cure Project for MS has launched iConquerMS, which collects PROMs from persons with MS to further PRO research in MS and follows 4700 individuals with MS worldwide.¹⁰⁰ In 2018, the American College of Physicians announced a collaboration with an industry partner to share data to inform DMT clinical trials and develop and validate PROMs specifically designed for DMT clinical trials.¹⁰¹

Population Health

Registries following large cohorts of people with MS have the potential to develop knowledge about disease progression, treatment patterns, and outcomes.¹⁰² The Swedish EIMS study has identified associations between pre-disease body mass index and MS prognosis,¹⁰² alcohol and tobacco consumption affecting MS risk,^103,104 and exposure to shift work at a young age and increased MS risk.¹⁰⁵ The North American Research Committee on MS^83,106,107 and iConquerMS registries are “PROM-driven” and have been useful in identifying reductions in disease progression in people using DMTs.^107,108 The New York State MS Consortium has identified important demographic characteristics that influence MS progression.^109,110 PROs can also be used to determine risk of MS-related mortality¹¹¹ and decline in quality of life.^112,113 Limitations of these approaches include use of different PROMs, inconsistencies in data collection processes, and different follow-up intervals used across registries.¹⁰²

Patient-Centered Care

The Institute of Medicine defines patient-centeredness as “care that is respectful and responsive to individual patient preferences, needs, and values and ensures that patient values guide all clinical decisions.”¹¹⁴ PROs are useful for identifying a patient’s individual health concerns and preferences, something that is needed when treating a highly variable chronic health condition like MS. The use of PROs can help clinicicans visualize the lived experience of persons with MS and identify personal preferences,¹¹⁵ as well as improve self-monitoring, self-management, self-efficacy, adherence, wellness, and coping ability.¹¹⁶ At the system level, PROs can inform improvement initiatives and patient-centered care design efforts.^117-120

Selecting PROMs

Initiatives from groups like the COnsensus-based Standards for the Selection of health Measurement INstruments (COSMIN)¹²¹ and the International Society for Quality of Life Research (ISOQOL)¹⁰⁸ offer guidance on selecting PROs. The NINDS has promoted common data collection between clinical studies of the brain and nervous system.¹²² General guidance from these sources recommends first considering the outcome and target population, selecting PROMs to measure the outcome through a synthesis of the available evidence, assessing validity and reliability of selected PROMs, and using standard measures that can be compared across studies or populations.^108,121 Other factors include feasibility, acceptability, and burden of use for patients, clinicians, and systems, as well as literacy, cultural, and linguistic factors.¹²³

The NQF recommends that consideration be given to individual patient needs, insurance factors, clinical setting constraints, and available resources when selecting PROMs.¹²⁴ To maximize response rate, PROMs that are sensitive, reliable, valid, and developed in a comparative demographic of patients are advised.¹²⁵ ISOQOL has released a User’s Guide and several companion guides on implementing and utilizing PROMs.^108,126,127 Finally, PRO-Performance Measures (PRO-PMs) are sometimes used to assess whether PROMs are appropriately contributing to performance improvement and accountability.¹²⁴

The Cons of PROs

Time and Software Constraints

PROs can disrupt busy clinical care environments and overextend clinical staff.¹²⁵ Online collection of PROs outside of clinical encounters can relieve PRO-related burden, but this requires finding and funding appropriate secure online networks to effectively collect PROs.¹²⁸ In 2015, only 60% of people seen for primary care visits could access or view their records online, and of those, only 57% used messaging for medical questions or concerns.¹²⁹ Ideally, online patient portal or mobile health apps could synchronize directly to electronic health records or virtual scribes to transfer patient communications into clinical documentation.¹³⁰ There has been limited success with this approach in European countries¹³¹ and with some chronic illness conditions in the United States.⁷⁴

Electronic health technologies, including mobile health (mHealth) solutions, have improved the self-monitoring and self-management capability of patients with MS via information sharing in patient networks, assistive technologies, smartphone applications, and wearable devices.^132,133 A recent study found that communication modes included secure online patient portal use (29%) and email use (21%), and among those who owned tablets or smartphones, 46% used mHealth apps.¹³⁴ Social media use has been associated with increased peer/social/emotional support and increased access to health information, as well as clinical monitoring and behavior change.^134,135 Individuals using mHealth apps are younger, have comorbidities, and have higher socioeconomic and education levels,^135,136 suggesting that inequities in mHealth access exist.

Burden on People with MS

Questionnaires can be time-consuming and cause mental distress if not appropriately facilitated.¹³⁷ Decreasing questionnaire length and providing the option for PROMs to be delivered and completed online or outside of the clinic context can reduce burden.¹³⁸ Additionally, while some people are consistent in sharing their PROs, others struggle with using computers, especially while experiencing severe symptoms, forget to complete PROMs, or simply do not have internet access due to financial or geographic constraints.¹³⁹ A group of disabled and elderly persons with MS reported barriers to internet use due to visual deficits, small website font sizes, and distracting color schemes.¹⁴⁰

Interpretability

Interpreting PROMs and displays of longitudinal PROM data can be a challenge for persons with MS and their clinicians. There is little standardization in how PROMs are scored and presented, and there is often confusion about thresholds for clinical significance and how PROM scores can be compared to other PROMs.^141,142 While guidelines exist for implementing PRO scores in clinical settings,^126,143 there are few that aid PROM interpretation. As a result, clinicians often seek research evidence for PROMs used in other similar patient populations as a benchmark,^142-144 or compare them to other patients seen in their clinical practice.

Longitudinal PRO data are usually displayed in simple line graphs.^145,146 Overall, line graphs have been found to have the highest ease of understanding by both patients and clinicians, but sometimes can be confusing.¹⁴⁷ For example, upward trending lines are usually viewed as improvement and downward trending lines as decline; however, upward trending scores on a PROM can indicate decline, such as increasing fatigue severity. Annotation of visual displays can help. Patients and clinicians find that employing thresholds and color coding is useful, and better than “stoplight” red-yellow-green shading schemes or red-circle formats to indicate data that warrant attention.¹⁴²

Error Risks

PROs are not free of risk for error, especially if they are used independently of other information sources, such as clinical interview, examination, and diagnostic testing, or if they are utilized too frequently, too infrequently, or are duplicated in practice. If a PRO instrument is employed too frequently, score changes may reflect learning effects rather than actual clinical status. Conversely, if used too infrequently, PRO information will not be timely enough to inform real-time clinical practice. Duplication of PRO assessments (eg, multiple measures of the same PRO for the same patient on the same day) or use of multiple PRO measures to assess the same aspect (eg, 2 measures used to assess fatigue) could introduce unnecessary complexity and confusion to interpretation of PRO results.

PRO measures also can be biased or modified by clinical status and/or perceptions of people with MS at the time of assessment. For example, cognitive impairment, whether at baseline state or due to a cognitive MS relapse event, could impact patients’ ability to understand and respond to PRO assessments, producing erroneous results. However, when used appropriately, PROs targeting cognitive dysfunction may be able to detect onset of cognitive events or help to measure recovery from them. Finally, PROs measure perceived (self-reported) status, which may not be an accurate depiction of actual status.

All of these potential pitfalls support the argument that PROs should be utilized to augment the clinical interview, examination, and diagnostic (objective) testing aspects of comprehensive MS care. In this way, PROs can be correlated with other information sources to deepen the shared understanding of health status between a person with MS and her clinician, increasing the potential to make better treatment decisions and care plans together in partnership.

Value and Cost

National groups such as the Patient-Centered Outcomes Research Institute (PCORI) are working with regulatory bodies, funding agencies, insurance providers, patient advocacy groups, researchers, providers, and specialty groups to investigate how PROMs can be implemented into value-based health care reforms, including value-based reimbursement.¹⁴⁸ However, practical PRO implementation requires considerable time and resources, and many methodological and operational questions must be addressed before widespread adoption and reimbursement for PROMs will be feasible.^148,149

 

 

Summary

PROs can generate valuable information about perceived health status, function, quality of life, and experience of care using self-reported sources. Validated PRO assessment tools include PROMs and PREMs. PROs are currently utilized in research settings (especially PROMs) but are also being used in clinical practice, quality improvement initiatives, and population health applications using LHS approaches. PROs have the advantages of empowering and informing persons with MS and clinicians to optimize patient-centered care, improve systems of care, and study population health outcomes. Barriers include PROM validity, reliability, comparability, specificity, interpretability, equity, time, and cost. Generic PROMs and PREMs, and some MS-specific PROMs, can be used for persons with MS. Unfortunately, no PREMs have been developed specifically for persons with MS, and this is an area for future research. With appropriate development and utilization in LHS applications, PROs can inform patient-centered clinical care, system-level improvement initiatives, and population health research, and have the potential to help facilitate coproduction of health care services.

Acknowledgments: The authors thank Ann Cabot, DO, of the MS Specialty Care Program at Concord Hospital and (especially) peer mentors from a peer outreach wellness program for people with MS (who have asked to remain anonymous) for interviews conducted with their permission to inform the case study described in this article. The case study used in this manuscript has been de-identified, with some aspects modified from actual, and the person in the case study is fictitiously named.

Corresponding author: Brant Oliver, PhD, MS, MPH, APRN-BC, Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756; brant.j.oliver@dartmouth.edu.

Financial disclosures: None.

From the Dartmouth Institute for Health Policy & Clinical Practice, Geisel School of Medicine, Hanover, NH (Ms. Manohar and Dr. Oliver), the Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH (Ms. Perkins, Ms. Laurion, and Dr. Oliver), and the Multiple Sclerosis Specialty Care Program, Concord Hospital, Concord, NH (Dr. Oliver).

Abstract

• Background: Patient-reported outcomes (PROs), including patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs), can be used to assess perceived health status, functioning, quality of life, and experience of care. Complex chronic illnesses such as multiple sclerosis (MS) affect multiple aspects of health, and PROs can be applied in assessment and decision-making in MS care as well as in research pertaining to MS.
• Objective: To provide a general review of PROs, with a specific focus on implications for MS care.
• Methods: Evidence synthesis of available literature on PROs in MS care.
• Results: PROs (including PROMs and PREMs) have historically been utilized in research and are now being applied in clinical, improvement, and population health settings using learning health system approaches in many disease populations, including MS. Many challenges complicate the use of PROs in MS care, including reliability, validity, and interpretability of PROMs, as well as feasibility barriers due to time and financial constraints in clinical settings.
• Conclusion: PROs have the potential to better inform clinical care, empower patient-centered care, inform health care improvement efforts, and create the conditions for coproduction of health care services.

Keywords: PRO; PROM; patient-reported outcome measure; patient-reported experience measure; quality of life; patient-centered care.

Multiple sclerosis (MS) is a disabling, complex, chronic, immune-mediated disorder of the central nervous system (CNS). MS causes inflammatory and degenerative damage in the CNS, which disrupts signaling pathways.¹ It is most commonly diagnosed in young adults and affects 2.3 million people worldwide.² People with MS experience very different disease courses and a wide range of neurological symptoms, including visual, somatic, mental health, sensory, motor, and cognitive problems.^1-3 Relapsing-remitting MS, the most common form, affects 85% of those with MS and is characterized by periods of relapse (exacerbation) and remission.¹ Other forms of MS (primary progressive and secondary progressive MS) are characterized by progressive deterioration and worsening symptom severity without exacerbations. Disease-modifying therapies (DMTs) can reduce the frequency of exacerbations and disability progression, but unfortunately there is no cure for MS. Treatment is focused on increasing quality of life, minimizing disability, and maximizing wellness.

Patient-reported outcomes (PROs) describe the perceived health status, function, and/or experience of a person as obtained by direct self-report. Patient-reported outcome measures (PROMs) are validated PROs that can be used to inform clinical care,⁴ and have demonstrated effectiveness in improving patient-provider communication and decision-making.^5-7 PROMs are currently used in some MS clinical trials to determine the impact of experimental interventions,^8-10 and are also being used to inform and improve clinical care in some settings. Especially for persons with MS, they can provide individualized perspectives about health experience and outcomes.¹¹ In more advanced applications, PROMs can be used to improve face-to-face collaborations between clinicians and patients and to inform patient-centered systems of care.^12-14 PROMs can also be used to inform systems-level improvement for entire patient populations.^15,16

In this article, we review current applications of PROs and PROMs in the care of persons with MS, as well as current limitations and barriers to their use.

CASE STUDY

Marion is a 26-year-old woman who first developed MS symptoms at age 16, including increased sensitivity to heat, blurry vision, and numbness in her legs (note: this case was developed based on interviews with persons with MS, obtained with appropriate consents, and does not represent a specific patient). At that time, her clinician attributed her symptoms to a car accident she had been in a few months before. Later, at age 20, she developed abdominal paresthesia, which her clinician attributed to an episode of shingles. At age 23, she developed double vision. She was evaluated by a neurologist and was diagnosed with MS. Marion started care with an MS specialists, who worked with her towards her goals of having a family, working, and exercising. In addition to appropriate medical care, she started martial arts training and biking for exercise and transitioned to a consulting position with flexible hours and the ability to work from home. Her daughter was born a year later.

At a recent visit to her neurologist, Marion reviews her health diary, in which she has been tracking her fatigue levels throughout the day and when she has to visit the bathroom. The PRO diary also helps her remember details that she might not otherwise be able to recall at the time of her clinic visit. They review the diary entrees together to develop a shared understanding of what Marion has been experiencing and identify trends in the PRO data. They discuss symptom management and use the PRO information from the diary to help guide adjustments to her physical therapy routine and medication regimen.

Part of Marion’s “PRO package” includes the Center for Epidemiologic Studies Depression Scale (CES-D), a validated depression screening and symptom severity questionnaire that she completes every 3 months. Although she denies being depressed, she has noticed that her CES-D scores in recent months have been consistently increasing. This prompts a discussion about mental health in MS and a referral to work on depression with the MS mental health specialist. Marion and the mental health specialist use CES-D measures at baseline and during treatment to set a remission target and to track progress during treatment. Marion finds this helpful because she says it is hard for her to “wrap my hands around depression… it’s not something that there is a blood test or a MRI for.” Marion is encouraged by being able to see her CES-D scores change as her depression severity decreases, and this helps motivate her to keep engaged in treatment.

PROs and PROMs: General Applications

PROs are measures obtained directly from an individual without a priori interpretation by a clinician.^9,17 PROs capture individual perspectives on symptoms, capability, disability, and health-related quality of life.⁹ With increasing emphasis on patient-centered care,¹⁸ individual perspectives and preferences elicited using PROMs may be able to inform better quality of care and patient-centered disease treatment and management.^19-21

PROMs are standardized, validated questionnaires used to assess PROs and can be generic or condition-specific. Generic PROMs can be used in any patient population. The SF-36²² is a set of quality of life measures that assess perceived ability to complete physical tasks and routine activities, general health status, fatigue, social functioning, pain, and emotional and mental health.²³ Condition-specific PROMs can be used for particular patient populations and are helpful in identifying changes in health status for a specific disease, disability, or surgery. For example, the PDQ-39 assesses 8 dimensions of daily living, functioning, and well-being for people with Parkinson’s disease.²⁴

PROMs have been used in some MS clinical trials and research studies to determine the effectiveness of experimental treatments from the viewpoint of study participants.^9,25,26 PROs can also be utilized in clinical care to facilitate communication of needs and track health outcomes,²⁷ and can inform improvement in outcomes for health systems and populations. They can also be used to assess experience of care,²⁸ encouraging a focus on high-quality outcomes through PRO-connected reimbursement mechanisms,²⁹ and provide aggregate data to evaluate clinical practice, population health outcomes, and the effectiveness of public policies.²⁷

Patient-reported experience measures (PREMs) assess patient satisfaction and experience of health care.^30,31 CollaboRATE³² is a PREM that assesses the degree of shared decision-making occurring between patients and clinicians during clinical care. PREMs are currently used for assessing self-efficacy and in shared decision-making and health care improvement applications. PREMs have yet to be developed specifically for persons with MS.

PROMs in MS Care

Generic PROMs have shown that persons with MS are disproportionately burdened by poor quality of life.^33-35 Other generic PROMs, like the SF-36,³⁶ the Sickness Impact Profile,³⁷ and versions of the Health Utilities Index,³⁸ can be used to gather information on dysfunction and to determine quality and duration of life modified by MS-related dysfunction and disability. MS-specific PROMs are used to assess MS impairments, including pain, fatigue, cognition, sexual dysfunction, and depression.^12,39-42 PROMs have also been used in MS clinical trials, including the Multiple Sclerosis Impact Scale-29 (MSIS-29),^43,44 the Leeds MS QoL (LMSQoL),^45,46 the Functional Assessment of MS (FAMS),⁴⁷ the Hamburg Quality of Life Questionnaire in MS (HAQUAMS),⁴⁸ the MS Quality of Life-54 (MSQoL-54),⁴⁹ the MS International QoL (MUSIQoL),⁵⁰ and the Patient-Reported Indices for MS Activity Limitations Scale (PRIMUS).⁵¹

Condition-specific PROMs are more sensitive to changes in health status and functioning for persons with MS compared to generic PROMs. They are also more reliable during MS remission and relapse periods.^44,52 For example, the SF-36 has floor and ceiling effects in MS populations—a high proportion of persons with MS are scored at the maximum or minimum levels of the scale, limiting discriminant capability.²² As a result, a “combined approach” using both generic and MS-specific measures is often recommended.⁵³ Some MS PROMs (eg, MSQoL-54) include generic questions found in the SF-36 as well as additional MS-specific questions or scales.

The variety of PROMs available (see Table for a selected listing) introduces a significant challenge to using them—limited generalizability and difficulty comparing PROs across MS studies. Efforts to establish common PROMs have been undertaken to address this problem.⁵⁴ The National Institute of Neurologicical Disorders and Stroke (NINDS) sponsored the development of a neurological quality of life battery, the Neuro-QOL.⁵⁵ Neuro-QOL measures the physical, mental, and social effects of neurological conditions in adults and children with neurological disorders and has the capability to facilitate comparisons across different neurological conditions. Additionally, the Patient-Reported Outcomes Measure Information System (PROMIS) has been developed to assess physical, mental, and social effects of chronic disease. PROMIS has a hybrid design that includes generic and MS-specific measures (such as PROMIS FatigueMS).⁵⁶ PROMIS can be used to assess persons with MS as well as to compare the MS population with other populations with chronic illness.

PROMs have varying levels of reliability and validity. The Evaluating the Measure of Patient-Reported Outcomes⁵⁷ study evaluated the development process of MS PROMs,⁴³ and found that the MSIS-29 and LMSQoL had the highest overall reliability among the most common MS PROMs. However, both scored poorly on validity due to lack of patient involvement during development. This questions the overall capability of existing MS PROMs to accurately and consistently assess PROs in persons with MS.

 

 

“Feed-Forward” PROMs

Oliver and colleagues¹⁶ have described “feed-forward” PROM applications in MS care in a community hospital setting using a learning health system approach. This MS clinic uses feed-forward PROs to inform clinical care—PRO data are gathered before the clinic visit and analyzed ahead of or during the clinic visit by the clinician. Patients are asked to arrive early and complete a questionnaire comprised of PROMs measuring disability, functioning, quality of life, cognitive ability, pain, fatigue, sleep quality, anxiety, and depression. Clinicians score the PROMs and input scores into the electronic health record before the clinical encounter. During the clinic visit, PROM data is visually displayed so that the clinician and patient can discuss results and use the data to better inform decision-making. The visual data display contains longitudinal information, displaying trends in health status across multiple domains, and includes specified thresholds for clinically active symptom levels (Figure).¹⁶ Longitudinal monitoring of PROM data allows for real-time assessment of goal-related progress throughout treatment. As illustrated previously by Marion’s case study, the use of real-time feed-forward PROM data can strengthen the partnership between patient and clinician as well as improve empowerment, engagement, self-monitoring, and adherence.

PRO Dashboards

Performance dashboards are increasingly used in health care to visually display clinical and PRO data for individual patients, systems, and populations over time. Dashboards display a parsimonious group of critically important measures to give clinicians and patients a longitudinal view of PRO status. They can inform decision-making in clinical care, operations, health care improvement efforts, and population health initiatives.⁵⁸ Effective dashboards allow for user customization with meaningful measures, knowledge discovery for analysis of health problems, accessibility of health information, clear visualization, alerts for unexpected data values, and system connectivity.^59,60 Appropriate development of PRO dashboards requires meaningful patient and clinician involvement via focus groups and key informant interviews, Delphi process approaches to prioritize and finalize selection of priority measures, iterative building of the interface with design input from key informants and stakeholders (co-design), and pilot testing to assess feasibility and acceptability of use.^61-63

Other Applications of PROs/PROMs in MS

Learning Health Systems

The National Quality Forum (NQF) and the Centers for Medicaid and Medicare Services have adopted PROs for use in quality measurement.^64-66 This includes a movement towards the use of LHS, defined as a health system in which information from patients and clinicians is systematically collected and synthesized with external evidence to inform clinical care, improvement, and research.^67-70 Often a LHS is undertaken as a collaborative effort between multiple health care centers to improve quality and outcomes of care.⁷⁰ The MS Continuous Quality Improvement Collaborative (MS-CQI), the first multi-center systems-level health care improvement research collaborative for MS,⁷¹ as well as IBD Qorus and the Cystic Fibrosis Care Center Network utilize LHS approaches.^72-77

IBD Qorus is a LHS developed by the Crohn’s and Colitis Foundation that uses performance dashboards to better inform clinical care for people with inflammatory bowel disease. It also employs system-level dashboards for performance benchmarking in quality improvement initiatives and aggregate-level dashboards to assess population health status.^78,79 MS-CQI uses a LHS approach to inform the improvement of MS care across multiple centers using a comprehensive dashboard, including PROMs, for benchmarking and to monitor system and population health status. MS-CQI collects PROMs using a secure online platform that can be accessed by persons with MS and their clinicians and also includes a journaling feature for collecting qualitative information and for reference and self-monitoring.⁷¹

MS Research

PROMs are used in clinical and epidemiological research to evaluate many aspects of MS, including the FAMS, the PDSS, the Fatigue Impact Scale (FIS), and others.^80-82 For example, the PROMIS FatigueMS and the Fatigue Performance Scale have been used to assess the impact of MS-related fatigue on social participation.⁸³ Generic and MS-specific PROMs have been used to assess pain levels for people with MS,^84-87 and multiple MS-specific PROMs, like PRIMUS and MSQoL-54,⁴³ as well as the SF-36³⁹ include pain assessment scales. PROMs have also been used to assess MS-related bladder, bowel, and sexual dysfunction. Urgency, frequency, and incontinence affect up to 75% of patients with MS,⁸⁸ and many PROMs, such as the LMSQoL, MUSIQoL, and the MSQoL-54, are able to evaluate bladder control and sexual functioning.^43,89

PROMs are employed in MS clinical trials to help assess the tolerability and effectiveness of DMTs.^90,91 PROs have been used as secondary endpoints to understand the global experience of a DMT from the patient perspective.^92-94 There are 15 FDA-approved DMTs for MS, and clinical trials for 6 of these have used PROMs as an effectiveness end point.^54,91,95,96 However, most DMT clinical trials are powered for MRI, relapse rate, or disease progression primary outcomes rather than PROMs, often resulting in underpowered PROM analyses.⁹⁷ In addition, many PROMs are not appropriate for use in DMT clinical trials.^98,99

In order to bridge the gap between clinical research and practice, some industry entities are championing “patient-focused drug development” approaches. The Accelerated Cure Project for MS has launched iConquerMS, which collects PROMs from persons with MS to further PRO research in MS and follows 4700 individuals with MS worldwide.¹⁰⁰ In 2018, the American College of Physicians announced a collaboration with an industry partner to share data to inform DMT clinical trials and develop and validate PROMs specifically designed for DMT clinical trials.¹⁰¹

Population Health

Registries following large cohorts of people with MS have the potential to develop knowledge about disease progression, treatment patterns, and outcomes.¹⁰² The Swedish EIMS study has identified associations between pre-disease body mass index and MS prognosis,¹⁰² alcohol and tobacco consumption affecting MS risk,^103,104 and exposure to shift work at a young age and increased MS risk.¹⁰⁵ The North American Research Committee on MS^83,106,107 and iConquerMS registries are “PROM-driven” and have been useful in identifying reductions in disease progression in people using DMTs.^107,108 The New York State MS Consortium has identified important demographic characteristics that influence MS progression.^109,110 PROs can also be used to determine risk of MS-related mortality¹¹¹ and decline in quality of life.^112,113 Limitations of these approaches include use of different PROMs, inconsistencies in data collection processes, and different follow-up intervals used across registries.¹⁰²

Patient-Centered Care

The Institute of Medicine defines patient-centeredness as “care that is respectful and responsive to individual patient preferences, needs, and values and ensures that patient values guide all clinical decisions.”¹¹⁴ PROs are useful for identifying a patient’s individual health concerns and preferences, something that is needed when treating a highly variable chronic health condition like MS. The use of PROs can help clinicicans visualize the lived experience of persons with MS and identify personal preferences,¹¹⁵ as well as improve self-monitoring, self-management, self-efficacy, adherence, wellness, and coping ability.¹¹⁶ At the system level, PROs can inform improvement initiatives and patient-centered care design efforts.^117-120

Selecting PROMs

Initiatives from groups like the COnsensus-based Standards for the Selection of health Measurement INstruments (COSMIN)¹²¹ and the International Society for Quality of Life Research (ISOQOL)¹⁰⁸ offer guidance on selecting PROs. The NINDS has promoted common data collection between clinical studies of the brain and nervous system.¹²² General guidance from these sources recommends first considering the outcome and target population, selecting PROMs to measure the outcome through a synthesis of the available evidence, assessing validity and reliability of selected PROMs, and using standard measures that can be compared across studies or populations.^108,121 Other factors include feasibility, acceptability, and burden of use for patients, clinicians, and systems, as well as literacy, cultural, and linguistic factors.¹²³

The NQF recommends that consideration be given to individual patient needs, insurance factors, clinical setting constraints, and available resources when selecting PROMs.¹²⁴ To maximize response rate, PROMs that are sensitive, reliable, valid, and developed in a comparative demographic of patients are advised.¹²⁵ ISOQOL has released a User’s Guide and several companion guides on implementing and utilizing PROMs.^108,126,127 Finally, PRO-Performance Measures (PRO-PMs) are sometimes used to assess whether PROMs are appropriately contributing to performance improvement and accountability.¹²⁴

The Cons of PROs

Time and Software Constraints

PROs can disrupt busy clinical care environments and overextend clinical staff.¹²⁵ Online collection of PROs outside of clinical encounters can relieve PRO-related burden, but this requires finding and funding appropriate secure online networks to effectively collect PROs.¹²⁸ In 2015, only 60% of people seen for primary care visits could access or view their records online, and of those, only 57% used messaging for medical questions or concerns.¹²⁹ Ideally, online patient portal or mobile health apps could synchronize directly to electronic health records or virtual scribes to transfer patient communications into clinical documentation.¹³⁰ There has been limited success with this approach in European countries¹³¹ and with some chronic illness conditions in the United States.⁷⁴

Electronic health technologies, including mobile health (mHealth) solutions, have improved the self-monitoring and self-management capability of patients with MS via information sharing in patient networks, assistive technologies, smartphone applications, and wearable devices.^132,133 A recent study found that communication modes included secure online patient portal use (29%) and email use (21%), and among those who owned tablets or smartphones, 46% used mHealth apps.¹³⁴ Social media use has been associated with increased peer/social/emotional support and increased access to health information, as well as clinical monitoring and behavior change.^134,135 Individuals using mHealth apps are younger, have comorbidities, and have higher socioeconomic and education levels,^135,136 suggesting that inequities in mHealth access exist.

Burden on People with MS

Questionnaires can be time-consuming and cause mental distress if not appropriately facilitated.¹³⁷ Decreasing questionnaire length and providing the option for PROMs to be delivered and completed online or outside of the clinic context can reduce burden.¹³⁸ Additionally, while some people are consistent in sharing their PROs, others struggle with using computers, especially while experiencing severe symptoms, forget to complete PROMs, or simply do not have internet access due to financial or geographic constraints.¹³⁹ A group of disabled and elderly persons with MS reported barriers to internet use due to visual deficits, small website font sizes, and distracting color schemes.¹⁴⁰

Interpretability

Interpreting PROMs and displays of longitudinal PROM data can be a challenge for persons with MS and their clinicians. There is little standardization in how PROMs are scored and presented, and there is often confusion about thresholds for clinical significance and how PROM scores can be compared to other PROMs.^141,142 While guidelines exist for implementing PRO scores in clinical settings,^126,143 there are few that aid PROM interpretation. As a result, clinicians often seek research evidence for PROMs used in other similar patient populations as a benchmark,^142-144 or compare them to other patients seen in their clinical practice.

Longitudinal PRO data are usually displayed in simple line graphs.^145,146 Overall, line graphs have been found to have the highest ease of understanding by both patients and clinicians, but sometimes can be confusing.¹⁴⁷ For example, upward trending lines are usually viewed as improvement and downward trending lines as decline; however, upward trending scores on a PROM can indicate decline, such as increasing fatigue severity. Annotation of visual displays can help. Patients and clinicians find that employing thresholds and color coding is useful, and better than “stoplight” red-yellow-green shading schemes or red-circle formats to indicate data that warrant attention.¹⁴²

Error Risks

PROs are not free of risk for error, especially if they are used independently of other information sources, such as clinical interview, examination, and diagnostic testing, or if they are utilized too frequently, too infrequently, or are duplicated in practice. If a PRO instrument is employed too frequently, score changes may reflect learning effects rather than actual clinical status. Conversely, if used too infrequently, PRO information will not be timely enough to inform real-time clinical practice. Duplication of PRO assessments (eg, multiple measures of the same PRO for the same patient on the same day) or use of multiple PRO measures to assess the same aspect (eg, 2 measures used to assess fatigue) could introduce unnecessary complexity and confusion to interpretation of PRO results.

PRO measures also can be biased or modified by clinical status and/or perceptions of people with MS at the time of assessment. For example, cognitive impairment, whether at baseline state or due to a cognitive MS relapse event, could impact patients’ ability to understand and respond to PRO assessments, producing erroneous results. However, when used appropriately, PROs targeting cognitive dysfunction may be able to detect onset of cognitive events or help to measure recovery from them. Finally, PROs measure perceived (self-reported) status, which may not be an accurate depiction of actual status.

All of these potential pitfalls support the argument that PROs should be utilized to augment the clinical interview, examination, and diagnostic (objective) testing aspects of comprehensive MS care. In this way, PROs can be correlated with other information sources to deepen the shared understanding of health status between a person with MS and her clinician, increasing the potential to make better treatment decisions and care plans together in partnership.

Value and Cost

National groups such as the Patient-Centered Outcomes Research Institute (PCORI) are working with regulatory bodies, funding agencies, insurance providers, patient advocacy groups, researchers, providers, and specialty groups to investigate how PROMs can be implemented into value-based health care reforms, including value-based reimbursement.¹⁴⁸ However, practical PRO implementation requires considerable time and resources, and many methodological and operational questions must be addressed before widespread adoption and reimbursement for PROMs will be feasible.^148,149

 

 

Summary

PROs can generate valuable information about perceived health status, function, quality of life, and experience of care using self-reported sources. Validated PRO assessment tools include PROMs and PREMs. PROs are currently utilized in research settings (especially PROMs) but are also being used in clinical practice, quality improvement initiatives, and population health applications using LHS approaches. PROs have the advantages of empowering and informing persons with MS and clinicians to optimize patient-centered care, improve systems of care, and study population health outcomes. Barriers include PROM validity, reliability, comparability, specificity, interpretability, equity, time, and cost. Generic PROMs and PREMs, and some MS-specific PROMs, can be used for persons with MS. Unfortunately, no PREMs have been developed specifically for persons with MS, and this is an area for future research. With appropriate development and utilization in LHS applications, PROs can inform patient-centered clinical care, system-level improvement initiatives, and population health research, and have the potential to help facilitate coproduction of health care services.

Acknowledgments: The authors thank Ann Cabot, DO, of the MS Specialty Care Program at Concord Hospital and (especially) peer mentors from a peer outreach wellness program for people with MS (who have asked to remain anonymous) for interviews conducted with their permission to inform the case study described in this article. The case study used in this manuscript has been de-identified, with some aspects modified from actual, and the person in the case study is fictitiously named.

Corresponding author: Brant Oliver, PhD, MS, MPH, APRN-BC, Department of Community & Family Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756; brant.j.oliver@dartmouth.edu.

Financial disclosures: None.

CHARLOTTE, N.C. – Most children who undergo hemispherectomy for severe, intractable epilepsy report headaches after the procedure, according to a study presented at the annual meeting of the Child Neurology Society. Patients with headache before hemispherectomy may be at risk of increased headache frequency after the procedure. The most common type of headache reported is nonmigrainous headache.

“We recommend that hemispherectomy patients be evaluated and followed closely postoperatively and questioned regarding the presence of headache,” said William Bingaman, MD, vice-chair of the neurological institute and head of the section of epilepsy surgery at the Cleveland Clinic, and colleagues. “Patients should be assessed and treated quickly to decrease prolonged pain and suffering and increase function.”

The two main types of hemispherectomy are anatomical and functional. Anatomical hemispherectomy entails the removal of a large amount of brain mass. Functional hemispherectomy entails the removal of a smaller amount of brain mass, as well as the disconnection of the brain’s hemispheres. Most patients are seizure free or have reduced seizure frequency after hemispherectomy. Other common postoperative outcomes include changes in behavior, cognition, motor function, and speech. Many studies have explored these outcomes, but few have examined the frequency of postoperative headache in children who undergo hemispherectomy.

Dr. Bingaman and colleagues retrospectively reviewed the charts of 74 children who underwent hemispherectomy at the Cleveland Clinic during the previous 5 years. They excluded 14 patients who were too young to respond for the analysis. The investigators sent the remaining 60 patients an informative letter and followed up with a 10-minute phone questionnaire about patients’ postoperative headache symptoms.

Twenty-two (36.7%) eligible patients completed the questionnaire. Thirty-eight patients could not be reached or declined to participate. Half of the 22 respondents were male. Participants’ median age at surgery was 6.5 years. The most common types of hemispherectomy were left functional (50%) and right functional (31.8%).

Nine (39.1%) of the 22 respondents had headache before surgery, and seven (31.8%) reported a family history of headache. In all, 19 (86.4%) patients had headache after surgery, and 10 (45.5%) had headaches that began after the surgery. Of the nine patients with preoperative headache, six (66.6%) had an increase in headache frequency after surgery, two (22.2%) reported no change, and one (11.1%) had decreased headache frequency. The most common type of headache reported was tension-type headache, and migraine was the second most common.

“The cause of any posthemispherectomy headache has thus far only been attributed to hydrocephalus,” wrote Dr. Bingaman and colleagues. “The tendency of headache to worsen following stresses such as illness, stroke, trauma, etc. has been studied extensively. The pathophysiology of posthemispherectomy headache can be investigated further by classifying hemispherectomy as a type of trauma or injury, which would explain the development of postoperative headache. Previous studies on posttraumatic headache have ascribed these headaches to neuroinflammation following the injury. Additionally, posthemispherectomy headache could also be due to the buildup of debris and fluid following the operation. Future hemispherectomy patients should be treated prophylactically for headache.”

The authors did not report funding for their study or declare any disclosures.

egreb@mdedge.com

SOURCE: Pandit I et al. CNS 2019. Abstract 99.

CHARLOTTE, N.C. – Most children who undergo hemispherectomy for severe, intractable epilepsy report headaches after the procedure, according to a study presented at the annual meeting of the Child Neurology Society. Patients with headache before hemispherectomy may be at risk of increased headache frequency after the procedure. The most common type of headache reported is nonmigrainous headache.

“We recommend that hemispherectomy patients be evaluated and followed closely postoperatively and questioned regarding the presence of headache,” said William Bingaman, MD, vice-chair of the neurological institute and head of the section of epilepsy surgery at the Cleveland Clinic, and colleagues. “Patients should be assessed and treated quickly to decrease prolonged pain and suffering and increase function.”

The two main types of hemispherectomy are anatomical and functional. Anatomical hemispherectomy entails the removal of a large amount of brain mass. Functional hemispherectomy entails the removal of a smaller amount of brain mass, as well as the disconnection of the brain’s hemispheres. Most patients are seizure free or have reduced seizure frequency after hemispherectomy. Other common postoperative outcomes include changes in behavior, cognition, motor function, and speech. Many studies have explored these outcomes, but few have examined the frequency of postoperative headache in children who undergo hemispherectomy.

Dr. Bingaman and colleagues retrospectively reviewed the charts of 74 children who underwent hemispherectomy at the Cleveland Clinic during the previous 5 years. They excluded 14 patients who were too young to respond for the analysis. The investigators sent the remaining 60 patients an informative letter and followed up with a 10-minute phone questionnaire about patients’ postoperative headache symptoms.

Twenty-two (36.7%) eligible patients completed the questionnaire. Thirty-eight patients could not be reached or declined to participate. Half of the 22 respondents were male. Participants’ median age at surgery was 6.5 years. The most common types of hemispherectomy were left functional (50%) and right functional (31.8%).

Nine (39.1%) of the 22 respondents had headache before surgery, and seven (31.8%) reported a family history of headache. In all, 19 (86.4%) patients had headache after surgery, and 10 (45.5%) had headaches that began after the surgery. Of the nine patients with preoperative headache, six (66.6%) had an increase in headache frequency after surgery, two (22.2%) reported no change, and one (11.1%) had decreased headache frequency. The most common type of headache reported was tension-type headache, and migraine was the second most common.

“The cause of any posthemispherectomy headache has thus far only been attributed to hydrocephalus,” wrote Dr. Bingaman and colleagues. “The tendency of headache to worsen following stresses such as illness, stroke, trauma, etc. has been studied extensively. The pathophysiology of posthemispherectomy headache can be investigated further by classifying hemispherectomy as a type of trauma or injury, which would explain the development of postoperative headache. Previous studies on posttraumatic headache have ascribed these headaches to neuroinflammation following the injury. Additionally, posthemispherectomy headache could also be due to the buildup of debris and fluid following the operation. Future hemispherectomy patients should be treated prophylactically for headache.”

The authors did not report funding for their study or declare any disclosures.

egreb@mdedge.com

SOURCE: Pandit I et al. CNS 2019. Abstract 99.

CHARLOTTE, N.C. – Most children who undergo hemispherectomy for severe, intractable epilepsy report headaches after the procedure, according to a study presented at the annual meeting of the Child Neurology Society. Patients with headache before hemispherectomy may be at risk of increased headache frequency after the procedure. The most common type of headache reported is nonmigrainous headache.

“We recommend that hemispherectomy patients be evaluated and followed closely postoperatively and questioned regarding the presence of headache,” said William Bingaman, MD, vice-chair of the neurological institute and head of the section of epilepsy surgery at the Cleveland Clinic, and colleagues. “Patients should be assessed and treated quickly to decrease prolonged pain and suffering and increase function.”

The two main types of hemispherectomy are anatomical and functional. Anatomical hemispherectomy entails the removal of a large amount of brain mass. Functional hemispherectomy entails the removal of a smaller amount of brain mass, as well as the disconnection of the brain’s hemispheres. Most patients are seizure free or have reduced seizure frequency after hemispherectomy. Other common postoperative outcomes include changes in behavior, cognition, motor function, and speech. Many studies have explored these outcomes, but few have examined the frequency of postoperative headache in children who undergo hemispherectomy.

Dr. Bingaman and colleagues retrospectively reviewed the charts of 74 children who underwent hemispherectomy at the Cleveland Clinic during the previous 5 years. They excluded 14 patients who were too young to respond for the analysis. The investigators sent the remaining 60 patients an informative letter and followed up with a 10-minute phone questionnaire about patients’ postoperative headache symptoms.

Twenty-two (36.7%) eligible patients completed the questionnaire. Thirty-eight patients could not be reached or declined to participate. Half of the 22 respondents were male. Participants’ median age at surgery was 6.5 years. The most common types of hemispherectomy were left functional (50%) and right functional (31.8%).

Nine (39.1%) of the 22 respondents had headache before surgery, and seven (31.8%) reported a family history of headache. In all, 19 (86.4%) patients had headache after surgery, and 10 (45.5%) had headaches that began after the surgery. Of the nine patients with preoperative headache, six (66.6%) had an increase in headache frequency after surgery, two (22.2%) reported no change, and one (11.1%) had decreased headache frequency. The most common type of headache reported was tension-type headache, and migraine was the second most common.

“The cause of any posthemispherectomy headache has thus far only been attributed to hydrocephalus,” wrote Dr. Bingaman and colleagues. “The tendency of headache to worsen following stresses such as illness, stroke, trauma, etc. has been studied extensively. The pathophysiology of posthemispherectomy headache can be investigated further by classifying hemispherectomy as a type of trauma or injury, which would explain the development of postoperative headache. Previous studies on posttraumatic headache have ascribed these headaches to neuroinflammation following the injury. Additionally, posthemispherectomy headache could also be due to the buildup of debris and fluid following the operation. Future hemispherectomy patients should be treated prophylactically for headache.”

The authors did not report funding for their study or declare any disclosures.

egreb@mdedge.com

SOURCE: Pandit I et al. CNS 2019. Abstract 99.