LAS VEGAS – Mounting evidence demonstrates that a family-based approach to treating adolescents with anorexia nervosa usually is more effective than hospitalization.

“In the history of psychiatric literature, families have been blamed a lot for psychiatric problems in their children,” James Lock, MD, PhD, said at the annual psychopharmacology update held by the Nevada Psychiatric Association. “Parents are put off by anorexia nervosa, because it’s a very confusing illness and terrifying for them to have their children radically change their behavior. These are kids who are often high achieving and have generally been easy to manage: self-starters, self-directors. Then, suddenly, over a period of 6-7 months, they go from being very well to being at death’s door.”

Enter family-based treatment (FBT) for anorexia nervosa, an outpatient intervention appropriate for children and adolescents who are medically stable. Developed around 2001, FBT is designed to restore weight and put the patient’s development back on track. It’s a team approach consisting of a primary therapist, a pediatrician, and a child and adolescent psychiatrist. Brief hospitalization sometimes is used to resolve medical concerns. Dr. Lock, professor of psychiatry and behavioral sciences at Stanford (Calif.) University, described FBT as “a highly focused staged treatment that emphasizes behavioral recovery rather than insight and understanding or cognitive change. This approach might indirectly improve family functioning and reduce eating-related cognitive distortions for the adolescent.”

According to Dr. Lock, coauthor with Daniel Le Grange, PhD, of “Treatment Manual for Anorexia Nervosa: A Family-Based Approach” second edition, (New York: Guilford Press, 2015), the current evidence base for FBT is limited, consisting of 879 patients enrolled in 11 studies at 12 different sites in four countries, as well as one meta-analysis. “We have not done the kind of research in anorexia nervosa that we need to do,” he said. “Parents ask me this every time I sit down with them: ‘Why don’t we know more? Why don’t we have more clinical guidance?’ It’s not been a priority despite the seriousness of this problem [and the] lifelong impact it has.”

Interest in FBT emerged in part because of studies demonstrating the limitations of hospitalizing patients with the disorder. One trial from the United Kingdom found that, among 90 children who were randomized to one of two outpatient treatments, to an inpatient arm, or to no treatment, no differences in outcomes were observed among the treatment groups (Br J Psychiatry. 1991;159:325-33). Similar results were found in a trial of 167 children who were randomized to either inpatient psychiatric treatment or two forms of outpatient management (Br J Psychiatry. 2007;191[5]:427-35). “If you think hospitalization will cure kids with anorexia, this study tells you that isn’t true,” Dr. Lock said. “It doesn’t say that it doesn’t benefit some people. What it says is that, on average, it’s not better than outpatient treatment for adolescents with anorexia nervosa. It’s important to build systems of care around that knowledge.”

Dr. Lock has his own opinion as to why inpatient psychiatric treatment alone usually doesn’t help anorexia nervosa patients in the long-term. “Learning in an inpatient setting is not generalizable,” he said. “You cannot learn and apply the learning that you get in the hospital to your real life: in your family and your school and your social processes. You can dress up psychotherapy any way you want to, but ultimately, it’s about learning. Can parents learn to be effective at helping their children with anorexia nervosa recover?”

In general, FBT is delivered in three phases over the course of 6-12 months. Phase I involves helping parents assume control of weight restoration in their child. “It tries to accomplish at home what could have been accomplished at a hospital by a nursing staff who are trained and able to disrupt and manage destructive behaviors that lead to weight loss and reinforce cognitive distortions,” Dr. Lock said. In phase II, parents gradually hand control over eating back to their child, while phase III involves shifting the family back to discussing adolescent issues without anorexia nervosa at the center of their concern. One fundamental assumption of FBT, he continued, is that it takes an agnostic view as to the cause of anorexia.

“We don’t have to address cause in order to have an effective treatment,” said Dr. Lock, also a professor of pediatrics at the university. “We are going to try to help patients and parents feel valued, not blamed. Secondly, we need to engage parents in a consultative way, recognizing their skills around their family, and help them apply that to anorexia nervosa.” The expected outcome should be a healthy weight, based on the child’s age. According to Dr. Lock, 79% of patients who have gained at least 4 pounds after 4 weeks of FBT will have a favorable treatment response, while 71% of those who don’t meet that benchmark are likely to fail treatment. “The therapeutic alliance is important in treatment outcome, but our studies suggest it is not enough,” he said. “You have to engage people in treatment to get them started, but if you don’t help the parents be effective in promoting weight gain, your therapeutic alliance will diminish.”

In a randomized trial that compared FBT with adolescent-focused individual therapy (AFT) for adolescents with anorexia nervosa, Dr. Lock and his associates found that, at both 6- and 12-month follow-up, FBT was significantly superior to AFT in helping patients achieve full remission, which was defined as normal weight for age and a mean global Eating Disorder Examination score within one standard deviation of published means (Arch Gen Psychiatry. 2010;67[10]:1025-32). A separate trial found that, after FBT was implemented at the Royal Children’s Hospital, Melbourne, admissions decreased by 50%, readmissions decreased by 75%, and the overall number of days patients spent in the hospital fell by 51% (J Pediatr Health Care. 2014 Jul-Aug 28[4]:322-30).

During the first FBT meeting with patients and their families, Dr. Lock discusses the hazards of anorexia nervosa, including the increased risk of death by cardiac arrest and suicide. “I instill the fact that we have a crisis on our hands, and we need to block the development of anorexia nervosa,” he said. “We have no evidence-based treatments for anorexia nervosa once it becomes chronic, and that occurs after about 5 years. The onset is about age 14. At age 19, on average, your chances of complete recovery are greatly diminished. Of course, you can still be of help by supporting improvement in the quality of their lives; you may help improve their thinking and you may help them restore weight, but many will live with the ongoing anorexia nervosa. So, our greatest chance to be effective is early intervention and the window of opportunity is 3-4 years.” Emphasizing these realities “stops people,” he said. “It’s meant to bring them into clear awareness of what they’re facing.”

Dr. Lock disclosed that he has received grant or research support from the National Institute of Mental Health. He also is a consultant for the Training Institute for Child and Adolescent Eating Disorders and has received royalties from Guilford Press and Oxford Press.

[email protected]

LAS VEGAS – Mounting evidence demonstrates that a family-based approach to treating adolescents with anorexia nervosa usually is more effective than hospitalization.

“In the history of psychiatric literature, families have been blamed a lot for psychiatric problems in their children,” James Lock, MD, PhD, said at the annual psychopharmacology update held by the Nevada Psychiatric Association. “Parents are put off by anorexia nervosa, because it’s a very confusing illness and terrifying for them to have their children radically change their behavior. These are kids who are often high achieving and have generally been easy to manage: self-starters, self-directors. Then, suddenly, over a period of 6-7 months, they go from being very well to being at death’s door.”

Enter family-based treatment (FBT) for anorexia nervosa, an outpatient intervention appropriate for children and adolescents who are medically stable. Developed around 2001, FBT is designed to restore weight and put the patient’s development back on track. It’s a team approach consisting of a primary therapist, a pediatrician, and a child and adolescent psychiatrist. Brief hospitalization sometimes is used to resolve medical concerns. Dr. Lock, professor of psychiatry and behavioral sciences at Stanford (Calif.) University, described FBT as “a highly focused staged treatment that emphasizes behavioral recovery rather than insight and understanding or cognitive change. This approach might indirectly improve family functioning and reduce eating-related cognitive distortions for the adolescent.”

According to Dr. Lock, coauthor with Daniel Le Grange, PhD, of “Treatment Manual for Anorexia Nervosa: A Family-Based Approach” second edition, (New York: Guilford Press, 2015), the current evidence base for FBT is limited, consisting of 879 patients enrolled in 11 studies at 12 different sites in four countries, as well as one meta-analysis. “We have not done the kind of research in anorexia nervosa that we need to do,” he said. “Parents ask me this every time I sit down with them: ‘Why don’t we know more? Why don’t we have more clinical guidance?’ It’s not been a priority despite the seriousness of this problem [and the] lifelong impact it has.”

Interest in FBT emerged in part because of studies demonstrating the limitations of hospitalizing patients with the disorder. One trial from the United Kingdom found that, among 90 children who were randomized to one of two outpatient treatments, to an inpatient arm, or to no treatment, no differences in outcomes were observed among the treatment groups (Br J Psychiatry. 1991;159:325-33). Similar results were found in a trial of 167 children who were randomized to either inpatient psychiatric treatment or two forms of outpatient management (Br J Psychiatry. 2007;191[5]:427-35). “If you think hospitalization will cure kids with anorexia, this study tells you that isn’t true,” Dr. Lock said. “It doesn’t say that it doesn’t benefit some people. What it says is that, on average, it’s not better than outpatient treatment for adolescents with anorexia nervosa. It’s important to build systems of care around that knowledge.”

Dr. Lock has his own opinion as to why inpatient psychiatric treatment alone usually doesn’t help anorexia nervosa patients in the long-term. “Learning in an inpatient setting is not generalizable,” he said. “You cannot learn and apply the learning that you get in the hospital to your real life: in your family and your school and your social processes. You can dress up psychotherapy any way you want to, but ultimately, it’s about learning. Can parents learn to be effective at helping their children with anorexia nervosa recover?”

In general, FBT is delivered in three phases over the course of 6-12 months. Phase I involves helping parents assume control of weight restoration in their child. “It tries to accomplish at home what could have been accomplished at a hospital by a nursing staff who are trained and able to disrupt and manage destructive behaviors that lead to weight loss and reinforce cognitive distortions,” Dr. Lock said. In phase II, parents gradually hand control over eating back to their child, while phase III involves shifting the family back to discussing adolescent issues without anorexia nervosa at the center of their concern. One fundamental assumption of FBT, he continued, is that it takes an agnostic view as to the cause of anorexia.

“We don’t have to address cause in order to have an effective treatment,” said Dr. Lock, also a professor of pediatrics at the university. “We are going to try to help patients and parents feel valued, not blamed. Secondly, we need to engage parents in a consultative way, recognizing their skills around their family, and help them apply that to anorexia nervosa.” The expected outcome should be a healthy weight, based on the child’s age. According to Dr. Lock, 79% of patients who have gained at least 4 pounds after 4 weeks of FBT will have a favorable treatment response, while 71% of those who don’t meet that benchmark are likely to fail treatment. “The therapeutic alliance is important in treatment outcome, but our studies suggest it is not enough,” he said. “You have to engage people in treatment to get them started, but if you don’t help the parents be effective in promoting weight gain, your therapeutic alliance will diminish.”

In a randomized trial that compared FBT with adolescent-focused individual therapy (AFT) for adolescents with anorexia nervosa, Dr. Lock and his associates found that, at both 6- and 12-month follow-up, FBT was significantly superior to AFT in helping patients achieve full remission, which was defined as normal weight for age and a mean global Eating Disorder Examination score within one standard deviation of published means (Arch Gen Psychiatry. 2010;67[10]:1025-32). A separate trial found that, after FBT was implemented at the Royal Children’s Hospital, Melbourne, admissions decreased by 50%, readmissions decreased by 75%, and the overall number of days patients spent in the hospital fell by 51% (J Pediatr Health Care. 2014 Jul-Aug 28[4]:322-30).

During the first FBT meeting with patients and their families, Dr. Lock discusses the hazards of anorexia nervosa, including the increased risk of death by cardiac arrest and suicide. “I instill the fact that we have a crisis on our hands, and we need to block the development of anorexia nervosa,” he said. “We have no evidence-based treatments for anorexia nervosa once it becomes chronic, and that occurs after about 5 years. The onset is about age 14. At age 19, on average, your chances of complete recovery are greatly diminished. Of course, you can still be of help by supporting improvement in the quality of their lives; you may help improve their thinking and you may help them restore weight, but many will live with the ongoing anorexia nervosa. So, our greatest chance to be effective is early intervention and the window of opportunity is 3-4 years.” Emphasizing these realities “stops people,” he said. “It’s meant to bring them into clear awareness of what they’re facing.”

Dr. Lock disclosed that he has received grant or research support from the National Institute of Mental Health. He also is a consultant for the Training Institute for Child and Adolescent Eating Disorders and has received royalties from Guilford Press and Oxford Press.

[email protected]

LAS VEGAS – Mounting evidence demonstrates that a family-based approach to treating adolescents with anorexia nervosa usually is more effective than hospitalization.

“In the history of psychiatric literature, families have been blamed a lot for psychiatric problems in their children,” James Lock, MD, PhD, said at the annual psychopharmacology update held by the Nevada Psychiatric Association. “Parents are put off by anorexia nervosa, because it’s a very confusing illness and terrifying for them to have their children radically change their behavior. These are kids who are often high achieving and have generally been easy to manage: self-starters, self-directors. Then, suddenly, over a period of 6-7 months, they go from being very well to being at death’s door.”

Enter family-based treatment (FBT) for anorexia nervosa, an outpatient intervention appropriate for children and adolescents who are medically stable. Developed around 2001, FBT is designed to restore weight and put the patient’s development back on track. It’s a team approach consisting of a primary therapist, a pediatrician, and a child and adolescent psychiatrist. Brief hospitalization sometimes is used to resolve medical concerns. Dr. Lock, professor of psychiatry and behavioral sciences at Stanford (Calif.) University, described FBT as “a highly focused staged treatment that emphasizes behavioral recovery rather than insight and understanding or cognitive change. This approach might indirectly improve family functioning and reduce eating-related cognitive distortions for the adolescent.”

According to Dr. Lock, coauthor with Daniel Le Grange, PhD, of “Treatment Manual for Anorexia Nervosa: A Family-Based Approach” second edition, (New York: Guilford Press, 2015), the current evidence base for FBT is limited, consisting of 879 patients enrolled in 11 studies at 12 different sites in four countries, as well as one meta-analysis. “We have not done the kind of research in anorexia nervosa that we need to do,” he said. “Parents ask me this every time I sit down with them: ‘Why don’t we know more? Why don’t we have more clinical guidance?’ It’s not been a priority despite the seriousness of this problem [and the] lifelong impact it has.”

Interest in FBT emerged in part because of studies demonstrating the limitations of hospitalizing patients with the disorder. One trial from the United Kingdom found that, among 90 children who were randomized to one of two outpatient treatments, to an inpatient arm, or to no treatment, no differences in outcomes were observed among the treatment groups (Br J Psychiatry. 1991;159:325-33). Similar results were found in a trial of 167 children who were randomized to either inpatient psychiatric treatment or two forms of outpatient management (Br J Psychiatry. 2007;191[5]:427-35). “If you think hospitalization will cure kids with anorexia, this study tells you that isn’t true,” Dr. Lock said. “It doesn’t say that it doesn’t benefit some people. What it says is that, on average, it’s not better than outpatient treatment for adolescents with anorexia nervosa. It’s important to build systems of care around that knowledge.”

Dr. Lock has his own opinion as to why inpatient psychiatric treatment alone usually doesn’t help anorexia nervosa patients in the long-term. “Learning in an inpatient setting is not generalizable,” he said. “You cannot learn and apply the learning that you get in the hospital to your real life: in your family and your school and your social processes. You can dress up psychotherapy any way you want to, but ultimately, it’s about learning. Can parents learn to be effective at helping their children with anorexia nervosa recover?”

In general, FBT is delivered in three phases over the course of 6-12 months. Phase I involves helping parents assume control of weight restoration in their child. “It tries to accomplish at home what could have been accomplished at a hospital by a nursing staff who are trained and able to disrupt and manage destructive behaviors that lead to weight loss and reinforce cognitive distortions,” Dr. Lock said. In phase II, parents gradually hand control over eating back to their child, while phase III involves shifting the family back to discussing adolescent issues without anorexia nervosa at the center of their concern. One fundamental assumption of FBT, he continued, is that it takes an agnostic view as to the cause of anorexia.

“We don’t have to address cause in order to have an effective treatment,” said Dr. Lock, also a professor of pediatrics at the university. “We are going to try to help patients and parents feel valued, not blamed. Secondly, we need to engage parents in a consultative way, recognizing their skills around their family, and help them apply that to anorexia nervosa.” The expected outcome should be a healthy weight, based on the child’s age. According to Dr. Lock, 79% of patients who have gained at least 4 pounds after 4 weeks of FBT will have a favorable treatment response, while 71% of those who don’t meet that benchmark are likely to fail treatment. “The therapeutic alliance is important in treatment outcome, but our studies suggest it is not enough,” he said. “You have to engage people in treatment to get them started, but if you don’t help the parents be effective in promoting weight gain, your therapeutic alliance will diminish.”

In a randomized trial that compared FBT with adolescent-focused individual therapy (AFT) for adolescents with anorexia nervosa, Dr. Lock and his associates found that, at both 6- and 12-month follow-up, FBT was significantly superior to AFT in helping patients achieve full remission, which was defined as normal weight for age and a mean global Eating Disorder Examination score within one standard deviation of published means (Arch Gen Psychiatry. 2010;67[10]:1025-32). A separate trial found that, after FBT was implemented at the Royal Children’s Hospital, Melbourne, admissions decreased by 50%, readmissions decreased by 75%, and the overall number of days patients spent in the hospital fell by 51% (J Pediatr Health Care. 2014 Jul-Aug 28[4]:322-30).

During the first FBT meeting with patients and their families, Dr. Lock discusses the hazards of anorexia nervosa, including the increased risk of death by cardiac arrest and suicide. “I instill the fact that we have a crisis on our hands, and we need to block the development of anorexia nervosa,” he said. “We have no evidence-based treatments for anorexia nervosa once it becomes chronic, and that occurs after about 5 years. The onset is about age 14. At age 19, on average, your chances of complete recovery are greatly diminished. Of course, you can still be of help by supporting improvement in the quality of their lives; you may help improve their thinking and you may help them restore weight, but many will live with the ongoing anorexia nervosa. So, our greatest chance to be effective is early intervention and the window of opportunity is 3-4 years.” Emphasizing these realities “stops people,” he said. “It’s meant to bring them into clear awareness of what they’re facing.”

Dr. Lock disclosed that he has received grant or research support from the National Institute of Mental Health. He also is a consultant for the Training Institute for Child and Adolescent Eating Disorders and has received royalties from Guilford Press and Oxford Press.

[email protected]

Mild cognitive impairment (MCI) in early Parkinson’s disease may predict subsequent dementia, whether or not the person reverts to normal cognition, according to research published online ahead of print January 20 in Neurology.

There is limited information about the incidence, persistence, and outcome of MCI due to Parkinson’s disease (PD-MCI) over time. A previous study suggested that PD-MCI in patients with newly diagnosed Parkinson’s disease predicts a highly increased risk for dementia within three years of diagnosis. Many patients with PD-MCI reverted to normal cognition during the investigation, however.

A Population-Based Cohort

Dr. Pedersen and his colleagues conducted a study to examine the incidence, progression, and reversion of MCI in patients with Parkinson’s disease over a five-year period. Patients included in the study were all participants in the Norwegian ParkWest project, an ongoing, prospective, population-based cohort study of the incidence, neurobiology, and prognosis of Parkinson’s disease. All participants were white and met diagnostic criteria for Parkinson’s disease.

Of the 212 patients recruited for the study, 196 were drug-naïve and without major depression or dementia at baseline. Among these 196 patients, 18 were rediagnosed during follow-up; as a result, 178 patients were eligible for the study.

After baseline examinations, researchers initiated dopaminergic medication and assessed patients clinically every six months. In addition, the investigators conducted standardized examinations of motor, neuropsychiatric, and cognitive function at study entry and after one, three, and five years of follow-up.

Diagnosing Parkinson’s Disease Dementia

Investigators identified patients with PD-MCI and determined dementia status using the Movement Disorder Society criteria. In addition, researchers made a diagnosis of Parkinson’s disease-associated dementia if they found evidence of cognitive decline during follow-up. Parkinson’s disease dementia exclusion criteria included comorbid conditions or disease that could cause or contribute to mental impairments. None of the participants met diagnostic criteria for dementia with Lewy bodies, Alzheimer dementia, or other dementia syndromes.

In all, 36 patients fulfilled criteria for PD-MCI at baseline. Among participants who were cognitively normal at baseline, the cumulative incidence of PD-MCI was 9.9% after one year of follow-up, 23.2% after three years, and 28.9% after five years. Also, 39.1% of patients with baseline or incident PD-MCI progressed to dementia during the five-year study period. A 59.1% rate of conversion to dementia was observed in patients with persistent PD-MCI at one year. Investigators also found that 27.8% of patients with baseline PD-MCI had reverted to normal cognition by the end of the study. Finally, PD-MCI reverters within the first three years of follow-up were at an increased risk of subsequently developing dementia, compared with cognitively normal patients.

One of the investigation’s limitations was that it had a short duration, considering the typically slow progression of Parkinson’s disease. In addition, the number of PD-MCI reverters was limited, and the cognitive test battery did not include language tests. Despite these limitations, the findings overall were valid and representative of the general population of patients with Parkinson’s disease, said the researchers.

“A remarkable observation in our study is the increased risk of dementia even in PD-MCI reverters. This [result] suggests that PD-MCI has clinical implications once diagnosed in early Parkinson’s disease,” said Dr. Pedersen and colleagues.

“This [finding] is important because patients with PD-MCI who revert to normal cognition may be excellent candidates for timely interventions to prevent progressive cognitive decline when they become available in the future.”

—Erica Tricarico

Suggested Reading

Pedersen KF, Larsen JP, Tysnes OB, Alves G. Natural course of mild cognitive impairment in Parkinson disease: A 5-year population-based study. Neurology. 2017 Jan 20 [Epub ahead of print].

Mild cognitive impairment (MCI) in early Parkinson’s disease may predict subsequent dementia, whether or not the person reverts to normal cognition, according to research published online ahead of print January 20 in Neurology.

There is limited information about the incidence, persistence, and outcome of MCI due to Parkinson’s disease (PD-MCI) over time. A previous study suggested that PD-MCI in patients with newly diagnosed Parkinson’s disease predicts a highly increased risk for dementia within three years of diagnosis. Many patients with PD-MCI reverted to normal cognition during the investigation, however.

A Population-Based Cohort

Dr. Pedersen and his colleagues conducted a study to examine the incidence, progression, and reversion of MCI in patients with Parkinson’s disease over a five-year period. Patients included in the study were all participants in the Norwegian ParkWest project, an ongoing, prospective, population-based cohort study of the incidence, neurobiology, and prognosis of Parkinson’s disease. All participants were white and met diagnostic criteria for Parkinson’s disease.

Of the 212 patients recruited for the study, 196 were drug-naïve and without major depression or dementia at baseline. Among these 196 patients, 18 were rediagnosed during follow-up; as a result, 178 patients were eligible for the study.

After baseline examinations, researchers initiated dopaminergic medication and assessed patients clinically every six months. In addition, the investigators conducted standardized examinations of motor, neuropsychiatric, and cognitive function at study entry and after one, three, and five years of follow-up.

Diagnosing Parkinson’s Disease Dementia

Investigators identified patients with PD-MCI and determined dementia status using the Movement Disorder Society criteria. In addition, researchers made a diagnosis of Parkinson’s disease-associated dementia if they found evidence of cognitive decline during follow-up. Parkinson’s disease dementia exclusion criteria included comorbid conditions or disease that could cause or contribute to mental impairments. None of the participants met diagnostic criteria for dementia with Lewy bodies, Alzheimer dementia, or other dementia syndromes.

In all, 36 patients fulfilled criteria for PD-MCI at baseline. Among participants who were cognitively normal at baseline, the cumulative incidence of PD-MCI was 9.9% after one year of follow-up, 23.2% after three years, and 28.9% after five years. Also, 39.1% of patients with baseline or incident PD-MCI progressed to dementia during the five-year study period. A 59.1% rate of conversion to dementia was observed in patients with persistent PD-MCI at one year. Investigators also found that 27.8% of patients with baseline PD-MCI had reverted to normal cognition by the end of the study. Finally, PD-MCI reverters within the first three years of follow-up were at an increased risk of subsequently developing dementia, compared with cognitively normal patients.

One of the investigation’s limitations was that it had a short duration, considering the typically slow progression of Parkinson’s disease. In addition, the number of PD-MCI reverters was limited, and the cognitive test battery did not include language tests. Despite these limitations, the findings overall were valid and representative of the general population of patients with Parkinson’s disease, said the researchers.

“A remarkable observation in our study is the increased risk of dementia even in PD-MCI reverters. This [result] suggests that PD-MCI has clinical implications once diagnosed in early Parkinson’s disease,” said Dr. Pedersen and colleagues.

“This [finding] is important because patients with PD-MCI who revert to normal cognition may be excellent candidates for timely interventions to prevent progressive cognitive decline when they become available in the future.”

—Erica Tricarico

Suggested Reading

Pedersen KF, Larsen JP, Tysnes OB, Alves G. Natural course of mild cognitive impairment in Parkinson disease: A 5-year population-based study. Neurology. 2017 Jan 20 [Epub ahead of print].

Mild cognitive impairment (MCI) in early Parkinson’s disease may predict subsequent dementia, whether or not the person reverts to normal cognition, according to research published online ahead of print January 20 in Neurology.

There is limited information about the incidence, persistence, and outcome of MCI due to Parkinson’s disease (PD-MCI) over time. A previous study suggested that PD-MCI in patients with newly diagnosed Parkinson’s disease predicts a highly increased risk for dementia within three years of diagnosis. Many patients with PD-MCI reverted to normal cognition during the investigation, however.

A Population-Based Cohort

Dr. Pedersen and his colleagues conducted a study to examine the incidence, progression, and reversion of MCI in patients with Parkinson’s disease over a five-year period. Patients included in the study were all participants in the Norwegian ParkWest project, an ongoing, prospective, population-based cohort study of the incidence, neurobiology, and prognosis of Parkinson’s disease. All participants were white and met diagnostic criteria for Parkinson’s disease.

Of the 212 patients recruited for the study, 196 were drug-naïve and without major depression or dementia at baseline. Among these 196 patients, 18 were rediagnosed during follow-up; as a result, 178 patients were eligible for the study.

After baseline examinations, researchers initiated dopaminergic medication and assessed patients clinically every six months. In addition, the investigators conducted standardized examinations of motor, neuropsychiatric, and cognitive function at study entry and after one, three, and five years of follow-up.

Diagnosing Parkinson’s Disease Dementia

Investigators identified patients with PD-MCI and determined dementia status using the Movement Disorder Society criteria. In addition, researchers made a diagnosis of Parkinson’s disease-associated dementia if they found evidence of cognitive decline during follow-up. Parkinson’s disease dementia exclusion criteria included comorbid conditions or disease that could cause or contribute to mental impairments. None of the participants met diagnostic criteria for dementia with Lewy bodies, Alzheimer dementia, or other dementia syndromes.

In all, 36 patients fulfilled criteria for PD-MCI at baseline. Among participants who were cognitively normal at baseline, the cumulative incidence of PD-MCI was 9.9% after one year of follow-up, 23.2% after three years, and 28.9% after five years. Also, 39.1% of patients with baseline or incident PD-MCI progressed to dementia during the five-year study period. A 59.1% rate of conversion to dementia was observed in patients with persistent PD-MCI at one year. Investigators also found that 27.8% of patients with baseline PD-MCI had reverted to normal cognition by the end of the study. Finally, PD-MCI reverters within the first three years of follow-up were at an increased risk of subsequently developing dementia, compared with cognitively normal patients.

One of the investigation’s limitations was that it had a short duration, considering the typically slow progression of Parkinson’s disease. In addition, the number of PD-MCI reverters was limited, and the cognitive test battery did not include language tests. Despite these limitations, the findings overall were valid and representative of the general population of patients with Parkinson’s disease, said the researchers.

“A remarkable observation in our study is the increased risk of dementia even in PD-MCI reverters. This [result] suggests that PD-MCI has clinical implications once diagnosed in early Parkinson’s disease,” said Dr. Pedersen and colleagues.

“This [finding] is important because patients with PD-MCI who revert to normal cognition may be excellent candidates for timely interventions to prevent progressive cognitive decline when they become available in the future.”

—Erica Tricarico

Suggested Reading

Pedersen KF, Larsen JP, Tysnes OB, Alves G. Natural course of mild cognitive impairment in Parkinson disease: A 5-year population-based study. Neurology. 2017 Jan 20 [Epub ahead of print].

Quantification of blood neurofilament light chain (NfL) concentration effectively distinguishes Parkinson’s disease from atypical parkinsonian disorders (APD), according to research published online ahead of print February 8 in Neurology. In addition, NfL in blood may also improve the diagnostic examination of patients with parkinsonian symptoms in primary and specialized settings, as well as improve treatment of axonal degeneration. It can be challenging to differentiate Parkinson’s disease from APD, especially during the early stages of the diseases. Although there are no established diagnostic methods to accurately distinguish Parkinson’s disease from APD, previous studies suggest that the NfL protein in CSF may be a reliable biomarker for APD. Several studies also indicate that CSF concentration of NfL is increased in APD, but not in Parkinson’s disease. The diagnostic utility of blood NfL had not been studied previously, however.

The investigators found a significant correlation between blood and CSF concentrations of NfL. In addition, they observed in all cohorts that blood NfL was increased in patients with MSA, PSP, and CBS, when compared with patients with Parkinson’s disease and healthy controls. Researchers concluded that blood NfL accurately differentiated Parkinson’s disease from APD in all three cohorts.

“Development of a fully automated clinical-grade assay and establishment of cutoff points would be necessary for implementation of blood-based NfL measurements in clinical practice,” said the researchers.

—Erica Tricarico

Suggested Reading

Hansson O, Janelidze S, Hall S, et al. Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder. Neurology. 2017 Feb 8 [Epub ahead of print].

Quantification of blood neurofilament light chain (NfL) concentration effectively distinguishes Parkinson’s disease from atypical parkinsonian disorders (APD), according to research published online ahead of print February 8 in Neurology. In addition, NfL in blood may also improve the diagnostic examination of patients with parkinsonian symptoms in primary and specialized settings, as well as improve treatment of axonal degeneration. It can be challenging to differentiate Parkinson’s disease from APD, especially during the early stages of the diseases. Although there are no established diagnostic methods to accurately distinguish Parkinson’s disease from APD, previous studies suggest that the NfL protein in CSF may be a reliable biomarker for APD. Several studies also indicate that CSF concentration of NfL is increased in APD, but not in Parkinson’s disease. The diagnostic utility of blood NfL had not been studied previously, however.

The investigators found a significant correlation between blood and CSF concentrations of NfL. In addition, they observed in all cohorts that blood NfL was increased in patients with MSA, PSP, and CBS, when compared with patients with Parkinson’s disease and healthy controls. Researchers concluded that blood NfL accurately differentiated Parkinson’s disease from APD in all three cohorts.

“Development of a fully automated clinical-grade assay and establishment of cutoff points would be necessary for implementation of blood-based NfL measurements in clinical practice,” said the researchers.

—Erica Tricarico

Suggested Reading

Hansson O, Janelidze S, Hall S, et al. Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder. Neurology. 2017 Feb 8 [Epub ahead of print].

Quantification of blood neurofilament light chain (NfL) concentration effectively distinguishes Parkinson’s disease from atypical parkinsonian disorders (APD), according to research published online ahead of print February 8 in Neurology. In addition, NfL in blood may also improve the diagnostic examination of patients with parkinsonian symptoms in primary and specialized settings, as well as improve treatment of axonal degeneration. It can be challenging to differentiate Parkinson’s disease from APD, especially during the early stages of the diseases. Although there are no established diagnostic methods to accurately distinguish Parkinson’s disease from APD, previous studies suggest that the NfL protein in CSF may be a reliable biomarker for APD. Several studies also indicate that CSF concentration of NfL is increased in APD, but not in Parkinson’s disease. The diagnostic utility of blood NfL had not been studied previously, however.

The investigators found a significant correlation between blood and CSF concentrations of NfL. In addition, they observed in all cohorts that blood NfL was increased in patients with MSA, PSP, and CBS, when compared with patients with Parkinson’s disease and healthy controls. Researchers concluded that blood NfL accurately differentiated Parkinson’s disease from APD in all three cohorts.

“Development of a fully automated clinical-grade assay and establishment of cutoff points would be necessary for implementation of blood-based NfL measurements in clinical practice,” said the researchers.

—Erica Tricarico

Suggested Reading

Hansson O, Janelidze S, Hall S, et al. Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder. Neurology. 2017 Feb 8 [Epub ahead of print].

By Jusleen Ahluwalia, MD, and Lawrence F. Eichenfield, MD

Subcutaneous fat necrosis of the newborn

The clinical history and morphology of our patient’s cutaneous manifestation is highly suggestive of subcutaneous fat necrosis of the newborn (SFN). SFN is a self-limited, lobular form of panniculitis that typically affects newborns at term or post term until the first 6 weeks of life.1 Delivery complications resulting in perinatal stress – including perinatal hypothermia, hypoxia, and birth trauma – have been associated with the development of SFN.2 Other risk factors include maternal disorders during pregnancy, such as diabetes, hypertension, exposure to tobacco, and thrombotic events.^1,2 SFN has been noted after therapeutic hypothermia that is utilized to minimize neurologic effects of neonatal hypoxic ischemic encephalopathy.¹

It has been hypothesized that SFN follows hypoxic injury to fat caused by local trauma, while in some cases it is proposed that SFN results from an imbalance of saturated and monounsaturated fats leading to crystallization at certain temperatures in the neonatal subcutis.¹

The clinical presentation of SFN is characterized by the development of one to several erythematous violaceous subcutaneous nodules and plaques that can evolve into firm calcifications, and may be tender to palpation. They are characteristically located on the shoulders, back, and upper limbs. Spontaneous regression has been observed without scarring within 2-5 months; however, cutaneous atrophy of the affected areas can follow recovery from the condition.^1-3

Hypercalcemia is a potentially fatal complication of SFN that infrequently occurs in a subset of patients. Its risk increases with the extent of perinatal injury and degree of fat necrosis.¹ Several studies have documented a prevalence of hypercalcemia in 36%-56% of infants with SFN; however, most of these cases were mild and conservatively managed.^2,4  Hypercalcemia may manifest without symptoms or present with vomiting, irritability, and seizures.¹ Nephrocalcinosis can complicate high calcium levels and is detected by abdominal ultrasonography. Other complications that can accompany the development of SFN include thrombocytopenia, hyperglycemia, and hypertriglyceridemia, although this relationship is controversial as these conditions can be attributed to other neonatal disease or maternal factors.⁵

Differential diagnosis

Although SFN is generally a transient, self-limited condition, recognition of SFN is critical to monitor and avoid metabolic alterations associated with SFN. Sclerema neonatorum is another rare condition characterized by diffuse hardening of the skin affecting infants up to 4 months of age with severe underlying disease and systemic symptoms.¹

Deep soft tissue infections, such as cellulitis, are usually accompanied with fever and other signs of infection.1 Mechanical trauma may induce firm, subcutaneous nodules in areas where fat is adjacent to bone and should be considered in any infant or child with subcutaneous nodules over areas prone to injury.¹ Sudden withdrawal of systemic steroids can cause subcutaneous nodules typically located on cheeks, arms, and trunk.¹

Management

Most infants with SFN are managed conservatively.¹ Recently proposed guidelines for the management of SFN include weekly monitoring of calcium levels until 1 month of age and monthly until 6 months of age or after resolution of the cutaneous lesion, and more frequently if hypercalcemia is documented. Platelet count and creatinine, glucose, and triglyceride levels also should be assessed.⁵ At-risk infants should be evaluated for nephrocalcinosis with abdominal ultrasonagraphy.^1,6 Treatment of hypercalcemia can consist of modification of diet with low levels of calcium and vitamin D, intravenous saline, calcium-wasting diuretics, or occasionally corticosteroids. Bisphosphonates also have been reported to successfully treat hypercalcemia in the setting of SFN.^1,6 

References

1. Disorders of the subcutaneous tissue, in “Neonatal and Infant Dermatology,” 3rd ed. (Philadelphia: Saunders, 2015, p. 443-55).

2. Br J Dermatol. 2007 Apr;156(4):709-15.

3. An Bras Dermatol. 2013 Nov-Dec;88(6 Suppl 1):154-7.

4. Pediatr Dermatol. 1999 Sep-Oct;16(5):384-7. 

5. Pediatr Dermatol. 2016 Nov;33(6):e353-5.

6. Arch Dis Child Fetal Neonatal Ed. 2014 Sep;99(5):F419-21. 

By Jusleen Ahluwalia, MD, and Lawrence F. Eichenfield, MD

Subcutaneous fat necrosis of the newborn

The clinical history and morphology of our patient’s cutaneous manifestation is highly suggestive of subcutaneous fat necrosis of the newborn (SFN). SFN is a self-limited, lobular form of panniculitis that typically affects newborns at term or post term until the first 6 weeks of life.1 Delivery complications resulting in perinatal stress – including perinatal hypothermia, hypoxia, and birth trauma – have been associated with the development of SFN.2 Other risk factors include maternal disorders during pregnancy, such as diabetes, hypertension, exposure to tobacco, and thrombotic events.^1,2 SFN has been noted after therapeutic hypothermia that is utilized to minimize neurologic effects of neonatal hypoxic ischemic encephalopathy.¹

It has been hypothesized that SFN follows hypoxic injury to fat caused by local trauma, while in some cases it is proposed that SFN results from an imbalance of saturated and monounsaturated fats leading to crystallization at certain temperatures in the neonatal subcutis.¹

The clinical presentation of SFN is characterized by the development of one to several erythematous violaceous subcutaneous nodules and plaques that can evolve into firm calcifications, and may be tender to palpation. They are characteristically located on the shoulders, back, and upper limbs. Spontaneous regression has been observed without scarring within 2-5 months; however, cutaneous atrophy of the affected areas can follow recovery from the condition.^1-3

Hypercalcemia is a potentially fatal complication of SFN that infrequently occurs in a subset of patients. Its risk increases with the extent of perinatal injury and degree of fat necrosis.¹ Several studies have documented a prevalence of hypercalcemia in 36%-56% of infants with SFN; however, most of these cases were mild and conservatively managed.^2,4  Hypercalcemia may manifest without symptoms or present with vomiting, irritability, and seizures.¹ Nephrocalcinosis can complicate high calcium levels and is detected by abdominal ultrasonography. Other complications that can accompany the development of SFN include thrombocytopenia, hyperglycemia, and hypertriglyceridemia, although this relationship is controversial as these conditions can be attributed to other neonatal disease or maternal factors.⁵

Differential diagnosis

Although SFN is generally a transient, self-limited condition, recognition of SFN is critical to monitor and avoid metabolic alterations associated with SFN. Sclerema neonatorum is another rare condition characterized by diffuse hardening of the skin affecting infants up to 4 months of age with severe underlying disease and systemic symptoms.¹

Deep soft tissue infections, such as cellulitis, are usually accompanied with fever and other signs of infection.1 Mechanical trauma may induce firm, subcutaneous nodules in areas where fat is adjacent to bone and should be considered in any infant or child with subcutaneous nodules over areas prone to injury.¹ Sudden withdrawal of systemic steroids can cause subcutaneous nodules typically located on cheeks, arms, and trunk.¹

Management

Most infants with SFN are managed conservatively.¹ Recently proposed guidelines for the management of SFN include weekly monitoring of calcium levels until 1 month of age and monthly until 6 months of age or after resolution of the cutaneous lesion, and more frequently if hypercalcemia is documented. Platelet count and creatinine, glucose, and triglyceride levels also should be assessed.⁵ At-risk infants should be evaluated for nephrocalcinosis with abdominal ultrasonagraphy.^1,6 Treatment of hypercalcemia can consist of modification of diet with low levels of calcium and vitamin D, intravenous saline, calcium-wasting diuretics, or occasionally corticosteroids. Bisphosphonates also have been reported to successfully treat hypercalcemia in the setting of SFN.^1,6 

References

1. Disorders of the subcutaneous tissue, in “Neonatal and Infant Dermatology,” 3rd ed. (Philadelphia: Saunders, 2015, p. 443-55).

2. Br J Dermatol. 2007 Apr;156(4):709-15.

3. An Bras Dermatol. 2013 Nov-Dec;88(6 Suppl 1):154-7.

4. Pediatr Dermatol. 1999 Sep-Oct;16(5):384-7. 

5. Pediatr Dermatol. 2016 Nov;33(6):e353-5.

6. Arch Dis Child Fetal Neonatal Ed. 2014 Sep;99(5):F419-21. 

By Jusleen Ahluwalia, MD, and Lawrence F. Eichenfield, MD

Subcutaneous fat necrosis of the newborn

The clinical history and morphology of our patient’s cutaneous manifestation is highly suggestive of subcutaneous fat necrosis of the newborn (SFN). SFN is a self-limited, lobular form of panniculitis that typically affects newborns at term or post term until the first 6 weeks of life.1 Delivery complications resulting in perinatal stress – including perinatal hypothermia, hypoxia, and birth trauma – have been associated with the development of SFN.2 Other risk factors include maternal disorders during pregnancy, such as diabetes, hypertension, exposure to tobacco, and thrombotic events.^1,2 SFN has been noted after therapeutic hypothermia that is utilized to minimize neurologic effects of neonatal hypoxic ischemic encephalopathy.¹

It has been hypothesized that SFN follows hypoxic injury to fat caused by local trauma, while in some cases it is proposed that SFN results from an imbalance of saturated and monounsaturated fats leading to crystallization at certain temperatures in the neonatal subcutis.¹

The clinical presentation of SFN is characterized by the development of one to several erythematous violaceous subcutaneous nodules and plaques that can evolve into firm calcifications, and may be tender to palpation. They are characteristically located on the shoulders, back, and upper limbs. Spontaneous regression has been observed without scarring within 2-5 months; however, cutaneous atrophy of the affected areas can follow recovery from the condition.^1-3

Hypercalcemia is a potentially fatal complication of SFN that infrequently occurs in a subset of patients. Its risk increases with the extent of perinatal injury and degree of fat necrosis.¹ Several studies have documented a prevalence of hypercalcemia in 36%-56% of infants with SFN; however, most of these cases were mild and conservatively managed.^2,4  Hypercalcemia may manifest without symptoms or present with vomiting, irritability, and seizures.¹ Nephrocalcinosis can complicate high calcium levels and is detected by abdominal ultrasonography. Other complications that can accompany the development of SFN include thrombocytopenia, hyperglycemia, and hypertriglyceridemia, although this relationship is controversial as these conditions can be attributed to other neonatal disease or maternal factors.⁵

Differential diagnosis

Although SFN is generally a transient, self-limited condition, recognition of SFN is critical to monitor and avoid metabolic alterations associated with SFN. Sclerema neonatorum is another rare condition characterized by diffuse hardening of the skin affecting infants up to 4 months of age with severe underlying disease and systemic symptoms.¹

Deep soft tissue infections, such as cellulitis, are usually accompanied with fever and other signs of infection.1 Mechanical trauma may induce firm, subcutaneous nodules in areas where fat is adjacent to bone and should be considered in any infant or child with subcutaneous nodules over areas prone to injury.¹ Sudden withdrawal of systemic steroids can cause subcutaneous nodules typically located on cheeks, arms, and trunk.¹

Management

Most infants with SFN are managed conservatively.¹ Recently proposed guidelines for the management of SFN include weekly monitoring of calcium levels until 1 month of age and monthly until 6 months of age or after resolution of the cutaneous lesion, and more frequently if hypercalcemia is documented. Platelet count and creatinine, glucose, and triglyceride levels also should be assessed.⁵ At-risk infants should be evaluated for nephrocalcinosis with abdominal ultrasonagraphy.^1,6 Treatment of hypercalcemia can consist of modification of diet with low levels of calcium and vitamin D, intravenous saline, calcium-wasting diuretics, or occasionally corticosteroids. Bisphosphonates also have been reported to successfully treat hypercalcemia in the setting of SFN.^1,6 

References

1. Disorders of the subcutaneous tissue, in “Neonatal and Infant Dermatology,” 3rd ed. (Philadelphia: Saunders, 2015, p. 443-55).

2. Br J Dermatol. 2007 Apr;156(4):709-15.

3. An Bras Dermatol. 2013 Nov-Dec;88(6 Suppl 1):154-7.

4. Pediatr Dermatol. 1999 Sep-Oct;16(5):384-7. 

5. Pediatr Dermatol. 2016 Nov;33(6):e353-5.

6. Arch Dis Child Fetal Neonatal Ed. 2014 Sep;99(5):F419-21. 

ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.

High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.

Tumor-induced immune suppression

Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.

“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.

In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.

“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
 

Higher levels correlate with outcomes

To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.

They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.

The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.

They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.

Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.

They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).

They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.

“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
 

‘A little bit curious’

Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.

[email protected]

ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.

High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.

Tumor-induced immune suppression

Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.

“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.

In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.

“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
 

Higher levels correlate with outcomes

To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.

They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.

The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.

They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.

Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.

They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).

They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.

“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
 

‘A little bit curious’

Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.

[email protected]

ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.

High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.

Tumor-induced immune suppression

Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.

“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.

In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.

“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
 

Higher levels correlate with outcomes

To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.

They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.

The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.

They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.

Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.

They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).

They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.

“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
 

‘A little bit curious’

Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.

[email protected]

ORLANDO—In patients with atrial fibrillation (AF) who fail to achieve rhythm control after catheter ablation, the risk of ischemic stroke may approach 30% over five or more years of follow-up, despite optimized anticoagulation therapy, according to data from 1,002 consecutive patients presented at the 22nd Annual International AF Symposium.

The retrospective analysis was conducted in 1,002 patients who underwent catheter ablation after failing pharmacologic treatment of AF. Of these, 169 (17%) failed the ablation, but the focus of this study was on the subgroup of 67 catheter ablation treatment failures that have been followed for at least five years. All had been maintained on anticoagulation therapy.

Within this group, 18 (27%) had an ischemic stroke during follow-up. The average time to stroke after the first ablation procedure was 3.9 years.

Prior to being declared catheter ablation failures, the average number of ablation procedures in this long-term follow-up group was 1.7. In 55.2% of patients, the first ablation was performed with a cryoballoon. The remaining first ablations were delivered with radiofrequency. For a second or third ablation, the same techniques were commonly repeated, but 25% received a cavotricuspid isthmus ablation, and 12% underwent a VATS-Maze procedure.

There were no deaths in this series, in which the average patient age was 66. The average duration of AF was 12 years, the mean left atrial size was 45 mm, and the average left ventricular ejection fraction was 55%.

In this study, researchers defined catheter ablation failure as inability to regain rhythm control despite repeated ablation procedures. However, many patients who initially achieve rhythm control after catheter ablation have recurrence of AF over time. It is unclear whether patients who initially achieve but then lose rhythm control face the same high risk for stroke as seen in the Dutch series if followed long-term.

One study suggests that they may not. In a study by Bottoni et al of 631 consecutive patients who underwent a mean 1.5 catheter ablations before achieving rhythm control, 34% had an AF recurrence at one year. When followed for a mean 4.1 years of additional follow-up (5.1 years from the initial ablation), only 10% had a serious adverse event, such as heart failure or hemorrhage, and only 2% had a cerebrovascular event.

Numerous clinical studies have shown that catheter ablation is more effective than pharmacologic therapy for both regaining rhythm control in AF patients and reducing symptoms, according to Dr. Martirosyan, but these long-term follow-up data confirm that the risk of thromboembolic complications remains high in those who fail the initial catheter ablation. Of the 18 strokes, only four occurred in the first year of follow-up. The remaining strokes accrued slowly over time. Strokes were recorded up until 10 years after the ablation, the longest period that any patient was followed.

—Ted Bosworth

ORLANDO—In patients with atrial fibrillation (AF) who fail to achieve rhythm control after catheter ablation, the risk of ischemic stroke may approach 30% over five or more years of follow-up, despite optimized anticoagulation therapy, according to data from 1,002 consecutive patients presented at the 22nd Annual International AF Symposium.

The retrospective analysis was conducted in 1,002 patients who underwent catheter ablation after failing pharmacologic treatment of AF. Of these, 169 (17%) failed the ablation, but the focus of this study was on the subgroup of 67 catheter ablation treatment failures that have been followed for at least five years. All had been maintained on anticoagulation therapy.

Within this group, 18 (27%) had an ischemic stroke during follow-up. The average time to stroke after the first ablation procedure was 3.9 years.

Prior to being declared catheter ablation failures, the average number of ablation procedures in this long-term follow-up group was 1.7. In 55.2% of patients, the first ablation was performed with a cryoballoon. The remaining first ablations were delivered with radiofrequency. For a second or third ablation, the same techniques were commonly repeated, but 25% received a cavotricuspid isthmus ablation, and 12% underwent a VATS-Maze procedure.

There were no deaths in this series, in which the average patient age was 66. The average duration of AF was 12 years, the mean left atrial size was 45 mm, and the average left ventricular ejection fraction was 55%.

In this study, researchers defined catheter ablation failure as inability to regain rhythm control despite repeated ablation procedures. However, many patients who initially achieve rhythm control after catheter ablation have recurrence of AF over time. It is unclear whether patients who initially achieve but then lose rhythm control face the same high risk for stroke as seen in the Dutch series if followed long-term.

One study suggests that they may not. In a study by Bottoni et al of 631 consecutive patients who underwent a mean 1.5 catheter ablations before achieving rhythm control, 34% had an AF recurrence at one year. When followed for a mean 4.1 years of additional follow-up (5.1 years from the initial ablation), only 10% had a serious adverse event, such as heart failure or hemorrhage, and only 2% had a cerebrovascular event.

Numerous clinical studies have shown that catheter ablation is more effective than pharmacologic therapy for both regaining rhythm control in AF patients and reducing symptoms, according to Dr. Martirosyan, but these long-term follow-up data confirm that the risk of thromboembolic complications remains high in those who fail the initial catheter ablation. Of the 18 strokes, only four occurred in the first year of follow-up. The remaining strokes accrued slowly over time. Strokes were recorded up until 10 years after the ablation, the longest period that any patient was followed.

—Ted Bosworth

ORLANDO—In patients with atrial fibrillation (AF) who fail to achieve rhythm control after catheter ablation, the risk of ischemic stroke may approach 30% over five or more years of follow-up, despite optimized anticoagulation therapy, according to data from 1,002 consecutive patients presented at the 22nd Annual International AF Symposium.

The retrospective analysis was conducted in 1,002 patients who underwent catheter ablation after failing pharmacologic treatment of AF. Of these, 169 (17%) failed the ablation, but the focus of this study was on the subgroup of 67 catheter ablation treatment failures that have been followed for at least five years. All had been maintained on anticoagulation therapy.

Within this group, 18 (27%) had an ischemic stroke during follow-up. The average time to stroke after the first ablation procedure was 3.9 years.

Prior to being declared catheter ablation failures, the average number of ablation procedures in this long-term follow-up group was 1.7. In 55.2% of patients, the first ablation was performed with a cryoballoon. The remaining first ablations were delivered with radiofrequency. For a second or third ablation, the same techniques were commonly repeated, but 25% received a cavotricuspid isthmus ablation, and 12% underwent a VATS-Maze procedure.

There were no deaths in this series, in which the average patient age was 66. The average duration of AF was 12 years, the mean left atrial size was 45 mm, and the average left ventricular ejection fraction was 55%.

In this study, researchers defined catheter ablation failure as inability to regain rhythm control despite repeated ablation procedures. However, many patients who initially achieve rhythm control after catheter ablation have recurrence of AF over time. It is unclear whether patients who initially achieve but then lose rhythm control face the same high risk for stroke as seen in the Dutch series if followed long-term.

One study suggests that they may not. In a study by Bottoni et al of 631 consecutive patients who underwent a mean 1.5 catheter ablations before achieving rhythm control, 34% had an AF recurrence at one year. When followed for a mean 4.1 years of additional follow-up (5.1 years from the initial ablation), only 10% had a serious adverse event, such as heart failure or hemorrhage, and only 2% had a cerebrovascular event.

Numerous clinical studies have shown that catheter ablation is more effective than pharmacologic therapy for both regaining rhythm control in AF patients and reducing symptoms, according to Dr. Martirosyan, but these long-term follow-up data confirm that the risk of thromboembolic complications remains high in those who fail the initial catheter ablation. Of the 18 strokes, only four occurred in the first year of follow-up. The remaining strokes accrued slowly over time. Strokes were recorded up until 10 years after the ablation, the longest period that any patient was followed.

—Ted Bosworth

Nine patients with relapsing multiple sclerosis had significant and unexpected disease activity within 12 months of switching from fingolimod to alemtuzumab, according to a report from six European neuroscience centers. The report was published January 10 in Neurology: Neuroimmunology & Neuroinflammation.

The centers treated 174 patients with alemtuzumab (Lemtrada); 36 had been on fingolimod (Gilenya) beforehand. “Therefore, these nine patients ... represent 25% of the fingolimod-alemtuzumab cohort,” said Mark Willis, MBBCh, Clinical Research Fellow at Cardiff University, Wales, and colleagues.

The researchers speculated that prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal allowed “these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provoke[d] disease reactivation ... This may have important implications for sequential drug selection and washout periods in a subset of patients who switch from fingolimod or drugs with similar biological mechanisms,” they said.

The nine patients were on fingolimod for between five and 33 months, but it was not effective. As a result, they were started on alemtuzumab following a median fingolimod washout period of six weeks. Eight patients had at least one clinical relapse within 12 months of the first alemtuzumab infusion cycle; the median time to relapse following alemtuzumab induction was 4.5 months. All nine patients had radiologic evidence of new disease activity.

Five patients had lymphocyte counts below normal when started on alemtuzumab. It has “been suggested that patients continue on an alternative [disease-modifying treatment] after fingolimod discontinuation, preferably until peripheral lymphocyte counts have normalized.” However, “there is currently no consensus as to which subsequent therapeutic agent is optimal,” the investigators said.

All nine patients went on to the second planned infusion of alemtuzumab; eight were relapse free during a mean follow-up of six months after the second treatment cycle. Of seven patients who had further imaging, four were radiologically stable, three had new T2 lesions, and one had a new gadolinium-enhancing lesion.

—M. Alexander Otto

Suggested Reading

Willis M, Pearson O, Illes Z, et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e320.

Nine patients with relapsing multiple sclerosis had significant and unexpected disease activity within 12 months of switching from fingolimod to alemtuzumab, according to a report from six European neuroscience centers. The report was published January 10 in Neurology: Neuroimmunology & Neuroinflammation.

The centers treated 174 patients with alemtuzumab (Lemtrada); 36 had been on fingolimod (Gilenya) beforehand. “Therefore, these nine patients ... represent 25% of the fingolimod-alemtuzumab cohort,” said Mark Willis, MBBCh, Clinical Research Fellow at Cardiff University, Wales, and colleagues.

The researchers speculated that prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal allowed “these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provoke[d] disease reactivation ... This may have important implications for sequential drug selection and washout periods in a subset of patients who switch from fingolimod or drugs with similar biological mechanisms,” they said.

The nine patients were on fingolimod for between five and 33 months, but it was not effective. As a result, they were started on alemtuzumab following a median fingolimod washout period of six weeks. Eight patients had at least one clinical relapse within 12 months of the first alemtuzumab infusion cycle; the median time to relapse following alemtuzumab induction was 4.5 months. All nine patients had radiologic evidence of new disease activity.

Five patients had lymphocyte counts below normal when started on alemtuzumab. It has “been suggested that patients continue on an alternative [disease-modifying treatment] after fingolimod discontinuation, preferably until peripheral lymphocyte counts have normalized.” However, “there is currently no consensus as to which subsequent therapeutic agent is optimal,” the investigators said.

All nine patients went on to the second planned infusion of alemtuzumab; eight were relapse free during a mean follow-up of six months after the second treatment cycle. Of seven patients who had further imaging, four were radiologically stable, three had new T2 lesions, and one had a new gadolinium-enhancing lesion.

—M. Alexander Otto

Suggested Reading

Willis M, Pearson O, Illes Z, et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e320.

Nine patients with relapsing multiple sclerosis had significant and unexpected disease activity within 12 months of switching from fingolimod to alemtuzumab, according to a report from six European neuroscience centers. The report was published January 10 in Neurology: Neuroimmunology & Neuroinflammation.

The centers treated 174 patients with alemtuzumab (Lemtrada); 36 had been on fingolimod (Gilenya) beforehand. “Therefore, these nine patients ... represent 25% of the fingolimod-alemtuzumab cohort,” said Mark Willis, MBBCh, Clinical Research Fellow at Cardiff University, Wales, and colleagues.

The researchers speculated that prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal allowed “these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provoke[d] disease reactivation ... This may have important implications for sequential drug selection and washout periods in a subset of patients who switch from fingolimod or drugs with similar biological mechanisms,” they said.

The nine patients were on fingolimod for between five and 33 months, but it was not effective. As a result, they were started on alemtuzumab following a median fingolimod washout period of six weeks. Eight patients had at least one clinical relapse within 12 months of the first alemtuzumab infusion cycle; the median time to relapse following alemtuzumab induction was 4.5 months. All nine patients had radiologic evidence of new disease activity.

Five patients had lymphocyte counts below normal when started on alemtuzumab. It has “been suggested that patients continue on an alternative [disease-modifying treatment] after fingolimod discontinuation, preferably until peripheral lymphocyte counts have normalized.” However, “there is currently no consensus as to which subsequent therapeutic agent is optimal,” the investigators said.

All nine patients went on to the second planned infusion of alemtuzumab; eight were relapse free during a mean follow-up of six months after the second treatment cycle. Of seven patients who had further imaging, four were radiologically stable, three had new T2 lesions, and one had a new gadolinium-enhancing lesion.

—M. Alexander Otto

Suggested Reading

Willis M, Pearson O, Illes Z, et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e320.

“Our results further point to a possible sequence of events leading to MS, in which changes in vibration sensitivity may precede the appearance of demyelinating lesions in the brain,” said the researchers.

Evaluating First-Degree Relatives

Dr. Xia and colleagues conducted the Genes and Environment in MS (GEMS) project, the first prospective study of populations at risk for MS and the first detailed cross-sectional examination of higher-risk and lower-risk family members of patients with MS. The study involved 100 neurologically asymptomatic adults (ages 18 to 50) who were first-degree relatives of patients with MS and participated in the GEMS project from August 2012 to July 2015.

Forty-one of the participants were high-risk patients who scored in the top 10% of a Genetic and Environmental Risk Score (GERS), and 59 participants were low-risk and scored in the bottom 10% of the GERS. The GERS included genetic risk factors (ie, HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, BMI, history of infectious mononucleosis and migraine, and vitamin D levels.

Since 40 of the 41 high-risk individuals were female, and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex,” the researchers said.

Testing Neurologic Function

To help identify early signs of MS, the investigators used brain MRI, optical coherence tomography, and other measures of neurologic function, including the Expanded Disability Status Scale, Timed 25-Foot Walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity.

Overall, women at high risk showed more subclinical signs of MS than women at low risk, based on an omnibus test that globally assessed the burden of neurologic dysfunction by comparing the overall differences between the two groups. Impaired vibration perception yielded a stronger result; of 47 women (27 at high risk and 20 at low risk) tested in this manner, women at high risk showed significantly reduced vibration perception in the distal lower extremities.

One patient in the high-risk group converted to clinically definite MS during the study. Four of the women at high risk had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one woman at low risk. Two women at high risk and one at low risk met the 2016 proposed consensus MRI criteria for MS diagnosis. In addition, radiologic isolated syndrome occurred in one woman from each group. Also, there was a single focus of leptomeningeal enhancement in three women at high risk and one woman at low risk.

Some limitations of this study include the small size, the lack of male participants, the cross-sectional design, and the fact that the vibration sensitivity thresholds were in the normal range for individuals at high risk and low risk. Researchers “plan to confirm the finding of change in vibration sensitivity with a follow-up study.” They added that the “study highlights the importantneed to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”

Identifying High-Risk Individuals

“The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening,” said Fredrik Piehl, MD, PhD, Professor of Neuroimmunology at Karolinska Institutet and Karolinska University Hospital in Stockholm, in an accompanying editorial. “Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking. The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors,” he added. Dr. Piehl disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.

—Heidi Splete

Suggested Reading

Xia Z, Steele SU, Bakshi A, et al. Assessment of early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk family members. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Piehl F. Multiple sclerosis-a tuning fork still required. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

“Our results further point to a possible sequence of events leading to MS, in which changes in vibration sensitivity may precede the appearance of demyelinating lesions in the brain,” said the researchers.

Evaluating First-Degree Relatives

Dr. Xia and colleagues conducted the Genes and Environment in MS (GEMS) project, the first prospective study of populations at risk for MS and the first detailed cross-sectional examination of higher-risk and lower-risk family members of patients with MS. The study involved 100 neurologically asymptomatic adults (ages 18 to 50) who were first-degree relatives of patients with MS and participated in the GEMS project from August 2012 to July 2015.

Forty-one of the participants were high-risk patients who scored in the top 10% of a Genetic and Environmental Risk Score (GERS), and 59 participants were low-risk and scored in the bottom 10% of the GERS. The GERS included genetic risk factors (ie, HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, BMI, history of infectious mononucleosis and migraine, and vitamin D levels.

Since 40 of the 41 high-risk individuals were female, and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex,” the researchers said.

Testing Neurologic Function

To help identify early signs of MS, the investigators used brain MRI, optical coherence tomography, and other measures of neurologic function, including the Expanded Disability Status Scale, Timed 25-Foot Walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity.

Overall, women at high risk showed more subclinical signs of MS than women at low risk, based on an omnibus test that globally assessed the burden of neurologic dysfunction by comparing the overall differences between the two groups. Impaired vibration perception yielded a stronger result; of 47 women (27 at high risk and 20 at low risk) tested in this manner, women at high risk showed significantly reduced vibration perception in the distal lower extremities.

One patient in the high-risk group converted to clinically definite MS during the study. Four of the women at high risk had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one woman at low risk. Two women at high risk and one at low risk met the 2016 proposed consensus MRI criteria for MS diagnosis. In addition, radiologic isolated syndrome occurred in one woman from each group. Also, there was a single focus of leptomeningeal enhancement in three women at high risk and one woman at low risk.

Some limitations of this study include the small size, the lack of male participants, the cross-sectional design, and the fact that the vibration sensitivity thresholds were in the normal range for individuals at high risk and low risk. Researchers “plan to confirm the finding of change in vibration sensitivity with a follow-up study.” They added that the “study highlights the importantneed to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”

Identifying High-Risk Individuals

“The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening,” said Fredrik Piehl, MD, PhD, Professor of Neuroimmunology at Karolinska Institutet and Karolinska University Hospital in Stockholm, in an accompanying editorial. “Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking. The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors,” he added. Dr. Piehl disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.

—Heidi Splete

Suggested Reading

Xia Z, Steele SU, Bakshi A, et al. Assessment of early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk family members. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Piehl F. Multiple sclerosis-a tuning fork still required. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

“Our results further point to a possible sequence of events leading to MS, in which changes in vibration sensitivity may precede the appearance of demyelinating lesions in the brain,” said the researchers.

Evaluating First-Degree Relatives

Dr. Xia and colleagues conducted the Genes and Environment in MS (GEMS) project, the first prospective study of populations at risk for MS and the first detailed cross-sectional examination of higher-risk and lower-risk family members of patients with MS. The study involved 100 neurologically asymptomatic adults (ages 18 to 50) who were first-degree relatives of patients with MS and participated in the GEMS project from August 2012 to July 2015.

Forty-one of the participants were high-risk patients who scored in the top 10% of a Genetic and Environmental Risk Score (GERS), and 59 participants were low-risk and scored in the bottom 10% of the GERS. The GERS included genetic risk factors (ie, HLA alleles and several MS-associated non-HLA genetic variants) and environmental factors, such as smoking status, BMI, history of infectious mononucleosis and migraine, and vitamin D levels.

Since 40 of the 41 high-risk individuals were female, and 25 of the 59 low-risk individuals were female, the investigators limited the study to the 65 female participants to avoid “attributing any potential difference primarily to the role of sex,” the researchers said.

Testing Neurologic Function

To help identify early signs of MS, the investigators used brain MRI, optical coherence tomography, and other measures of neurologic function, including the Expanded Disability Status Scale, Timed 25-Foot Walk, Nine-Hole Peg Test, Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Timed Up and Go, and high-contrast and low-contrast visual acuity.

Overall, women at high risk showed more subclinical signs of MS than women at low risk, based on an omnibus test that globally assessed the burden of neurologic dysfunction by comparing the overall differences between the two groups. Impaired vibration perception yielded a stronger result; of 47 women (27 at high risk and 20 at low risk) tested in this manner, women at high risk showed significantly reduced vibration perception in the distal lower extremities.

One patient in the high-risk group converted to clinically definite MS during the study. Four of the women at high risk had T2-weighted hyperintense lesions that met the 2010 McDonald MRI criteria for dissemination in space, compared with one woman at low risk. Two women at high risk and one at low risk met the 2016 proposed consensus MRI criteria for MS diagnosis. In addition, radiologic isolated syndrome occurred in one woman from each group. Also, there was a single focus of leptomeningeal enhancement in three women at high risk and one woman at low risk.

Some limitations of this study include the small size, the lack of male participants, the cross-sectional design, and the fact that the vibration sensitivity thresholds were in the normal range for individuals at high risk and low risk. Researchers “plan to confirm the finding of change in vibration sensitivity with a follow-up study.” They added that the “study highlights the importantneed to develop and test more sensitive measures, particularly with biometric devices, to detect subtle subclinical changes early in the disease process.”

Identifying High-Risk Individuals

“The GEMS study represents the most ambitious effort yet to identify presymptomatic individuals who are at increased risk for MS, and it is a valuable first step toward targeted screening,” said Fredrik Piehl, MD, PhD, Professor of Neuroimmunology at Karolinska Institutet and Karolinska University Hospital in Stockholm, in an accompanying editorial. “Even if we cannot yet intervene therapeutically using currently available disease-modifying treatments in presymptomatic stages of MS, the ability to better define high-risk individuals is likely to make active surveillance programs more cost effective. It also provides important information to counsel individuals about lifestyle changes, such as quitting smoking. The GERS also can likely be further refined with more up-to-date data on the interaction between specific genetic and environmental factors,” he added. Dr. Piehl disclosed research support, travel grants, and other relationships with Biogen, Genzyme, Novartis, Merck, Roche, Serono, and Teva.

—Heidi Splete

Suggested Reading

Xia Z, Steele SU, Bakshi A, et al. Assessment of early evidence of multiple sclerosis in a prospective study of asymptomatic high-risk family members. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

Piehl F. Multiple sclerosis-a tuning fork still required. JAMA Neurol. 2017 Jan 17 [Epub ahead of print].

The stand-alone diphtheria, tetanus, acellular, pertussis and inactivated poliovirus combination vaccine – DTaP5-IPV – is equivalent as a fifth dose to the separate DTaP5 plus IPV vaccines in children aged 4-6 years, according to a noninferiority study.

In a phase III, controlled, open-label study, 3,372 children who had completed the 4-dose infant/toddler vaccination were randomized to DTaP5-IPV plus MMR and varicella virus (VZV) vaccines, DTaP5+IPV with MMR and VZV, DTaP5-IPV with/without MMR/VZV, or DTaP5+IPV with/without MMR/VZV.

Michael J. Smith, MD, MSCE, of the University of Louisville (Ky.) and coauthors saw significantly higher pertussis antibody levels for all antigens in the group who received the DTaP5-IPV plus MMR and VZV vaccines than in the group who received the DTaP5+IPV with MMR and VZV. Twenty-eight days after the vaccine was given, booster responses ranged from 95% to 97% for the DTaP5-IPV group and from 87% to 93% in the DTaP5+IPV group.

Similarly, the DTaP5-IPV vaccine showed noninferiority in the booster response for antitetanus, antidiphtheria, and antipoliovirus antibody levels (Pediatr Infect Dis J. 2017 Mar;36[3]:319-25).

“Overall, the levels of immune responses described in both treatment groups in the current study are above the levels described in the Swedish infant efficacy study, which demonstrated 85% protective efficacy against World Health Organization–defined pertussis disease,” the authors wrote. “Thus, it is reasonable to conclude that protective efficacy against pertussis will be achieved when either DTaP5-IPV or DTaP5+IPV is given as a booster dose to children 4-6 years of age.”

The two vaccines showed a similar safety profile. The rate of immediate, unsolicited, adverse systemic events was 0.9% in the DTaP5-IPV group and 1% in the DTaP5+IPV group, while the rate of immediate, unsolicited, adverse reactions was 0.1% in the DTaP5-IPV group and 0.2% in the DTaP5+IPV group.

Solicited reactions also were similar between the two groups: 93% of participants who received DTaP5-IPV and 92% of those who received DTaP5+IPV reported reactions such as myalgia, malaise, pain, erythema, and change in limb circumference.

“This is consistent with the established safety profile of DTaP5+IPV vaccine, based on 16 years of postmarketing surveillance and more than 7 million doses distributed,” the authors wrote.

There were also three serious adverse events in the DTaP5-IPV group within 28 days of the vaccination – lobular pneumonia, asthma, and new-onset type 1 diabetes mellitus – but the investigator decided these were unrelated to vaccination.

The study was sponsored by Sanofi Pasteur, which manufactures both vaccines. Three authors were employees of Sanofi Pasteur, and one author declared funding from Sanofi Pasteur to present the study results at a meeting.

[email protected]

The stand-alone diphtheria, tetanus, acellular, pertussis and inactivated poliovirus combination vaccine – DTaP5-IPV – is equivalent as a fifth dose to the separate DTaP5 plus IPV vaccines in children aged 4-6 years, according to a noninferiority study.

In a phase III, controlled, open-label study, 3,372 children who had completed the 4-dose infant/toddler vaccination were randomized to DTaP5-IPV plus MMR and varicella virus (VZV) vaccines, DTaP5+IPV with MMR and VZV, DTaP5-IPV with/without MMR/VZV, or DTaP5+IPV with/without MMR/VZV.

Michael J. Smith, MD, MSCE, of the University of Louisville (Ky.) and coauthors saw significantly higher pertussis antibody levels for all antigens in the group who received the DTaP5-IPV plus MMR and VZV vaccines than in the group who received the DTaP5+IPV with MMR and VZV. Twenty-eight days after the vaccine was given, booster responses ranged from 95% to 97% for the DTaP5-IPV group and from 87% to 93% in the DTaP5+IPV group.

Similarly, the DTaP5-IPV vaccine showed noninferiority in the booster response for antitetanus, antidiphtheria, and antipoliovirus antibody levels (Pediatr Infect Dis J. 2017 Mar;36[3]:319-25).

“Overall, the levels of immune responses described in both treatment groups in the current study are above the levels described in the Swedish infant efficacy study, which demonstrated 85% protective efficacy against World Health Organization–defined pertussis disease,” the authors wrote. “Thus, it is reasonable to conclude that protective efficacy against pertussis will be achieved when either DTaP5-IPV or DTaP5+IPV is given as a booster dose to children 4-6 years of age.”

The two vaccines showed a similar safety profile. The rate of immediate, unsolicited, adverse systemic events was 0.9% in the DTaP5-IPV group and 1% in the DTaP5+IPV group, while the rate of immediate, unsolicited, adverse reactions was 0.1% in the DTaP5-IPV group and 0.2% in the DTaP5+IPV group.

Solicited reactions also were similar between the two groups: 93% of participants who received DTaP5-IPV and 92% of those who received DTaP5+IPV reported reactions such as myalgia, malaise, pain, erythema, and change in limb circumference.

“This is consistent with the established safety profile of DTaP5+IPV vaccine, based on 16 years of postmarketing surveillance and more than 7 million doses distributed,” the authors wrote.

There were also three serious adverse events in the DTaP5-IPV group within 28 days of the vaccination – lobular pneumonia, asthma, and new-onset type 1 diabetes mellitus – but the investigator decided these were unrelated to vaccination.

The study was sponsored by Sanofi Pasteur, which manufactures both vaccines. Three authors were employees of Sanofi Pasteur, and one author declared funding from Sanofi Pasteur to present the study results at a meeting.

[email protected]

The stand-alone diphtheria, tetanus, acellular, pertussis and inactivated poliovirus combination vaccine – DTaP5-IPV – is equivalent as a fifth dose to the separate DTaP5 plus IPV vaccines in children aged 4-6 years, according to a noninferiority study.

In a phase III, controlled, open-label study, 3,372 children who had completed the 4-dose infant/toddler vaccination were randomized to DTaP5-IPV plus MMR and varicella virus (VZV) vaccines, DTaP5+IPV with MMR and VZV, DTaP5-IPV with/without MMR/VZV, or DTaP5+IPV with/without MMR/VZV.

Michael J. Smith, MD, MSCE, of the University of Louisville (Ky.) and coauthors saw significantly higher pertussis antibody levels for all antigens in the group who received the DTaP5-IPV plus MMR and VZV vaccines than in the group who received the DTaP5+IPV with MMR and VZV. Twenty-eight days after the vaccine was given, booster responses ranged from 95% to 97% for the DTaP5-IPV group and from 87% to 93% in the DTaP5+IPV group.

Similarly, the DTaP5-IPV vaccine showed noninferiority in the booster response for antitetanus, antidiphtheria, and antipoliovirus antibody levels (Pediatr Infect Dis J. 2017 Mar;36[3]:319-25).

“Overall, the levels of immune responses described in both treatment groups in the current study are above the levels described in the Swedish infant efficacy study, which demonstrated 85% protective efficacy against World Health Organization–defined pertussis disease,” the authors wrote. “Thus, it is reasonable to conclude that protective efficacy against pertussis will be achieved when either DTaP5-IPV or DTaP5+IPV is given as a booster dose to children 4-6 years of age.”

The two vaccines showed a similar safety profile. The rate of immediate, unsolicited, adverse systemic events was 0.9% in the DTaP5-IPV group and 1% in the DTaP5+IPV group, while the rate of immediate, unsolicited, adverse reactions was 0.1% in the DTaP5-IPV group and 0.2% in the DTaP5+IPV group.

Solicited reactions also were similar between the two groups: 93% of participants who received DTaP5-IPV and 92% of those who received DTaP5+IPV reported reactions such as myalgia, malaise, pain, erythema, and change in limb circumference.

“This is consistent with the established safety profile of DTaP5+IPV vaccine, based on 16 years of postmarketing surveillance and more than 7 million doses distributed,” the authors wrote.

There were also three serious adverse events in the DTaP5-IPV group within 28 days of the vaccination – lobular pneumonia, asthma, and new-onset type 1 diabetes mellitus – but the investigator decided these were unrelated to vaccination.

The study was sponsored by Sanofi Pasteur, which manufactures both vaccines. Three authors were employees of Sanofi Pasteur, and one author declared funding from Sanofi Pasteur to present the study results at a meeting.

[email protected]

The Advantages of Closed-Loop DBS

Closed-loop DBS has several advantages over conventional DBS, said Dr. Foote. It reduces the amount of labor-intensive programming required, which ordinarily is based on frequent symptom assessment. Furthermore, closed-loop DBS can adapt to the fluctuating symptoms and interpatient variability that often characterize movement disorders. The technique may reduce the frequency of stimulation-related adverse events, decrease the likelihood of habituation, and extend the stimulator’s battery life, thus reducing the number of replacement surgeries required. “It is the ultimate in patient-tailored treatment,” said Dr. Foote.

In the past 15 years, electrocorticography, the measurement of local field potentials, and mathematical decoding have increased understanding of the brain greatly and enabled researchers to identify biomarkers of disease. Investigators have observed that when a person moves, high-frequency band activity in the motor cortex increases, and low-frequency band (ie, beta band) activity decreases. Beta activity appears to be a suppressive mechanism that gates motor function. These observations have been the basis for recent research in closed-loop DBS for Parkinson’s disease.

Tourette Syndrome

Dr. Foote and his colleagues are studying closed-loop DBS in patients with Tourette syndrome. They believed that the episodic nature of the syndrome’s symptoms would make closed-loop DBS a potentially beneficial treatment. The group hypothesized that if they could find a signal for the premonitory urge that patients generally have before a tic, they could deliver therapeutic stimulation as needed. They decided to target the centromedian (CM) nucleus of the thalamus for stimulation.

When Dr. Foote and colleagues failed to find a biomarker to predict tic onset, they decided to study intermittent stimulation using the NeuroPace system. Scheduled stimulation yielded statistically significant improvements in the Yale Global Tic Severity Scale total score, although they did not reach the prespecified outcome of a 50% improvement. The participant who received the most stimulation had the least improvement.

After this study was completed, the Medtronic PC+S system became available. This system has a longer battery life and improved hardware, compared with the NeuroPace system, said Dr. Foote. Using the PC+S system, he and his colleagues implanted two 24-year-old women with severe, intractable Tourette syndrome with 16 bilateral DBS electrodes on the CM thalamus. The patients also received cortical strips on both sides of the premotor cortex and motor cortex. The investigators found high levels of activity in the CM thalamus during tics, but no activity in that region during voluntary movement. The finding provides “strong evidence that the CM thalamus is participating in that pathologic network,” said Dr. Foote.

Engineers collaborating with Dr. Foote’s group used measurements of local field potentials in the CM thalamus and motor cortex to create a device that detects tics. The detector has a sensitivity of approximately 90% and a precision of 96%. When the investigators implanted the tic detector in one of the patients with Tourette syndrome who had received implantation of the NeuroPace device, it successfully initiated and terminated responsive DBS and reduced the patient’s tics.

Parkinson’s Disease

Investigators have found exaggerated phase amplitude coupling and increased beta activity in the subthalamic nucleus (STN), globus pallidus internus, and primary motor cortex of patients with Parkinson’s disease. In addition, data suggest that STN beta power correlates with the severity of bradykinesia and rigidity. Originally, researchers hypothesized that DBS provided benefit to patients with Parkinson’s disease by decreasing beta activity. A 2015 study by de Hemptinne et al, however, indicated that the main mechanism of action of DBS is disruption of phase amplitude coupling.

Patients with Tourette syndrome have the opposite problem, compared with patients with Parkinson’s disease. Therapeutic DBS reduces excessive movement in Tourette syndrome by increasing phase amplitude coupling, which is low at baseline. “We are helping [patients with Tourette syndrome] apply the brakes, because … they are failing to suppress these extra movements,” said Dr. Foote.

The tic detector has enabled the first chronic closed-loop DBS treatment for movement disorders, but many more such applications will emerge in the near future, he added. Research has suggested that phase amplitude coupling is a better biomarker in movement disorders than beta activity is. Dr. Foote and his colleagues are studying closed-loop DBS in essential tremor, and other researchers around the world are examining the treatment for Parkinson’s disease, Tourette syndrome, and obsessive–compulsive disorder.

“All DBS will be adaptive in the relatively near future,” concluded Dr. Foote. “It is just more intelligent to do it this way.”

—Erik Greb

Suggested Reading

Air EL, Ryapolova-Webb E, de Hemptinne C, et al. Acute effects of thalamic deep brain stimulation and thalamotomy on sensorimotor cortex local field potentials in essential tremor. Clin Neurophysiol. 2012;123(11):2232-2238.

de Hemptinne C, Swann NC, Ostrem JL, et al. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson’s disease. Nat Neurosci. 2015;18(5): 779-786.

Miller KJ, Hermes D, Honey CJ, et al. Human motor cortical activity is selectively phase-entrained on underlying rhythms. PLoS Comput Biol. 2012;8(9):e1002655.

Okun MS, Foote KD, Wu SS, et al. A trial of scheduled deep brain stimulation for Tourette syndrome: moving away from continuous deep brain stimulation paradigms. JAMA Neurol. 2013;70(1):85-94.

The Advantages of Closed-Loop DBS

Closed-loop DBS has several advantages over conventional DBS, said Dr. Foote. It reduces the amount of labor-intensive programming required, which ordinarily is based on frequent symptom assessment. Furthermore, closed-loop DBS can adapt to the fluctuating symptoms and interpatient variability that often characterize movement disorders. The technique may reduce the frequency of stimulation-related adverse events, decrease the likelihood of habituation, and extend the stimulator’s battery life, thus reducing the number of replacement surgeries required. “It is the ultimate in patient-tailored treatment,” said Dr. Foote.

In the past 15 years, electrocorticography, the measurement of local field potentials, and mathematical decoding have increased understanding of the brain greatly and enabled researchers to identify biomarkers of disease. Investigators have observed that when a person moves, high-frequency band activity in the motor cortex increases, and low-frequency band (ie, beta band) activity decreases. Beta activity appears to be a suppressive mechanism that gates motor function. These observations have been the basis for recent research in closed-loop DBS for Parkinson’s disease.

Tourette Syndrome

Dr. Foote and his colleagues are studying closed-loop DBS in patients with Tourette syndrome. They believed that the episodic nature of the syndrome’s symptoms would make closed-loop DBS a potentially beneficial treatment. The group hypothesized that if they could find a signal for the premonitory urge that patients generally have before a tic, they could deliver therapeutic stimulation as needed. They decided to target the centromedian (CM) nucleus of the thalamus for stimulation.

When Dr. Foote and colleagues failed to find a biomarker to predict tic onset, they decided to study intermittent stimulation using the NeuroPace system. Scheduled stimulation yielded statistically significant improvements in the Yale Global Tic Severity Scale total score, although they did not reach the prespecified outcome of a 50% improvement. The participant who received the most stimulation had the least improvement.

After this study was completed, the Medtronic PC+S system became available. This system has a longer battery life and improved hardware, compared with the NeuroPace system, said Dr. Foote. Using the PC+S system, he and his colleagues implanted two 24-year-old women with severe, intractable Tourette syndrome with 16 bilateral DBS electrodes on the CM thalamus. The patients also received cortical strips on both sides of the premotor cortex and motor cortex. The investigators found high levels of activity in the CM thalamus during tics, but no activity in that region during voluntary movement. The finding provides “strong evidence that the CM thalamus is participating in that pathologic network,” said Dr. Foote.

Engineers collaborating with Dr. Foote’s group used measurements of local field potentials in the CM thalamus and motor cortex to create a device that detects tics. The detector has a sensitivity of approximately 90% and a precision of 96%. When the investigators implanted the tic detector in one of the patients with Tourette syndrome who had received implantation of the NeuroPace device, it successfully initiated and terminated responsive DBS and reduced the patient’s tics.

Parkinson’s Disease

Investigators have found exaggerated phase amplitude coupling and increased beta activity in the subthalamic nucleus (STN), globus pallidus internus, and primary motor cortex of patients with Parkinson’s disease. In addition, data suggest that STN beta power correlates with the severity of bradykinesia and rigidity. Originally, researchers hypothesized that DBS provided benefit to patients with Parkinson’s disease by decreasing beta activity. A 2015 study by de Hemptinne et al, however, indicated that the main mechanism of action of DBS is disruption of phase amplitude coupling.

Patients with Tourette syndrome have the opposite problem, compared with patients with Parkinson’s disease. Therapeutic DBS reduces excessive movement in Tourette syndrome by increasing phase amplitude coupling, which is low at baseline. “We are helping [patients with Tourette syndrome] apply the brakes, because … they are failing to suppress these extra movements,” said Dr. Foote.

The tic detector has enabled the first chronic closed-loop DBS treatment for movement disorders, but many more such applications will emerge in the near future, he added. Research has suggested that phase amplitude coupling is a better biomarker in movement disorders than beta activity is. Dr. Foote and his colleagues are studying closed-loop DBS in essential tremor, and other researchers around the world are examining the treatment for Parkinson’s disease, Tourette syndrome, and obsessive–compulsive disorder.

“All DBS will be adaptive in the relatively near future,” concluded Dr. Foote. “It is just more intelligent to do it this way.”

—Erik Greb

Suggested Reading

Air EL, Ryapolova-Webb E, de Hemptinne C, et al. Acute effects of thalamic deep brain stimulation and thalamotomy on sensorimotor cortex local field potentials in essential tremor. Clin Neurophysiol. 2012;123(11):2232-2238.

de Hemptinne C, Swann NC, Ostrem JL, et al. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson’s disease. Nat Neurosci. 2015;18(5): 779-786.

Miller KJ, Hermes D, Honey CJ, et al. Human motor cortical activity is selectively phase-entrained on underlying rhythms. PLoS Comput Biol. 2012;8(9):e1002655.

Okun MS, Foote KD, Wu SS, et al. A trial of scheduled deep brain stimulation for Tourette syndrome: moving away from continuous deep brain stimulation paradigms. JAMA Neurol. 2013;70(1):85-94.

The Advantages of Closed-Loop DBS

Closed-loop DBS has several advantages over conventional DBS, said Dr. Foote. It reduces the amount of labor-intensive programming required, which ordinarily is based on frequent symptom assessment. Furthermore, closed-loop DBS can adapt to the fluctuating symptoms and interpatient variability that often characterize movement disorders. The technique may reduce the frequency of stimulation-related adverse events, decrease the likelihood of habituation, and extend the stimulator’s battery life, thus reducing the number of replacement surgeries required. “It is the ultimate in patient-tailored treatment,” said Dr. Foote.

In the past 15 years, electrocorticography, the measurement of local field potentials, and mathematical decoding have increased understanding of the brain greatly and enabled researchers to identify biomarkers of disease. Investigators have observed that when a person moves, high-frequency band activity in the motor cortex increases, and low-frequency band (ie, beta band) activity decreases. Beta activity appears to be a suppressive mechanism that gates motor function. These observations have been the basis for recent research in closed-loop DBS for Parkinson’s disease.

Tourette Syndrome

Dr. Foote and his colleagues are studying closed-loop DBS in patients with Tourette syndrome. They believed that the episodic nature of the syndrome’s symptoms would make closed-loop DBS a potentially beneficial treatment. The group hypothesized that if they could find a signal for the premonitory urge that patients generally have before a tic, they could deliver therapeutic stimulation as needed. They decided to target the centromedian (CM) nucleus of the thalamus for stimulation.

When Dr. Foote and colleagues failed to find a biomarker to predict tic onset, they decided to study intermittent stimulation using the NeuroPace system. Scheduled stimulation yielded statistically significant improvements in the Yale Global Tic Severity Scale total score, although they did not reach the prespecified outcome of a 50% improvement. The participant who received the most stimulation had the least improvement.

After this study was completed, the Medtronic PC+S system became available. This system has a longer battery life and improved hardware, compared with the NeuroPace system, said Dr. Foote. Using the PC+S system, he and his colleagues implanted two 24-year-old women with severe, intractable Tourette syndrome with 16 bilateral DBS electrodes on the CM thalamus. The patients also received cortical strips on both sides of the premotor cortex and motor cortex. The investigators found high levels of activity in the CM thalamus during tics, but no activity in that region during voluntary movement. The finding provides “strong evidence that the CM thalamus is participating in that pathologic network,” said Dr. Foote.

Engineers collaborating with Dr. Foote’s group used measurements of local field potentials in the CM thalamus and motor cortex to create a device that detects tics. The detector has a sensitivity of approximately 90% and a precision of 96%. When the investigators implanted the tic detector in one of the patients with Tourette syndrome who had received implantation of the NeuroPace device, it successfully initiated and terminated responsive DBS and reduced the patient’s tics.

Parkinson’s Disease

Investigators have found exaggerated phase amplitude coupling and increased beta activity in the subthalamic nucleus (STN), globus pallidus internus, and primary motor cortex of patients with Parkinson’s disease. In addition, data suggest that STN beta power correlates with the severity of bradykinesia and rigidity. Originally, researchers hypothesized that DBS provided benefit to patients with Parkinson’s disease by decreasing beta activity. A 2015 study by de Hemptinne et al, however, indicated that the main mechanism of action of DBS is disruption of phase amplitude coupling.

Patients with Tourette syndrome have the opposite problem, compared with patients with Parkinson’s disease. Therapeutic DBS reduces excessive movement in Tourette syndrome by increasing phase amplitude coupling, which is low at baseline. “We are helping [patients with Tourette syndrome] apply the brakes, because … they are failing to suppress these extra movements,” said Dr. Foote.

The tic detector has enabled the first chronic closed-loop DBS treatment for movement disorders, but many more such applications will emerge in the near future, he added. Research has suggested that phase amplitude coupling is a better biomarker in movement disorders than beta activity is. Dr. Foote and his colleagues are studying closed-loop DBS in essential tremor, and other researchers around the world are examining the treatment for Parkinson’s disease, Tourette syndrome, and obsessive–compulsive disorder.

“All DBS will be adaptive in the relatively near future,” concluded Dr. Foote. “It is just more intelligent to do it this way.”

—Erik Greb

Suggested Reading

Air EL, Ryapolova-Webb E, de Hemptinne C, et al. Acute effects of thalamic deep brain stimulation and thalamotomy on sensorimotor cortex local field potentials in essential tremor. Clin Neurophysiol. 2012;123(11):2232-2238.

de Hemptinne C, Swann NC, Ostrem JL, et al. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson’s disease. Nat Neurosci. 2015;18(5): 779-786.

Miller KJ, Hermes D, Honey CJ, et al. Human motor cortical activity is selectively phase-entrained on underlying rhythms. PLoS Comput Biol. 2012;8(9):e1002655.

Okun MS, Foote KD, Wu SS, et al. A trial of scheduled deep brain stimulation for Tourette syndrome: moving away from continuous deep brain stimulation paradigms. JAMA Neurol. 2013;70(1):85-94.