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Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

Stroke is a strong independent risk factor for all-cause dementia, according to research published online ahead of print August 25 in Alzheimer’s & Dementia. Clinicians should incorporate stroke-prevention strategies into their health interventions to reduce patients’ risk of dementia, said the authors.

“Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke,” said David Llewellyn, PhD, Senior Research Fellow at University of Exeter Medical School in the United Kingdom. “Our findings indicate that this figure could be even higher and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia.”

Meta-Analysis of Previous Research

Stroke is a recognized risk factor for all-cause dementia, but no researchers had previously performed a meta-analysis to quantify the risk. Dr. Llewellyn and colleagues searched Medline, PsycINFO, and Embase databases for prospective studies that investigated the association between prevalent or incident stroke and incident all-cause dementia. They excluded studies that lacked a comparison group or that had a comparison group other than a stroke-free group. The investigators pooled adjusted estimates across studies using random effects meta-analysis and evaluated potential effect modifiers with meta-regression.

Dr. Llewellyn and colleagues identified 11,129 articles, 26 of which were eligible for analysis. They also included 16 studies from a previous systematic review and four studies identified through backward and forward citation searches. In all, 36 studies examined prevalent stroke (1.9 million participants), and 12 studies examined incident stroke (1.3 million participants). The studies were conducted in America, Europe, Asia, and Australia and included more than three million participants. Follow-up periods ranged from nine months to 25 years.

Stroke Affected Dementia Risk

When the researchers pooled results from 22 cohorts of participants who were cognitively normal at baseline, they found that those with prevalent stroke had a higher adjusted risk of incident dementia, compared with those without stroke (hazard ratio [HR], 1.69). Sensitivity analyses did not change the results significantly. Prevalent stroke was associated with a higher risk of incident dementia among men than among women. Sex explained 50.2% of heterogeneity between studies for prevalent stroke.

After combining the adjusted results from eight studies, Dr. Llewellyn and colleagues found that incident stroke more than doubled the risk of incident all-cause dementia, compared with no incident stroke (risk ratio [RR], 2.18). For a sensitivity analysis, the investigators excluded three studies that combined stroke with transient ischemic attack; this adjustment strengthened the association.

The study’s strengths include the investigators’ search of several major databases and their contacts with authors who provided relevant data. The analysis reflects the limitations of the original studies, however. These limitations include selective samples and differences in stroke assessment and dementia diagnosis criteria. In addition, dementia may develop years before it is diagnosed. “More detailed reporting of the interval between stroke occurrence and dementia diagnosis in future studies will help to better characterize the role of time since stroke in the risk of dementia,” said Dr. Llewellyn.

—Erik Greb

Suggested Reading

Kuz´ma E, Lourida I, Moore SF, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement. 2018 Aug 25 [Epub ahead of print].

A new system that incorporates clinical and serologic data may help classify idiopathic inflammatory myopathies, according to an analysis published online ahead of print September 10 in JAMA Neurology.

By analyzing the patterns of relationships between 47 variables in this observational, retrospective cohort study, investigators identified four clusters of patients that corresponded to known subtypes of idiopathic inflammatory myopathy. Myositis-specific autoantibodies played a key role in predicting whether a patient belonged in a given cluster, according to the investigators. Myositis-specific antibodies known to be associated with certain subgroups were observed in the corresponding clusters that the researchers identified.

“This [finding] emphasizes that muscle biopsy may no longer be necessary for diagnosis of idiopathic inflammatory myopathies in patients with myositis-specific antibodies and corresponding phenotypes,” said Kubéraka Mariampillai, PhD, of the Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris, and colleagues.

The study was based on data for 260 patients in the database of the French Myositis Network. Patients’ mean age was 60, and 63% were women.

Investigators conducted a multiple correspondence analysis based on 47 selected variables, including age, ethnicity, historical and recent diagnoses, dermatologic changes, creatine kinase levels, myositis-specific antibodies, and pathologic characteristics. They identified four subgroups of patients corresponding to dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome.

Using decisional algorithm trees, investigators found that the pathologic data were “dispensable,” said the authors. The best tree omitted variables related to muscle biopsy and had a 78% correct estimation based on antisynthetase syndrome antibodies, dermatomyositis rash, and finger flexor scores of 3 or less, said the investigators. “The classification quality of the tree was appreciated on the basis of all classification criteria, with an overall sensitivity of 77.0% and a specificity of 92.0%.”

Patients with polymyositis were included in the study, but were grouped mainly in the clusters corresponding to immune-mediated necrotizing myopathy and antisynthetase syndrome. “This finding indicates that patients with polymyositis do not represent a subgroup of patients, and use of this term should probably be discontinued,” Dr. Mariampillai and colleagues concluded.

—Andrew D. Bowser

Suggested Reading

Mariampillai K, Granger B, Amelin D, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol. 2018 Sep 10 [Epub ahead of print].

A new system that incorporates clinical and serologic data may help classify idiopathic inflammatory myopathies, according to an analysis published online ahead of print September 10 in JAMA Neurology.

By analyzing the patterns of relationships between 47 variables in this observational, retrospective cohort study, investigators identified four clusters of patients that corresponded to known subtypes of idiopathic inflammatory myopathy. Myositis-specific autoantibodies played a key role in predicting whether a patient belonged in a given cluster, according to the investigators. Myositis-specific antibodies known to be associated with certain subgroups were observed in the corresponding clusters that the researchers identified.

“This [finding] emphasizes that muscle biopsy may no longer be necessary for diagnosis of idiopathic inflammatory myopathies in patients with myositis-specific antibodies and corresponding phenotypes,” said Kubéraka Mariampillai, PhD, of the Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris, and colleagues.

The study was based on data for 260 patients in the database of the French Myositis Network. Patients’ mean age was 60, and 63% were women.

Investigators conducted a multiple correspondence analysis based on 47 selected variables, including age, ethnicity, historical and recent diagnoses, dermatologic changes, creatine kinase levels, myositis-specific antibodies, and pathologic characteristics. They identified four subgroups of patients corresponding to dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome.

Using decisional algorithm trees, investigators found that the pathologic data were “dispensable,” said the authors. The best tree omitted variables related to muscle biopsy and had a 78% correct estimation based on antisynthetase syndrome antibodies, dermatomyositis rash, and finger flexor scores of 3 or less, said the investigators. “The classification quality of the tree was appreciated on the basis of all classification criteria, with an overall sensitivity of 77.0% and a specificity of 92.0%.”

Patients with polymyositis were included in the study, but were grouped mainly in the clusters corresponding to immune-mediated necrotizing myopathy and antisynthetase syndrome. “This finding indicates that patients with polymyositis do not represent a subgroup of patients, and use of this term should probably be discontinued,” Dr. Mariampillai and colleagues concluded.

—Andrew D. Bowser

Suggested Reading

Mariampillai K, Granger B, Amelin D, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol. 2018 Sep 10 [Epub ahead of print].

A new system that incorporates clinical and serologic data may help classify idiopathic inflammatory myopathies, according to an analysis published online ahead of print September 10 in JAMA Neurology.

By analyzing the patterns of relationships between 47 variables in this observational, retrospective cohort study, investigators identified four clusters of patients that corresponded to known subtypes of idiopathic inflammatory myopathy. Myositis-specific autoantibodies played a key role in predicting whether a patient belonged in a given cluster, according to the investigators. Myositis-specific antibodies known to be associated with certain subgroups were observed in the corresponding clusters that the researchers identified.

“This [finding] emphasizes that muscle biopsy may no longer be necessary for diagnosis of idiopathic inflammatory myopathies in patients with myositis-specific antibodies and corresponding phenotypes,” said Kubéraka Mariampillai, PhD, of the Université Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris, and colleagues.

The study was based on data for 260 patients in the database of the French Myositis Network. Patients’ mean age was 60, and 63% were women.

Investigators conducted a multiple correspondence analysis based on 47 selected variables, including age, ethnicity, historical and recent diagnoses, dermatologic changes, creatine kinase levels, myositis-specific antibodies, and pathologic characteristics. They identified four subgroups of patients corresponding to dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome.

Using decisional algorithm trees, investigators found that the pathologic data were “dispensable,” said the authors. The best tree omitted variables related to muscle biopsy and had a 78% correct estimation based on antisynthetase syndrome antibodies, dermatomyositis rash, and finger flexor scores of 3 or less, said the investigators. “The classification quality of the tree was appreciated on the basis of all classification criteria, with an overall sensitivity of 77.0% and a specificity of 92.0%.”

Patients with polymyositis were included in the study, but were grouped mainly in the clusters corresponding to immune-mediated necrotizing myopathy and antisynthetase syndrome. “This finding indicates that patients with polymyositis do not represent a subgroup of patients, and use of this term should probably be discontinued,” Dr. Mariampillai and colleagues concluded.

—Andrew D. Bowser

Suggested Reading

Mariampillai K, Granger B, Amelin D, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurol. 2018 Sep 10 [Epub ahead of print].

Subcutaneous apomorphine infusion significantly reduces off time in patients with Parkinson’s disease and inadequately controlled motor fluctuations, according to data published in the September issue of Lancet Neurology. The data result from the first randomized controlled trial of apomorphine in this population.

In 1988, an open-label study indicated that apomorphine had antiparkinsonian efficacy equivalent to that of levodopa. Several uncontrolled studies have indicated that it effectively reduces off time, improves dyskinesias, and allows doses of oral levodopa to be decreased.

A Multicenter European Study

Regina Katzenschlager, MD, a neurologist at Danube Hospital in Vienna, and colleagues investigated the safety and efficacy of apomorphine infusion in a randomized, placebo-controlled, double-blind trial. They enrolled patients at 23 European hospitals who had received a diagnosis of Parkinson’s disease more than three years previously and had motor fluctuations that were inadequately controlled. Patients were randomized in equal groups to 3–8-mg/h infusions of apomorphine or saline for approximately 16 h/day. The treatment period lasted for 12 weeks. During the first four weeks, investigators adjusted the dose according to efficacy and tolerability, and the remaining eight weeks were a maintenance period.

Patients completed home diary assessments of motor status and visited the hospital for regular evaluations. The study’s primary end point was the absolute change in off time from baseline to 12 weeks, based on diary assessments. Secondary end points included response to therapy (ie, a reduction in off time of at least two hours from baseline), absolute change in on time without troublesome dyskinesia, Patient Global Impression of Change (PGIC) score, change in levodopa dose, change in motor score, and change in quality of life.

Results Were Consistent in Prespecified Subgroups

A total of 53 patients were randomized to apomorphine, and 54 patients were randomized to placebo. The mean final dose of study drug was 4.68 mg/h in the apomorphine group and 5.76 mg/h in the placebo group.

Mean reduction in off time was significantly greater at week 12 in the apomorphine group (−2.47 h/day) than among controls (−0.58 h/day). The results were consistent in sensitivity analyses. Approximately 62% of patients in the apomorphine group responded to therapy, compared with 29% of controls.

Mean on time without troublesome dyskinesia was significantly increased in the apomorphine group (2.77 h/day), compared with the placebo group (0.80 h/day). Apomorphine also improved PGIC scores significantly at 12 weeks, compared with placebo. Mean reduction in oral levodopa dose was greater in the apomorphine group, but the difference between groups was not statistically significant. Changes in motor score and quality of life were not significantly different between groups at 12 weeks.

The treatment was well tolerated, and the researchers found no unexpected safety signals. The rate of treatment-emergent adverse events was 93% in the apomorphine group and 57% among controls. The most common adverse events were skin reactions, nausea, and somnolence. Six patients had an adverse event that prompted study withdrawal; all were in the apomorphine group. Five patients in the apomorphine group had serious adverse events, including severe hypotension, myocardial infarction, and persistently abnormal hematology test results indicating mild leukopenia and moderate anemia.

“From a practical viewpoint, our study shows that some patients tolerate and receive benefit from doses exceeding the common range of hourly flow rates currently used in practice,” said the authors. “Many centers use higher flow rates than the mean dose in our study, and it is possible that the full potential of apomorphine has not been investigated here.”

How Effective Would Apomorphine Monotherapy Be?

The findings of Dr. Katzenschlager and colleagues “should help guide clinicians in making decisions about management of patients with advanced Parkinson’s disease, particularly when considering use of deep brain stimulation or intestinal infusion of levodopa–carbidopa gel,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan, in an accompanying editorial. “In view of its efficacy and safety profile, apomorphine infusion should be considered before embarking on other invasive therapies.”

On average, apomorphine infusion decreased off time by approximately one-third from patients’ baseline levels. “One might ask why the study did not achieve better results,” said Dr. LeWitt. A potential explanation is that impaired brain circuitry in patients with advanced Parkinson’s disease loses its long-term response to levodopa and is associated with dyskinesias and freezing of gait, he added. It also is possible that participants’ medical treatment had not been optimized at baseline.

“Despite a heavy load of levodopa and adjunctive medications (most participants in the study also received dopaminergic agonists, and inhibitors of catechol-O-methyltransferase and monoamine oxidase type B were used liberally), many patients continue to be burdened by substantial daily off time fluctuations,” said Dr. LeWitt. “A final question unanswered by this study is the effectiveness of apomorphine monotherapy, which has been previously tested in only a few studies. Future studies might investigate this question and what benefit, if any, is offered by concomitant levodopa treatment.”

—Erik Greb

Suggested Reading

Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759.

LeWitt PA. At last, a randomised controlled trial of apomorphine infusion. Lancet Neurol. 2018;17(9):732-733.

Subcutaneous apomorphine infusion significantly reduces off time in patients with Parkinson’s disease and inadequately controlled motor fluctuations, according to data published in the September issue of Lancet Neurology. The data result from the first randomized controlled trial of apomorphine in this population.

In 1988, an open-label study indicated that apomorphine had antiparkinsonian efficacy equivalent to that of levodopa. Several uncontrolled studies have indicated that it effectively reduces off time, improves dyskinesias, and allows doses of oral levodopa to be decreased.

A Multicenter European Study

Regina Katzenschlager, MD, a neurologist at Danube Hospital in Vienna, and colleagues investigated the safety and efficacy of apomorphine infusion in a randomized, placebo-controlled, double-blind trial. They enrolled patients at 23 European hospitals who had received a diagnosis of Parkinson’s disease more than three years previously and had motor fluctuations that were inadequately controlled. Patients were randomized in equal groups to 3–8-mg/h infusions of apomorphine or saline for approximately 16 h/day. The treatment period lasted for 12 weeks. During the first four weeks, investigators adjusted the dose according to efficacy and tolerability, and the remaining eight weeks were a maintenance period.

Patients completed home diary assessments of motor status and visited the hospital for regular evaluations. The study’s primary end point was the absolute change in off time from baseline to 12 weeks, based on diary assessments. Secondary end points included response to therapy (ie, a reduction in off time of at least two hours from baseline), absolute change in on time without troublesome dyskinesia, Patient Global Impression of Change (PGIC) score, change in levodopa dose, change in motor score, and change in quality of life.

Results Were Consistent in Prespecified Subgroups

A total of 53 patients were randomized to apomorphine, and 54 patients were randomized to placebo. The mean final dose of study drug was 4.68 mg/h in the apomorphine group and 5.76 mg/h in the placebo group.

Mean reduction in off time was significantly greater at week 12 in the apomorphine group (−2.47 h/day) than among controls (−0.58 h/day). The results were consistent in sensitivity analyses. Approximately 62% of patients in the apomorphine group responded to therapy, compared with 29% of controls.

Mean on time without troublesome dyskinesia was significantly increased in the apomorphine group (2.77 h/day), compared with the placebo group (0.80 h/day). Apomorphine also improved PGIC scores significantly at 12 weeks, compared with placebo. Mean reduction in oral levodopa dose was greater in the apomorphine group, but the difference between groups was not statistically significant. Changes in motor score and quality of life were not significantly different between groups at 12 weeks.

The treatment was well tolerated, and the researchers found no unexpected safety signals. The rate of treatment-emergent adverse events was 93% in the apomorphine group and 57% among controls. The most common adverse events were skin reactions, nausea, and somnolence. Six patients had an adverse event that prompted study withdrawal; all were in the apomorphine group. Five patients in the apomorphine group had serious adverse events, including severe hypotension, myocardial infarction, and persistently abnormal hematology test results indicating mild leukopenia and moderate anemia.

“From a practical viewpoint, our study shows that some patients tolerate and receive benefit from doses exceeding the common range of hourly flow rates currently used in practice,” said the authors. “Many centers use higher flow rates than the mean dose in our study, and it is possible that the full potential of apomorphine has not been investigated here.”

How Effective Would Apomorphine Monotherapy Be?

The findings of Dr. Katzenschlager and colleagues “should help guide clinicians in making decisions about management of patients with advanced Parkinson’s disease, particularly when considering use of deep brain stimulation or intestinal infusion of levodopa–carbidopa gel,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan, in an accompanying editorial. “In view of its efficacy and safety profile, apomorphine infusion should be considered before embarking on other invasive therapies.”

On average, apomorphine infusion decreased off time by approximately one-third from patients’ baseline levels. “One might ask why the study did not achieve better results,” said Dr. LeWitt. A potential explanation is that impaired brain circuitry in patients with advanced Parkinson’s disease loses its long-term response to levodopa and is associated with dyskinesias and freezing of gait, he added. It also is possible that participants’ medical treatment had not been optimized at baseline.

“Despite a heavy load of levodopa and adjunctive medications (most participants in the study also received dopaminergic agonists, and inhibitors of catechol-O-methyltransferase and monoamine oxidase type B were used liberally), many patients continue to be burdened by substantial daily off time fluctuations,” said Dr. LeWitt. “A final question unanswered by this study is the effectiveness of apomorphine monotherapy, which has been previously tested in only a few studies. Future studies might investigate this question and what benefit, if any, is offered by concomitant levodopa treatment.”

—Erik Greb

Suggested Reading

Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759.

LeWitt PA. At last, a randomised controlled trial of apomorphine infusion. Lancet Neurol. 2018;17(9):732-733.

Subcutaneous apomorphine infusion significantly reduces off time in patients with Parkinson’s disease and inadequately controlled motor fluctuations, according to data published in the September issue of Lancet Neurology. The data result from the first randomized controlled trial of apomorphine in this population.

In 1988, an open-label study indicated that apomorphine had antiparkinsonian efficacy equivalent to that of levodopa. Several uncontrolled studies have indicated that it effectively reduces off time, improves dyskinesias, and allows doses of oral levodopa to be decreased.

A Multicenter European Study

Regina Katzenschlager, MD, a neurologist at Danube Hospital in Vienna, and colleagues investigated the safety and efficacy of apomorphine infusion in a randomized, placebo-controlled, double-blind trial. They enrolled patients at 23 European hospitals who had received a diagnosis of Parkinson’s disease more than three years previously and had motor fluctuations that were inadequately controlled. Patients were randomized in equal groups to 3–8-mg/h infusions of apomorphine or saline for approximately 16 h/day. The treatment period lasted for 12 weeks. During the first four weeks, investigators adjusted the dose according to efficacy and tolerability, and the remaining eight weeks were a maintenance period.

Patients completed home diary assessments of motor status and visited the hospital for regular evaluations. The study’s primary end point was the absolute change in off time from baseline to 12 weeks, based on diary assessments. Secondary end points included response to therapy (ie, a reduction in off time of at least two hours from baseline), absolute change in on time without troublesome dyskinesia, Patient Global Impression of Change (PGIC) score, change in levodopa dose, change in motor score, and change in quality of life.

Results Were Consistent in Prespecified Subgroups

A total of 53 patients were randomized to apomorphine, and 54 patients were randomized to placebo. The mean final dose of study drug was 4.68 mg/h in the apomorphine group and 5.76 mg/h in the placebo group.

Mean reduction in off time was significantly greater at week 12 in the apomorphine group (−2.47 h/day) than among controls (−0.58 h/day). The results were consistent in sensitivity analyses. Approximately 62% of patients in the apomorphine group responded to therapy, compared with 29% of controls.

Mean on time without troublesome dyskinesia was significantly increased in the apomorphine group (2.77 h/day), compared with the placebo group (0.80 h/day). Apomorphine also improved PGIC scores significantly at 12 weeks, compared with placebo. Mean reduction in oral levodopa dose was greater in the apomorphine group, but the difference between groups was not statistically significant. Changes in motor score and quality of life were not significantly different between groups at 12 weeks.

The treatment was well tolerated, and the researchers found no unexpected safety signals. The rate of treatment-emergent adverse events was 93% in the apomorphine group and 57% among controls. The most common adverse events were skin reactions, nausea, and somnolence. Six patients had an adverse event that prompted study withdrawal; all were in the apomorphine group. Five patients in the apomorphine group had serious adverse events, including severe hypotension, myocardial infarction, and persistently abnormal hematology test results indicating mild leukopenia and moderate anemia.

“From a practical viewpoint, our study shows that some patients tolerate and receive benefit from doses exceeding the common range of hourly flow rates currently used in practice,” said the authors. “Many centers use higher flow rates than the mean dose in our study, and it is possible that the full potential of apomorphine has not been investigated here.”

How Effective Would Apomorphine Monotherapy Be?

The findings of Dr. Katzenschlager and colleagues “should help guide clinicians in making decisions about management of patients with advanced Parkinson’s disease, particularly when considering use of deep brain stimulation or intestinal infusion of levodopa–carbidopa gel,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan, in an accompanying editorial. “In view of its efficacy and safety profile, apomorphine infusion should be considered before embarking on other invasive therapies.”

On average, apomorphine infusion decreased off time by approximately one-third from patients’ baseline levels. “One might ask why the study did not achieve better results,” said Dr. LeWitt. A potential explanation is that impaired brain circuitry in patients with advanced Parkinson’s disease loses its long-term response to levodopa and is associated with dyskinesias and freezing of gait, he added. It also is possible that participants’ medical treatment had not been optimized at baseline.

“Despite a heavy load of levodopa and adjunctive medications (most participants in the study also received dopaminergic agonists, and inhibitors of catechol-O-methyltransferase and monoamine oxidase type B were used liberally), many patients continue to be burdened by substantial daily off time fluctuations,” said Dr. LeWitt. “A final question unanswered by this study is the effectiveness of apomorphine monotherapy, which has been previously tested in only a few studies. Future studies might investigate this question and what benefit, if any, is offered by concomitant levodopa treatment.”

—Erik Greb

Suggested Reading

Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759.

LeWitt PA. At last, a randomised controlled trial of apomorphine infusion. Lancet Neurol. 2018;17(9):732-733.

Fremanezumab increases the number of headache-free days with normal function for patients with episodic or chronic migraine, according to post hoc analyses published online ahead of print August 17 in Neurology. Fremanezumab appears to improve all measures of function in patients with episodic migraine, and some measures in patients with chronic migraine.

“The results should be considered exploratory,” said Juliana VanderPluym, MD, a neurologist at Mayo Clinic in Phoenix, and colleagues. “Further research is needed to confirm these preliminary findings and to understand the factors contributing to perceived functional status on headache-free days.”

Examining Two Phase II Trials

Fremanezumab is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP). Dr. VanderPluym and colleagues analyzed data from randomized, double-blind phase II trials of the therapy for prevention of high-frequency episodic migraine (ie, eight to 14 headache days per month) and chronic migraine. Patients with high-frequency episodic migraine received placebo or monthly subcutaneous fremanezumab injections of 225 mg or 675 mg. Patients with chronic migraine received placebo or an initial 675-mg fremanezumab dose followed by monthly subcutaneous injections of 225 mg or 900 mg. The treatment period was three months.

Participants entered information into an electronic diary daily. Questions about functional performance elicited information about “work/school/household chore performance” and “concentration/mental fatigue.” For the former category, patients recorded their performance as normal, less than 50% impaired, or at least 50% impaired. For the latter category, patients recorded how much time they had spent working more slowly, finding it difficult to concentrate, and feeling tired or drained.

Fremanezumab Improved Concentration

In the high-frequency episodic migraine study, patients who received fremanezumab had a greater increase in headache-free days with normal concentration and normal performance at work, school, and home, compared with controls.

In the study of chronic migraine, the 900-mg dose was associated with consistent improvements in function on headache-free days. Patients with chronic migraine in the 225-mg dose group had increases compared with controls in the number of headache-free days in which they performed household chores normally and had no time with difficulty concentrating. The 225-mg group had minimal changes in the number of headache-free days in which work/study and household chore performance was impaired by 50% or more, as well as in in time with difficulty concentrating, but its results were better than those of controls.

“One could postulate that patients had more headache-free days with normal functional performance simply because they had more headache-free days on fremanezumab,” said Dr. VanderPluym. “With increased headache-free days, patients may have had reduced interictal anxiety and thus reduced avoidance behavior and lifestyle compromise, allowing them to function normally.”

Patients receiving fremanezumab significantly reduced their intake of acute medications, compared with controls. This reduction likely decreased the number of side effects associated with acute medications and could have contributed to better functional performance, said the authors.

A limitation of the analysis is that the assessment of function was not based on standardized questionnaires such as the Headache Impact Test-6 or the Migraine-Specific Quality of Life Questionnaire.

—Erik Greb

Suggested Reading

VanderPluym J, Dodick DW, Lipton RB, et al. Fremanezumab for preventive treatment of migraine: functional status on headache-free days. Neurology. 2018 Aug 17 [Epub ahead of print].

Fremanezumab increases the number of headache-free days with normal function for patients with episodic or chronic migraine, according to post hoc analyses published online ahead of print August 17 in Neurology. Fremanezumab appears to improve all measures of function in patients with episodic migraine, and some measures in patients with chronic migraine.

“The results should be considered exploratory,” said Juliana VanderPluym, MD, a neurologist at Mayo Clinic in Phoenix, and colleagues. “Further research is needed to confirm these preliminary findings and to understand the factors contributing to perceived functional status on headache-free days.”

Examining Two Phase II Trials

Fremanezumab is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP). Dr. VanderPluym and colleagues analyzed data from randomized, double-blind phase II trials of the therapy for prevention of high-frequency episodic migraine (ie, eight to 14 headache days per month) and chronic migraine. Patients with high-frequency episodic migraine received placebo or monthly subcutaneous fremanezumab injections of 225 mg or 675 mg. Patients with chronic migraine received placebo or an initial 675-mg fremanezumab dose followed by monthly subcutaneous injections of 225 mg or 900 mg. The treatment period was three months.

Participants entered information into an electronic diary daily. Questions about functional performance elicited information about “work/school/household chore performance” and “concentration/mental fatigue.” For the former category, patients recorded their performance as normal, less than 50% impaired, or at least 50% impaired. For the latter category, patients recorded how much time they had spent working more slowly, finding it difficult to concentrate, and feeling tired or drained.

Fremanezumab Improved Concentration

In the high-frequency episodic migraine study, patients who received fremanezumab had a greater increase in headache-free days with normal concentration and normal performance at work, school, and home, compared with controls.

In the study of chronic migraine, the 900-mg dose was associated with consistent improvements in function on headache-free days. Patients with chronic migraine in the 225-mg dose group had increases compared with controls in the number of headache-free days in which they performed household chores normally and had no time with difficulty concentrating. The 225-mg group had minimal changes in the number of headache-free days in which work/study and household chore performance was impaired by 50% or more, as well as in in time with difficulty concentrating, but its results were better than those of controls.

“One could postulate that patients had more headache-free days with normal functional performance simply because they had more headache-free days on fremanezumab,” said Dr. VanderPluym. “With increased headache-free days, patients may have had reduced interictal anxiety and thus reduced avoidance behavior and lifestyle compromise, allowing them to function normally.”

Patients receiving fremanezumab significantly reduced their intake of acute medications, compared with controls. This reduction likely decreased the number of side effects associated with acute medications and could have contributed to better functional performance, said the authors.

A limitation of the analysis is that the assessment of function was not based on standardized questionnaires such as the Headache Impact Test-6 or the Migraine-Specific Quality of Life Questionnaire.

—Erik Greb

Suggested Reading

VanderPluym J, Dodick DW, Lipton RB, et al. Fremanezumab for preventive treatment of migraine: functional status on headache-free days. Neurology. 2018 Aug 17 [Epub ahead of print].

Fremanezumab increases the number of headache-free days with normal function for patients with episodic or chronic migraine, according to post hoc analyses published online ahead of print August 17 in Neurology. Fremanezumab appears to improve all measures of function in patients with episodic migraine, and some measures in patients with chronic migraine.

“The results should be considered exploratory,” said Juliana VanderPluym, MD, a neurologist at Mayo Clinic in Phoenix, and colleagues. “Further research is needed to confirm these preliminary findings and to understand the factors contributing to perceived functional status on headache-free days.”

Examining Two Phase II Trials

Fremanezumab is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP). Dr. VanderPluym and colleagues analyzed data from randomized, double-blind phase II trials of the therapy for prevention of high-frequency episodic migraine (ie, eight to 14 headache days per month) and chronic migraine. Patients with high-frequency episodic migraine received placebo or monthly subcutaneous fremanezumab injections of 225 mg or 675 mg. Patients with chronic migraine received placebo or an initial 675-mg fremanezumab dose followed by monthly subcutaneous injections of 225 mg or 900 mg. The treatment period was three months.

Participants entered information into an electronic diary daily. Questions about functional performance elicited information about “work/school/household chore performance” and “concentration/mental fatigue.” For the former category, patients recorded their performance as normal, less than 50% impaired, or at least 50% impaired. For the latter category, patients recorded how much time they had spent working more slowly, finding it difficult to concentrate, and feeling tired or drained.

Fremanezumab Improved Concentration

In the high-frequency episodic migraine study, patients who received fremanezumab had a greater increase in headache-free days with normal concentration and normal performance at work, school, and home, compared with controls.

In the study of chronic migraine, the 900-mg dose was associated with consistent improvements in function on headache-free days. Patients with chronic migraine in the 225-mg dose group had increases compared with controls in the number of headache-free days in which they performed household chores normally and had no time with difficulty concentrating. The 225-mg group had minimal changes in the number of headache-free days in which work/study and household chore performance was impaired by 50% or more, as well as in in time with difficulty concentrating, but its results were better than those of controls.

“One could postulate that patients had more headache-free days with normal functional performance simply because they had more headache-free days on fremanezumab,” said Dr. VanderPluym. “With increased headache-free days, patients may have had reduced interictal anxiety and thus reduced avoidance behavior and lifestyle compromise, allowing them to function normally.”

Patients receiving fremanezumab significantly reduced their intake of acute medications, compared with controls. This reduction likely decreased the number of side effects associated with acute medications and could have contributed to better functional performance, said the authors.

A limitation of the analysis is that the assessment of function was not based on standardized questionnaires such as the Headache Impact Test-6 or the Migraine-Specific Quality of Life Questionnaire.

—Erik Greb

Suggested Reading

VanderPluym J, Dodick DW, Lipton RB, et al. Fremanezumab for preventive treatment of migraine: functional status on headache-free days. Neurology. 2018 Aug 17 [Epub ahead of print].

In patients with multiple sclerosis (MS), levels of light-chain neurofilament (NfL) in CSF at diagnosis seem to predict long-term clinical outcome and conversion from the relapsing-remitting phase of the disease to the secondary progressive phase, according to a study published in the September issue of Multiple Sclerosis Journal. “NfL is thought to reflect ongoing axonal degeneration, which dominates early in the disease phase, and our results support that increased early disease activity, as identified by increased levels of CSF-NfL, has a prognostic effect several years later,” said lead author Alok Bhan, MD, and colleagues. Dr. Bhan works in the Department of Neurology at Stavanger University Hospital in Norway.

Searching for Prognostic Markers

To test whether CSF-NfL levels in patients with MS could predict clinical outcome, Dr. Bhan and colleagues conducted standardized clinical assessments of patients with newly diagnosed MS at baseline and at five- and 10-year follow-up. Expanded Disability Status Scale (EDSS) progression between assessments was defined as an increase of 1 point or more for scores less than 6 and of 0.5 points or more for scores of 6 or greater. CSF obtained at baseline was analyzed for levels of NfL using enzyme-linked immunosorbent assay technology.

The study cohort included 44 patients, of whom 35 (80%) had relapsing-remitting MS, seven (16%) had secondary progressive MS, and two (4%) had primary progressive MS at baseline. Patients who progressed on EDSS tended to have higher median baseline CSF-NfL levels than patients who did not progress after five years (947 ng/L vs 246 ng/L, respectively) and those who did not progress after 10 years (708 ng/L vs 265 ng/L, respectively), although the latter difference was not statistically significant. Patients who converted from relapsing-remitting MS to secondary progressive MS at five years had a significantly higher median CSF level of NfL (2,122 ng/L), compared with those who did not convert (246 ng/L).

“We found a statistically significant correlation between NfL levels at baseline and EDSS progression and conversion from relapsing-remitting MS to secondary progressive MS at the five-year follow-up, but a weaker correlation at the 10-year follow-up,” the researchers said. “This [finding] may be due to the increasing number of patients on disease-modifying therapy throughout the study period, as only 16% received therapy at baseline, but 54% [did] at 10-year follow-up.”

The Predictive Value of NfL

“This is now another important report underscoring the predictive value of NfL levels for the evolution of future disability in MS, but the … study clearly suffers from the relatively low number of patients investigated,” said Michael Khalil, MD, PhD, in an accompanying editorial. Dr. Khalil is an Associate Professor of General Neurology at the Medical University of Graz in Austria. “Nevertheless, neurofilaments are currently the most promising markers to indicate neuro-axonal damage in MS and other neurologic diseases. The availability of a highly sensitive blood assay now facilitates its use for further research and in clinical practice.”

—Glenn S. Williams

Suggested Reading

Bhan A, Jacobsen C, Myhr KM, et al. Neurofilaments and 10-year follow-up in multiple sclerosis. Mult Scler. 2018; 24(10):1301-1307.

Khalil M. Are neurofilaments valuable biomarkers for long-term disease prognostication in MS? Mult Scler. 2018; 24(10):1270-1271.

In patients with multiple sclerosis (MS), levels of light-chain neurofilament (NfL) in CSF at diagnosis seem to predict long-term clinical outcome and conversion from the relapsing-remitting phase of the disease to the secondary progressive phase, according to a study published in the September issue of Multiple Sclerosis Journal. “NfL is thought to reflect ongoing axonal degeneration, which dominates early in the disease phase, and our results support that increased early disease activity, as identified by increased levels of CSF-NfL, has a prognostic effect several years later,” said lead author Alok Bhan, MD, and colleagues. Dr. Bhan works in the Department of Neurology at Stavanger University Hospital in Norway.

Searching for Prognostic Markers

To test whether CSF-NfL levels in patients with MS could predict clinical outcome, Dr. Bhan and colleagues conducted standardized clinical assessments of patients with newly diagnosed MS at baseline and at five- and 10-year follow-up. Expanded Disability Status Scale (EDSS) progression between assessments was defined as an increase of 1 point or more for scores less than 6 and of 0.5 points or more for scores of 6 or greater. CSF obtained at baseline was analyzed for levels of NfL using enzyme-linked immunosorbent assay technology.

The study cohort included 44 patients, of whom 35 (80%) had relapsing-remitting MS, seven (16%) had secondary progressive MS, and two (4%) had primary progressive MS at baseline. Patients who progressed on EDSS tended to have higher median baseline CSF-NfL levels than patients who did not progress after five years (947 ng/L vs 246 ng/L, respectively) and those who did not progress after 10 years (708 ng/L vs 265 ng/L, respectively), although the latter difference was not statistically significant. Patients who converted from relapsing-remitting MS to secondary progressive MS at five years had a significantly higher median CSF level of NfL (2,122 ng/L), compared with those who did not convert (246 ng/L).

“We found a statistically significant correlation between NfL levels at baseline and EDSS progression and conversion from relapsing-remitting MS to secondary progressive MS at the five-year follow-up, but a weaker correlation at the 10-year follow-up,” the researchers said. “This [finding] may be due to the increasing number of patients on disease-modifying therapy throughout the study period, as only 16% received therapy at baseline, but 54% [did] at 10-year follow-up.”

The Predictive Value of NfL

“This is now another important report underscoring the predictive value of NfL levels for the evolution of future disability in MS, but the … study clearly suffers from the relatively low number of patients investigated,” said Michael Khalil, MD, PhD, in an accompanying editorial. Dr. Khalil is an Associate Professor of General Neurology at the Medical University of Graz in Austria. “Nevertheless, neurofilaments are currently the most promising markers to indicate neuro-axonal damage in MS and other neurologic diseases. The availability of a highly sensitive blood assay now facilitates its use for further research and in clinical practice.”

—Glenn S. Williams

Suggested Reading

Bhan A, Jacobsen C, Myhr KM, et al. Neurofilaments and 10-year follow-up in multiple sclerosis. Mult Scler. 2018; 24(10):1301-1307.

Khalil M. Are neurofilaments valuable biomarkers for long-term disease prognostication in MS? Mult Scler. 2018; 24(10):1270-1271.

In patients with multiple sclerosis (MS), levels of light-chain neurofilament (NfL) in CSF at diagnosis seem to predict long-term clinical outcome and conversion from the relapsing-remitting phase of the disease to the secondary progressive phase, according to a study published in the September issue of Multiple Sclerosis Journal. “NfL is thought to reflect ongoing axonal degeneration, which dominates early in the disease phase, and our results support that increased early disease activity, as identified by increased levels of CSF-NfL, has a prognostic effect several years later,” said lead author Alok Bhan, MD, and colleagues. Dr. Bhan works in the Department of Neurology at Stavanger University Hospital in Norway.

Searching for Prognostic Markers

To test whether CSF-NfL levels in patients with MS could predict clinical outcome, Dr. Bhan and colleagues conducted standardized clinical assessments of patients with newly diagnosed MS at baseline and at five- and 10-year follow-up. Expanded Disability Status Scale (EDSS) progression between assessments was defined as an increase of 1 point or more for scores less than 6 and of 0.5 points or more for scores of 6 or greater. CSF obtained at baseline was analyzed for levels of NfL using enzyme-linked immunosorbent assay technology.

The study cohort included 44 patients, of whom 35 (80%) had relapsing-remitting MS, seven (16%) had secondary progressive MS, and two (4%) had primary progressive MS at baseline. Patients who progressed on EDSS tended to have higher median baseline CSF-NfL levels than patients who did not progress after five years (947 ng/L vs 246 ng/L, respectively) and those who did not progress after 10 years (708 ng/L vs 265 ng/L, respectively), although the latter difference was not statistically significant. Patients who converted from relapsing-remitting MS to secondary progressive MS at five years had a significantly higher median CSF level of NfL (2,122 ng/L), compared with those who did not convert (246 ng/L).

“We found a statistically significant correlation between NfL levels at baseline and EDSS progression and conversion from relapsing-remitting MS to secondary progressive MS at the five-year follow-up, but a weaker correlation at the 10-year follow-up,” the researchers said. “This [finding] may be due to the increasing number of patients on disease-modifying therapy throughout the study period, as only 16% received therapy at baseline, but 54% [did] at 10-year follow-up.”

The Predictive Value of NfL

“This is now another important report underscoring the predictive value of NfL levels for the evolution of future disability in MS, but the … study clearly suffers from the relatively low number of patients investigated,” said Michael Khalil, MD, PhD, in an accompanying editorial. Dr. Khalil is an Associate Professor of General Neurology at the Medical University of Graz in Austria. “Nevertheless, neurofilaments are currently the most promising markers to indicate neuro-axonal damage in MS and other neurologic diseases. The availability of a highly sensitive blood assay now facilitates its use for further research and in clinical practice.”

—Glenn S. Williams

Suggested Reading

Bhan A, Jacobsen C, Myhr KM, et al. Neurofilaments and 10-year follow-up in multiple sclerosis. Mult Scler. 2018; 24(10):1301-1307.

Khalil M. Are neurofilaments valuable biomarkers for long-term disease prognostication in MS? Mult Scler. 2018; 24(10):1270-1271.

Pooled data from an expanded-access program provide further evidence that adjunctive cannabidiol (CBD) provides meaningful reductions in seizure frequency in patients with treatment-resistant epilepsies. The data were published in the August issue of Epilepsia.

Studies have recently indicated that adjunctive CBD effectively reduces seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. An expanded-access program was created in January 2014 to offer CBD to patients with treatment-resistant epilepsies. Data on safety, tolerability, and efficacy during the first year of the study have been reported. Jerzy P. Szaflarski, MD, PhD, Professor of Neurology at the University of Alabama at Birmingham, and colleagues examined results for safety outcomes at 144 weeks and efficacy outcomes at 96 weeks.

An Expanded-Access Program

All participants in the program had treatment-resistant epilepsy and were receiving stable doses of antiepileptic drugs (AEDs) for at least four weeks before enrollment. During a four-week baseline period, parents and caregivers kept diaries of all countable seizure types. Participants subsequently received a plant-based oral pharmaceutical formulation of CBD (100 mg/mL). Treatment was initiated at a dose of 2–10 mg/kg/day and was titrated to a maximum dose of 25–50 mg/kg/day.

Patients were examined every two to four weeks until the 16th week, and every two to 12 weeks after that point. The efficacy outcomes included the percentage change from baseline in median monthly convulsive seizure frequency and total seizure frequency, and the percentages of patients with at least 50%, at least 75%, and 100% reductions in seizures, compared with baseline. Investigators documented adverse events at each visit.

CBD Was Well Tolerated

The safety analysis included 607 patients, and the efficacy analysis included 580 patients. Among patients included in the safety analysis, 24% withdrew from the study. The most common reasons for withdrawal were lack of efficacy (15%) and adverse events (5%). Participants’ mean age was 13, and 52% of patients were male. The median number of concomitant AEDs was three, the median dose of CBD was 25 mg/kg/day, and the median treatment duration was 48 weeks.

At 12 weeks, adjunctive CBD was associated with a 51% reduction in median monthly convulsive seizures and a 48% reduction in total seizures. Reductions in these seizure types were similar through 96 weeks. At 12 weeks, 52% of patients had a reduction in convulsive seizures of at least 50%, 31% had a reduction of at least 75%, and 11% had a 100% reduction. These response rates were similar through 96 weeks of treatment.

CBD was generally well tolerated. The most common adverse events were diarrhea (29%) and somnolence (22%). About 10% of patients had abnormal liver adverse events, and 75% of them were taking valproate. Among patients taking concomitant clobazam, 38% had somnolence, compared with 14% of patients not taking concomitant clobazam.

The expanded-access program is not placebo-controlled, and neither patients nor investigators are blinded. Furthermore, reporting methods varied between study sites. Despite these limitations, the data indicate that adjunctive CBD significantly reduces seizure frequency, according to the authors.

The data support the results of double-blind, placebo-controlled trials that found that add-on CBD reduces seizure frequency, compared with placebo. The FDA in June approved Epidiolex, the formulation of CBD used in the expanded-access program, for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.

—Erik Greb

Suggested Reading

Szaflarski JP, Bebin EM, Comi AM, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia. 2018;59(8):1540-1548.

Pooled data from an expanded-access program provide further evidence that adjunctive cannabidiol (CBD) provides meaningful reductions in seizure frequency in patients with treatment-resistant epilepsies. The data were published in the August issue of Epilepsia.

Studies have recently indicated that adjunctive CBD effectively reduces seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. An expanded-access program was created in January 2014 to offer CBD to patients with treatment-resistant epilepsies. Data on safety, tolerability, and efficacy during the first year of the study have been reported. Jerzy P. Szaflarski, MD, PhD, Professor of Neurology at the University of Alabama at Birmingham, and colleagues examined results for safety outcomes at 144 weeks and efficacy outcomes at 96 weeks.

An Expanded-Access Program

All participants in the program had treatment-resistant epilepsy and were receiving stable doses of antiepileptic drugs (AEDs) for at least four weeks before enrollment. During a four-week baseline period, parents and caregivers kept diaries of all countable seizure types. Participants subsequently received a plant-based oral pharmaceutical formulation of CBD (100 mg/mL). Treatment was initiated at a dose of 2–10 mg/kg/day and was titrated to a maximum dose of 25–50 mg/kg/day.

Patients were examined every two to four weeks until the 16th week, and every two to 12 weeks after that point. The efficacy outcomes included the percentage change from baseline in median monthly convulsive seizure frequency and total seizure frequency, and the percentages of patients with at least 50%, at least 75%, and 100% reductions in seizures, compared with baseline. Investigators documented adverse events at each visit.

CBD Was Well Tolerated

The safety analysis included 607 patients, and the efficacy analysis included 580 patients. Among patients included in the safety analysis, 24% withdrew from the study. The most common reasons for withdrawal were lack of efficacy (15%) and adverse events (5%). Participants’ mean age was 13, and 52% of patients were male. The median number of concomitant AEDs was three, the median dose of CBD was 25 mg/kg/day, and the median treatment duration was 48 weeks.

At 12 weeks, adjunctive CBD was associated with a 51% reduction in median monthly convulsive seizures and a 48% reduction in total seizures. Reductions in these seizure types were similar through 96 weeks. At 12 weeks, 52% of patients had a reduction in convulsive seizures of at least 50%, 31% had a reduction of at least 75%, and 11% had a 100% reduction. These response rates were similar through 96 weeks of treatment.

CBD was generally well tolerated. The most common adverse events were diarrhea (29%) and somnolence (22%). About 10% of patients had abnormal liver adverse events, and 75% of them were taking valproate. Among patients taking concomitant clobazam, 38% had somnolence, compared with 14% of patients not taking concomitant clobazam.

The expanded-access program is not placebo-controlled, and neither patients nor investigators are blinded. Furthermore, reporting methods varied between study sites. Despite these limitations, the data indicate that adjunctive CBD significantly reduces seizure frequency, according to the authors.

The data support the results of double-blind, placebo-controlled trials that found that add-on CBD reduces seizure frequency, compared with placebo. The FDA in June approved Epidiolex, the formulation of CBD used in the expanded-access program, for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.

—Erik Greb

Suggested Reading

Szaflarski JP, Bebin EM, Comi AM, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia. 2018;59(8):1540-1548.

Pooled data from an expanded-access program provide further evidence that adjunctive cannabidiol (CBD) provides meaningful reductions in seizure frequency in patients with treatment-resistant epilepsies. The data were published in the August issue of Epilepsia.

Studies have recently indicated that adjunctive CBD effectively reduces seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. An expanded-access program was created in January 2014 to offer CBD to patients with treatment-resistant epilepsies. Data on safety, tolerability, and efficacy during the first year of the study have been reported. Jerzy P. Szaflarski, MD, PhD, Professor of Neurology at the University of Alabama at Birmingham, and colleagues examined results for safety outcomes at 144 weeks and efficacy outcomes at 96 weeks.

An Expanded-Access Program

All participants in the program had treatment-resistant epilepsy and were receiving stable doses of antiepileptic drugs (AEDs) for at least four weeks before enrollment. During a four-week baseline period, parents and caregivers kept diaries of all countable seizure types. Participants subsequently received a plant-based oral pharmaceutical formulation of CBD (100 mg/mL). Treatment was initiated at a dose of 2–10 mg/kg/day and was titrated to a maximum dose of 25–50 mg/kg/day.

Patients were examined every two to four weeks until the 16th week, and every two to 12 weeks after that point. The efficacy outcomes included the percentage change from baseline in median monthly convulsive seizure frequency and total seizure frequency, and the percentages of patients with at least 50%, at least 75%, and 100% reductions in seizures, compared with baseline. Investigators documented adverse events at each visit.

CBD Was Well Tolerated

The safety analysis included 607 patients, and the efficacy analysis included 580 patients. Among patients included in the safety analysis, 24% withdrew from the study. The most common reasons for withdrawal were lack of efficacy (15%) and adverse events (5%). Participants’ mean age was 13, and 52% of patients were male. The median number of concomitant AEDs was three, the median dose of CBD was 25 mg/kg/day, and the median treatment duration was 48 weeks.

At 12 weeks, adjunctive CBD was associated with a 51% reduction in median monthly convulsive seizures and a 48% reduction in total seizures. Reductions in these seizure types were similar through 96 weeks. At 12 weeks, 52% of patients had a reduction in convulsive seizures of at least 50%, 31% had a reduction of at least 75%, and 11% had a 100% reduction. These response rates were similar through 96 weeks of treatment.

CBD was generally well tolerated. The most common adverse events were diarrhea (29%) and somnolence (22%). About 10% of patients had abnormal liver adverse events, and 75% of them were taking valproate. Among patients taking concomitant clobazam, 38% had somnolence, compared with 14% of patients not taking concomitant clobazam.

The expanded-access program is not placebo-controlled, and neither patients nor investigators are blinded. Furthermore, reporting methods varied between study sites. Despite these limitations, the data indicate that adjunctive CBD significantly reduces seizure frequency, according to the authors.

The data support the results of double-blind, placebo-controlled trials that found that add-on CBD reduces seizure frequency, compared with placebo. The FDA in June approved Epidiolex, the formulation of CBD used in the expanded-access program, for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.

—Erik Greb

Suggested Reading

Szaflarski JP, Bebin EM, Comi AM, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia. 2018;59(8):1540-1548.

Biologically active pituitary adenylate cyclase-activating polypeptide (PACAP) is released by mast cells: a finding that may provide an explanation for the association between allergy and migraine. “In the investigation of the role of mast cells in migraine pathology, we found that human mast cells contain PACAP in their cytoplasmic granules. Bioactive PACAP can be released from mast cells by inducing degranulation,” said lead author Angela J. Okragly, Senior Research Scientist at Eli Lilly and Company in Indianapolis, and colleagues. “This finding provides a potential explanation linking mast cell activation to migraine through the release of PACAP.” Their study was published in the August issue of Cephalalgia.

The relationship between allergy and migraine has long been noted. Many patients with migraines have allergies, and vice versa. In 1983, researchers hypothesized that mast cells, which are effectors of allergies, play a role in the pathophysiology of migraines. To investigate the relationship between mast cell activation and known neurogenic peptides related to migraine, researchers from Eli Lilly and Company assayed cultured human mast cells for the presence of neuropeptides and their receptors at the RNA and protein levels. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. The investigators also performed mast cell degranulation assays and measured PACAP activity with bioassay.

The team of Lilly researchers found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. In addition, the researchers confirmed existing evidence that several neurogenic peptides also can induce mast cell degranulation, which results in PACAP release.

“Since it has been demonstrated that PACAP infusion can trigger migraines, we propose that [our] finding provides a potential mechanistic explanation of how mast cell degranulation could contribute to migraines,” the authors said.

Migraine remains a complex disorder with multiple causes, the researchers noted. “Recent clinical trial results demonstrate a role for the calcitonin gene-related peptide (CGRP) pathway, since its blockade resulted in a high degree of efficacy in significant groups of patients. In our study, we found no direct relationship between mast cells and CGRP, suggesting that migraines involving mast cell activation, either via classical IgE or pseudoallergic pathways, involve a different pathophysiologic mechanism,” the authors said.

—Glenn S. Williams

Suggested Reading

Okragly AJ, Morin SM, DeRosa D, et al. Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP). Cephalalgia. 2018;38(9):1564-1574.

Biologically active pituitary adenylate cyclase-activating polypeptide (PACAP) is released by mast cells: a finding that may provide an explanation for the association between allergy and migraine. “In the investigation of the role of mast cells in migraine pathology, we found that human mast cells contain PACAP in their cytoplasmic granules. Bioactive PACAP can be released from mast cells by inducing degranulation,” said lead author Angela J. Okragly, Senior Research Scientist at Eli Lilly and Company in Indianapolis, and colleagues. “This finding provides a potential explanation linking mast cell activation to migraine through the release of PACAP.” Their study was published in the August issue of Cephalalgia.

The relationship between allergy and migraine has long been noted. Many patients with migraines have allergies, and vice versa. In 1983, researchers hypothesized that mast cells, which are effectors of allergies, play a role in the pathophysiology of migraines. To investigate the relationship between mast cell activation and known neurogenic peptides related to migraine, researchers from Eli Lilly and Company assayed cultured human mast cells for the presence of neuropeptides and their receptors at the RNA and protein levels. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. The investigators also performed mast cell degranulation assays and measured PACAP activity with bioassay.

The team of Lilly researchers found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. In addition, the researchers confirmed existing evidence that several neurogenic peptides also can induce mast cell degranulation, which results in PACAP release.

“Since it has been demonstrated that PACAP infusion can trigger migraines, we propose that [our] finding provides a potential mechanistic explanation of how mast cell degranulation could contribute to migraines,” the authors said.

Migraine remains a complex disorder with multiple causes, the researchers noted. “Recent clinical trial results demonstrate a role for the calcitonin gene-related peptide (CGRP) pathway, since its blockade resulted in a high degree of efficacy in significant groups of patients. In our study, we found no direct relationship between mast cells and CGRP, suggesting that migraines involving mast cell activation, either via classical IgE or pseudoallergic pathways, involve a different pathophysiologic mechanism,” the authors said.

—Glenn S. Williams

Suggested Reading

Okragly AJ, Morin SM, DeRosa D, et al. Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP). Cephalalgia. 2018;38(9):1564-1574.

Biologically active pituitary adenylate cyclase-activating polypeptide (PACAP) is released by mast cells: a finding that may provide an explanation for the association between allergy and migraine. “In the investigation of the role of mast cells in migraine pathology, we found that human mast cells contain PACAP in their cytoplasmic granules. Bioactive PACAP can be released from mast cells by inducing degranulation,” said lead author Angela J. Okragly, Senior Research Scientist at Eli Lilly and Company in Indianapolis, and colleagues. “This finding provides a potential explanation linking mast cell activation to migraine through the release of PACAP.” Their study was published in the August issue of Cephalalgia.

The relationship between allergy and migraine has long been noted. Many patients with migraines have allergies, and vice versa. In 1983, researchers hypothesized that mast cells, which are effectors of allergies, play a role in the pathophysiology of migraines. To investigate the relationship between mast cell activation and known neurogenic peptides related to migraine, researchers from Eli Lilly and Company assayed cultured human mast cells for the presence of neuropeptides and their receptors at the RNA and protein levels. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. The investigators also performed mast cell degranulation assays and measured PACAP activity with bioassay.

The team of Lilly researchers found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. In addition, the researchers confirmed existing evidence that several neurogenic peptides also can induce mast cell degranulation, which results in PACAP release.

“Since it has been demonstrated that PACAP infusion can trigger migraines, we propose that [our] finding provides a potential mechanistic explanation of how mast cell degranulation could contribute to migraines,” the authors said.

Migraine remains a complex disorder with multiple causes, the researchers noted. “Recent clinical trial results demonstrate a role for the calcitonin gene-related peptide (CGRP) pathway, since its blockade resulted in a high degree of efficacy in significant groups of patients. In our study, we found no direct relationship between mast cells and CGRP, suggesting that migraines involving mast cell activation, either via classical IgE or pseudoallergic pathways, involve a different pathophysiologic mechanism,” the authors said.

—Glenn S. Williams

Suggested Reading

Okragly AJ, Morin SM, DeRosa D, et al. Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP). Cephalalgia. 2018;38(9):1564-1574.

Self-management of epilepsy using a group-format, remote intervention improves mood, quality of life, and health functioning in high-risk individuals, according to a randomized, controlled trial published in the September issue of Epilepsia.

In the six-month trial, 120 individuals with epilepsy who had experienced at least one epilepsy-related negative health event in the previous six months were randomized to a wait-list control group or a novel self‐management intervention.

The eight-session intervention, known as SMART, focused on modifiable factors that can be addressed with self-management, such as stress, substance abuse, routine, nutrition, and social support. It was delivered remotely during eight to 10 weeks, either by telephone or online, after an initial in-person session.

“SMART combines the portability and low cost of a Web‐based intervention with the personally salient components of behavior modeling obtained by interacting with individuals who have walked the walk in living with epilepsy,” said Martha Sajatovic, MD, Professor of Psychiatry at Case Western Reserve University in Cleveland, and her colleagues.

—Bianca Nogrady

Suggested Reading

Sajatovic M, Colon-Zimmermann K, Kahriman M, et al. A 6-month prospective randomized controlled trial of remotely delivered group format epilepsy self-management versus waitlist control for high-risk people with epilepsy. Epilepsia. 2018;59(9):1684-1695.

Self-management of epilepsy using a group-format, remote intervention improves mood, quality of life, and health functioning in high-risk individuals, according to a randomized, controlled trial published in the September issue of Epilepsia.

In the six-month trial, 120 individuals with epilepsy who had experienced at least one epilepsy-related negative health event in the previous six months were randomized to a wait-list control group or a novel self‐management intervention.

The eight-session intervention, known as SMART, focused on modifiable factors that can be addressed with self-management, such as stress, substance abuse, routine, nutrition, and social support. It was delivered remotely during eight to 10 weeks, either by telephone or online, after an initial in-person session.

“SMART combines the portability and low cost of a Web‐based intervention with the personally salient components of behavior modeling obtained by interacting with individuals who have walked the walk in living with epilepsy,” said Martha Sajatovic, MD, Professor of Psychiatry at Case Western Reserve University in Cleveland, and her colleagues.

—Bianca Nogrady

Suggested Reading

Sajatovic M, Colon-Zimmermann K, Kahriman M, et al. A 6-month prospective randomized controlled trial of remotely delivered group format epilepsy self-management versus waitlist control for high-risk people with epilepsy. Epilepsia. 2018;59(9):1684-1695.

Self-management of epilepsy using a group-format, remote intervention improves mood, quality of life, and health functioning in high-risk individuals, according to a randomized, controlled trial published in the September issue of Epilepsia.

In the six-month trial, 120 individuals with epilepsy who had experienced at least one epilepsy-related negative health event in the previous six months were randomized to a wait-list control group or a novel self‐management intervention.

The eight-session intervention, known as SMART, focused on modifiable factors that can be addressed with self-management, such as stress, substance abuse, routine, nutrition, and social support. It was delivered remotely during eight to 10 weeks, either by telephone or online, after an initial in-person session.

“SMART combines the portability and low cost of a Web‐based intervention with the personally salient components of behavior modeling obtained by interacting with individuals who have walked the walk in living with epilepsy,” said Martha Sajatovic, MD, Professor of Psychiatry at Case Western Reserve University in Cleveland, and her colleagues.

—Bianca Nogrady

Suggested Reading

Sajatovic M, Colon-Zimmermann K, Kahriman M, et al. A 6-month prospective randomized controlled trial of remotely delivered group format epilepsy self-management versus waitlist control for high-risk people with epilepsy. Epilepsia. 2018;59(9):1684-1695.

An estimated 3% of patients with multiple sclerosis (MS) have a benign course of disease, according to findings from a population-based UK study published online ahead of print September 3 in Journal of Neurology, Neurosurgery & Psychiatry. The term “benign MS” remains problematic, however.

“The study of the individuals with extremely favorable outcomes may uncover insights about disease pathogenesis or repair. However, the insensitivity of Expanded Disability Status Scale [EDSS]–based definitions of benign MS and the discrepancy between patient and clinician perception of benign MS undermine use of the term ‘benign’ in the clinical setting,” said Emma Clare Tallantyre, BMBS, PhD, Clinical Senior Lecturer in Neurosciences at Cardiff University in the UK, and her colleagues.

The investigators found that of 1,049 patients with a disease duration of longer than 15 years, 200 had a recent EDSS score of less than 4.0. Of those patients, 60 were clinically assessed, and nine (15%) had benign MS, which was defined as an EDSS score less than 3.0 and lack of significant fatigue, mood disturbance, cognitive impairment, and disruption to employment in the absence of disease-modifying therapy at at least 15 years after symptom onset.

Extrapolating these data, the investigators estimated that 30 patients in the study population of 1,049 had benign MS, yielding a prevalence of 2.9%. Of the 60 patients who were clinically assessed, 39 thought they had benign MS, based on the following definition: “When referring to illness, ‘benign’ usually means a condition which has little or no harmful effects on a person. There are no complications, and there is a good outcome or prognosis.”

Patients who self-reported benign MS had significantly lower EDSS scores, fewer depressive symptoms, lower fatigue severity, and lower reported MS impact than did patients who did not report benign MS. “Self-reported benign MS status showed poor agreement with our composite definition of benign MS status and only fair agreement with EDSS-based definitions of benign MS status,” said the investigators.

—Jeff Evans

Suggested Reading

Tallantyre EC, Major PC, Atherton MJ, et al. How common is truly benign MS in a UK population? J Neurol Neurosurg Psychiatry. 2018 Sep 3 [Epub ahead of print].

An estimated 3% of patients with multiple sclerosis (MS) have a benign course of disease, according to findings from a population-based UK study published online ahead of print September 3 in Journal of Neurology, Neurosurgery & Psychiatry. The term “benign MS” remains problematic, however.

“The study of the individuals with extremely favorable outcomes may uncover insights about disease pathogenesis or repair. However, the insensitivity of Expanded Disability Status Scale [EDSS]–based definitions of benign MS and the discrepancy between patient and clinician perception of benign MS undermine use of the term ‘benign’ in the clinical setting,” said Emma Clare Tallantyre, BMBS, PhD, Clinical Senior Lecturer in Neurosciences at Cardiff University in the UK, and her colleagues.

The investigators found that of 1,049 patients with a disease duration of longer than 15 years, 200 had a recent EDSS score of less than 4.0. Of those patients, 60 were clinically assessed, and nine (15%) had benign MS, which was defined as an EDSS score less than 3.0 and lack of significant fatigue, mood disturbance, cognitive impairment, and disruption to employment in the absence of disease-modifying therapy at at least 15 years after symptom onset.

Extrapolating these data, the investigators estimated that 30 patients in the study population of 1,049 had benign MS, yielding a prevalence of 2.9%. Of the 60 patients who were clinically assessed, 39 thought they had benign MS, based on the following definition: “When referring to illness, ‘benign’ usually means a condition which has little or no harmful effects on a person. There are no complications, and there is a good outcome or prognosis.”

Patients who self-reported benign MS had significantly lower EDSS scores, fewer depressive symptoms, lower fatigue severity, and lower reported MS impact than did patients who did not report benign MS. “Self-reported benign MS status showed poor agreement with our composite definition of benign MS status and only fair agreement with EDSS-based definitions of benign MS status,” said the investigators.

—Jeff Evans

Suggested Reading

Tallantyre EC, Major PC, Atherton MJ, et al. How common is truly benign MS in a UK population? J Neurol Neurosurg Psychiatry. 2018 Sep 3 [Epub ahead of print].

An estimated 3% of patients with multiple sclerosis (MS) have a benign course of disease, according to findings from a population-based UK study published online ahead of print September 3 in Journal of Neurology, Neurosurgery & Psychiatry. The term “benign MS” remains problematic, however.

“The study of the individuals with extremely favorable outcomes may uncover insights about disease pathogenesis or repair. However, the insensitivity of Expanded Disability Status Scale [EDSS]–based definitions of benign MS and the discrepancy between patient and clinician perception of benign MS undermine use of the term ‘benign’ in the clinical setting,” said Emma Clare Tallantyre, BMBS, PhD, Clinical Senior Lecturer in Neurosciences at Cardiff University in the UK, and her colleagues.

The investigators found that of 1,049 patients with a disease duration of longer than 15 years, 200 had a recent EDSS score of less than 4.0. Of those patients, 60 were clinically assessed, and nine (15%) had benign MS, which was defined as an EDSS score less than 3.0 and lack of significant fatigue, mood disturbance, cognitive impairment, and disruption to employment in the absence of disease-modifying therapy at at least 15 years after symptom onset.

Extrapolating these data, the investigators estimated that 30 patients in the study population of 1,049 had benign MS, yielding a prevalence of 2.9%. Of the 60 patients who were clinically assessed, 39 thought they had benign MS, based on the following definition: “When referring to illness, ‘benign’ usually means a condition which has little or no harmful effects on a person. There are no complications, and there is a good outcome or prognosis.”

Patients who self-reported benign MS had significantly lower EDSS scores, fewer depressive symptoms, lower fatigue severity, and lower reported MS impact than did patients who did not report benign MS. “Self-reported benign MS status showed poor agreement with our composite definition of benign MS status and only fair agreement with EDSS-based definitions of benign MS status,” said the investigators.

—Jeff Evans

Suggested Reading

Tallantyre EC, Major PC, Atherton MJ, et al. How common is truly benign MS in a UK population? J Neurol Neurosurg Psychiatry. 2018 Sep 3 [Epub ahead of print].

NEW YORK – The cell therapy landscape increasingly involves strategies beyond chimeric antigen receptor (CAR) T-cell therapy, but those studies still predominate among investigational trials, according to Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa.

Researchers are looking at CAR T-cell therapy for earlier lines of treatment, especially in patients with aggressive lymphomas, Dr. Locke said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

Of 753 trials examining cell therapies and listed at ClinicalTrials.gov as of March 30, 2018, about half (404) were CAR T-cell therapies. The others included T-cell receptor therapies, tumor infiltrating lymphocyte therapies, dendritic cell vaccines, and natural killer cell–based therapies, according to an article in Nature Reviews.

“The development isn’t just here in the United States,” Dr. Locke said. “It’s really global. We see a lot of activity in Europe, but also in China. We’re seeing medical advances across the world through molecular biology and gene engineering of T cells and other immune cells which can be adoptively transferred into patients.”

That activity includes studies seeking to move CAR T-cell therapy earlier in the treatment paradigm for some diseases, he added. “CAR T-cell therapy in non-Hodgkin lymphoma is really beginning a paradigm shift, at least in my mind.”

Several large, randomized trials that are now comparing CD19 CAR T-cell therapy with second-line standard-of-care therapies for patients with aggressive B-cell lymphomas. Among those trials is ZUMA-7, a phase 3, randomized trial comparing axicabtagene ciloleucel with standard-of-care treatment in patients with relapsed or refractory diffuse large B-cell lymphoma.

While prognosis remains poor for relapsed or progressing aggressive B-cell lymphomas treated with chemotherapy, data to date suggest CAR T-cell therapy produces durable, long-term remissions in about 40% of patients at “a year out and counting,” Dr. Locke said.

He presented a proposed treatment algorithm that included R-CHOP chemotherapy up front and CAR T-cell therapy in later lines of treatment, an approach that Dr. Locke speculated could result in a cure rate of perhaps 80% in large-cell lymphomas.

Encouraging longer-term data is emerging, with some patients with aggressive T-cell lymphomas now without recurrence for 5 years or more following a single infusion of CAR T-cell therapy, he said.

Dr. Locke reported a financial disclosure related to Cellular Biomedicine Group.

NEW YORK – The cell therapy landscape increasingly involves strategies beyond chimeric antigen receptor (CAR) T-cell therapy, but those studies still predominate among investigational trials, according to Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa.

Researchers are looking at CAR T-cell therapy for earlier lines of treatment, especially in patients with aggressive lymphomas, Dr. Locke said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

Of 753 trials examining cell therapies and listed at ClinicalTrials.gov as of March 30, 2018, about half (404) were CAR T-cell therapies. The others included T-cell receptor therapies, tumor infiltrating lymphocyte therapies, dendritic cell vaccines, and natural killer cell–based therapies, according to an article in Nature Reviews.

“The development isn’t just here in the United States,” Dr. Locke said. “It’s really global. We see a lot of activity in Europe, but also in China. We’re seeing medical advances across the world through molecular biology and gene engineering of T cells and other immune cells which can be adoptively transferred into patients.”

That activity includes studies seeking to move CAR T-cell therapy earlier in the treatment paradigm for some diseases, he added. “CAR T-cell therapy in non-Hodgkin lymphoma is really beginning a paradigm shift, at least in my mind.”

Several large, randomized trials that are now comparing CD19 CAR T-cell therapy with second-line standard-of-care therapies for patients with aggressive B-cell lymphomas. Among those trials is ZUMA-7, a phase 3, randomized trial comparing axicabtagene ciloleucel with standard-of-care treatment in patients with relapsed or refractory diffuse large B-cell lymphoma.

While prognosis remains poor for relapsed or progressing aggressive B-cell lymphomas treated with chemotherapy, data to date suggest CAR T-cell therapy produces durable, long-term remissions in about 40% of patients at “a year out and counting,” Dr. Locke said.

He presented a proposed treatment algorithm that included R-CHOP chemotherapy up front and CAR T-cell therapy in later lines of treatment, an approach that Dr. Locke speculated could result in a cure rate of perhaps 80% in large-cell lymphomas.

Encouraging longer-term data is emerging, with some patients with aggressive T-cell lymphomas now without recurrence for 5 years or more following a single infusion of CAR T-cell therapy, he said.

Dr. Locke reported a financial disclosure related to Cellular Biomedicine Group.

NEW YORK – The cell therapy landscape increasingly involves strategies beyond chimeric antigen receptor (CAR) T-cell therapy, but those studies still predominate among investigational trials, according to Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa.

Researchers are looking at CAR T-cell therapy for earlier lines of treatment, especially in patients with aggressive lymphomas, Dr. Locke said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

Of 753 trials examining cell therapies and listed at ClinicalTrials.gov as of March 30, 2018, about half (404) were CAR T-cell therapies. The others included T-cell receptor therapies, tumor infiltrating lymphocyte therapies, dendritic cell vaccines, and natural killer cell–based therapies, according to an article in Nature Reviews.

“The development isn’t just here in the United States,” Dr. Locke said. “It’s really global. We see a lot of activity in Europe, but also in China. We’re seeing medical advances across the world through molecular biology and gene engineering of T cells and other immune cells which can be adoptively transferred into patients.”

That activity includes studies seeking to move CAR T-cell therapy earlier in the treatment paradigm for some diseases, he added. “CAR T-cell therapy in non-Hodgkin lymphoma is really beginning a paradigm shift, at least in my mind.”

Several large, randomized trials that are now comparing CD19 CAR T-cell therapy with second-line standard-of-care therapies for patients with aggressive B-cell lymphomas. Among those trials is ZUMA-7, a phase 3, randomized trial comparing axicabtagene ciloleucel with standard-of-care treatment in patients with relapsed or refractory diffuse large B-cell lymphoma.

While prognosis remains poor for relapsed or progressing aggressive B-cell lymphomas treated with chemotherapy, data to date suggest CAR T-cell therapy produces durable, long-term remissions in about 40% of patients at “a year out and counting,” Dr. Locke said.

He presented a proposed treatment algorithm that included R-CHOP chemotherapy up front and CAR T-cell therapy in later lines of treatment, an approach that Dr. Locke speculated could result in a cure rate of perhaps 80% in large-cell lymphomas.

Encouraging longer-term data is emerging, with some patients with aggressive T-cell lymphomas now without recurrence for 5 years or more following a single infusion of CAR T-cell therapy, he said.

Dr. Locke reported a financial disclosure related to Cellular Biomedicine Group.