Literature Review

The complement C5 inhibitor zilucoplan significantly improved muscle weakness and daily functioning in patients with moderate to severe generalized myasthenia gravis (gMG), according to investigators who conducted a phase 2, randomized, placebo-controlled study of the agent.

The clinical effect of the self-administered macrocyclic peptide inhibitor was “similar,” the investigators wrote, to what was seen in studies of the intravenously administered complement inhibitor eculizumab, which is approved by the Food and Drug Administration for treatment of gMG.

While eculizumab studies were restricted to patients with refractory gMG, the investigators wrote that their study of zilucoplan included a broader population, including patients who had not failed prior therapies, who were earlier in their disease course, and who had a history of thymoma.

“This observation is important because in gMG, disease severity frequently peaks within the first few years after diagnosis, before all treatment options have been exhausted, and before patients may be formally declared treatment refractory,” wrote James F. Howard Jr, MD, of the University of North Carolina in Chapel Hill, and coauthors.

Complement inhibition is a “targeted approach” that addresses the primary mechanism of tissue damage in gMG, the investigators wrote.

That stands in contrast to conventional gMG treatments including pyridostigmine, corticosteroids, and other immunosuppressants. “These treatments lack strong evidence from clinical trials to support their efficacy, are often poorly tolerated, and can be associated with considerable long-term toxicities,” Dr. Howard and colleagues wrote in their report, which was published in JAMA Neurology.

A total of 44 adult patients with gMG were randomized to receive daily zilucoplan 0.1 mg/kg, 0.3 mg/kg, or placebo for 12 weeks in this 25-center North American study. All patients had acetylcholine receptor autoantibody–positive disease and a Quantitative Myasthenia Gravis (QMG) score of 12 or higher. The QMG score ranges from 0, indicating no muscle weakness, to 39, or severe weakness.

Per the study protocol, patients had to keep taking their current gMG medication without changing the dose.

Change in QMG score from baseline to 12 weeks, the primary efficacy endpoint of the study, showed a significant and clinically meaningful difference favoring zilucoplan 0.3 mg/kg over placebo, according to the investigators.

The mean change was –6.0 points for zilucoplan 0.3 mg/kg and –3.2 for placebo (P = .05), according to their report, which indicated a rapid onset of action apparent 1 week after starting treatment.

Zilucoplan 0.1 mg/kg also yielded a significant and clinically meaningful improvement versus placebo, but its magnitude was smaller and took 4 weeks to become apparent.

Treatment with zilucoplan also significantly improved MG Activities of Daily Living scores versus placebo, a key secondary endpoint of the trial, according to the researchers.

Treatment-emergent adverse events, which included local injection-site reactions, were mild and judged to be unrelated to the study treatment, according to the report.

Ra Pharmaceuticals funded the study. Dr. Howard reported disclosures related to Ra Pharmaceuticals, Alexion Pharmaceuticals, argenx, Viela Bio, and others.

SOURCE: Howard Jr JF et al. JAMA Neurol. 2020 Feb 17. doi: 10.1001/jamaneurol.2019.5125.

The complement C5 inhibitor zilucoplan significantly improved muscle weakness and daily functioning in patients with moderate to severe generalized myasthenia gravis (gMG), according to investigators who conducted a phase 2, randomized, placebo-controlled study of the agent.

The clinical effect of the self-administered macrocyclic peptide inhibitor was “similar,” the investigators wrote, to what was seen in studies of the intravenously administered complement inhibitor eculizumab, which is approved by the Food and Drug Administration for treatment of gMG.

While eculizumab studies were restricted to patients with refractory gMG, the investigators wrote that their study of zilucoplan included a broader population, including patients who had not failed prior therapies, who were earlier in their disease course, and who had a history of thymoma.

“This observation is important because in gMG, disease severity frequently peaks within the first few years after diagnosis, before all treatment options have been exhausted, and before patients may be formally declared treatment refractory,” wrote James F. Howard Jr, MD, of the University of North Carolina in Chapel Hill, and coauthors.

Complement inhibition is a “targeted approach” that addresses the primary mechanism of tissue damage in gMG, the investigators wrote.

That stands in contrast to conventional gMG treatments including pyridostigmine, corticosteroids, and other immunosuppressants. “These treatments lack strong evidence from clinical trials to support their efficacy, are often poorly tolerated, and can be associated with considerable long-term toxicities,” Dr. Howard and colleagues wrote in their report, which was published in JAMA Neurology.

A total of 44 adult patients with gMG were randomized to receive daily zilucoplan 0.1 mg/kg, 0.3 mg/kg, or placebo for 12 weeks in this 25-center North American study. All patients had acetylcholine receptor autoantibody–positive disease and a Quantitative Myasthenia Gravis (QMG) score of 12 or higher. The QMG score ranges from 0, indicating no muscle weakness, to 39, or severe weakness.

Per the study protocol, patients had to keep taking their current gMG medication without changing the dose.

Change in QMG score from baseline to 12 weeks, the primary efficacy endpoint of the study, showed a significant and clinically meaningful difference favoring zilucoplan 0.3 mg/kg over placebo, according to the investigators.

The mean change was –6.0 points for zilucoplan 0.3 mg/kg and –3.2 for placebo (P = .05), according to their report, which indicated a rapid onset of action apparent 1 week after starting treatment.

Zilucoplan 0.1 mg/kg also yielded a significant and clinically meaningful improvement versus placebo, but its magnitude was smaller and took 4 weeks to become apparent.

Treatment with zilucoplan also significantly improved MG Activities of Daily Living scores versus placebo, a key secondary endpoint of the trial, according to the researchers.

Treatment-emergent adverse events, which included local injection-site reactions, were mild and judged to be unrelated to the study treatment, according to the report.

Ra Pharmaceuticals funded the study. Dr. Howard reported disclosures related to Ra Pharmaceuticals, Alexion Pharmaceuticals, argenx, Viela Bio, and others.

SOURCE: Howard Jr JF et al. JAMA Neurol. 2020 Feb 17. doi: 10.1001/jamaneurol.2019.5125.

The complement C5 inhibitor zilucoplan significantly improved muscle weakness and daily functioning in patients with moderate to severe generalized myasthenia gravis (gMG), according to investigators who conducted a phase 2, randomized, placebo-controlled study of the agent.

The clinical effect of the self-administered macrocyclic peptide inhibitor was “similar,” the investigators wrote, to what was seen in studies of the intravenously administered complement inhibitor eculizumab, which is approved by the Food and Drug Administration for treatment of gMG.

While eculizumab studies were restricted to patients with refractory gMG, the investigators wrote that their study of zilucoplan included a broader population, including patients who had not failed prior therapies, who were earlier in their disease course, and who had a history of thymoma.

“This observation is important because in gMG, disease severity frequently peaks within the first few years after diagnosis, before all treatment options have been exhausted, and before patients may be formally declared treatment refractory,” wrote James F. Howard Jr, MD, of the University of North Carolina in Chapel Hill, and coauthors.

Complement inhibition is a “targeted approach” that addresses the primary mechanism of tissue damage in gMG, the investigators wrote.

That stands in contrast to conventional gMG treatments including pyridostigmine, corticosteroids, and other immunosuppressants. “These treatments lack strong evidence from clinical trials to support their efficacy, are often poorly tolerated, and can be associated with considerable long-term toxicities,” Dr. Howard and colleagues wrote in their report, which was published in JAMA Neurology.

A total of 44 adult patients with gMG were randomized to receive daily zilucoplan 0.1 mg/kg, 0.3 mg/kg, or placebo for 12 weeks in this 25-center North American study. All patients had acetylcholine receptor autoantibody–positive disease and a Quantitative Myasthenia Gravis (QMG) score of 12 or higher. The QMG score ranges from 0, indicating no muscle weakness, to 39, or severe weakness.

Per the study protocol, patients had to keep taking their current gMG medication without changing the dose.

Change in QMG score from baseline to 12 weeks, the primary efficacy endpoint of the study, showed a significant and clinically meaningful difference favoring zilucoplan 0.3 mg/kg over placebo, according to the investigators.

The mean change was –6.0 points for zilucoplan 0.3 mg/kg and –3.2 for placebo (P = .05), according to their report, which indicated a rapid onset of action apparent 1 week after starting treatment.

Zilucoplan 0.1 mg/kg also yielded a significant and clinically meaningful improvement versus placebo, but its magnitude was smaller and took 4 weeks to become apparent.

Treatment with zilucoplan also significantly improved MG Activities of Daily Living scores versus placebo, a key secondary endpoint of the trial, according to the researchers.

Treatment-emergent adverse events, which included local injection-site reactions, were mild and judged to be unrelated to the study treatment, according to the report.

Ra Pharmaceuticals funded the study. Dr. Howard reported disclosures related to Ra Pharmaceuticals, Alexion Pharmaceuticals, argenx, Viela Bio, and others.

SOURCE: Howard Jr JF et al. JAMA Neurol. 2020 Feb 17. doi: 10.1001/jamaneurol.2019.5125.

No antiepileptic drug (AED) is independently associated with cognitive dysfunction, according to research published online ahead of print Feb. 3 in Neurology. Optimizing AED therapy to reduce or prevent seizures is thus unlikely to affect cognition, according to the investigators.

Patients who take AEDs commonly report cognitive problems, but investigations into the cognitive effects of AEDs have yielded inconsistent results. “We were also interested in this association, as we often treat complex patients taking multiple or high-dose AEDs, and our patients often report cognitive dysfunction,” said Emma Foster, MBBS, an epilepsy fellow at Alfred Health and the Royal Melbourne Hospital in Victoria, Australia. “We were particularly interested to examine how much AEDs affect cognition relative to other factors. We commonly see patients in our tertiary epilepsy care unit who have had severe epilepsy for a long time or who have psychiatric disorders, and these factors may also contribute to cognitive dysfunction.”
 

Researchers analyzed patients admitted for video EEG monitoring

For their study, Dr. Foster and colleagues prospectively enrolled patients admitted to the Royal Melbourne Hospital’s video EEG monitoring unit between January 2009 and December 2016. Patients were included in the study if they were age 18 years or older, had been admitted for diagnostic or surgical evaluation, and had complete data for the relevant variables. Patients were prescribed AED monotherapy or polytherapy.

The researchers based epilepsy diagnoses on the 2014 International League Against Epilepsy criteria. Diagnoses of psychogenic nonepileptic seizures (PNES) were based on a consensus of epileptologists at weekly multidisciplinary clinical meetings, which was supported by evaluation of all available data. Some patients received a diagnosis of comorbid epilepsy and PNES. If data were insufficient to support a diagnosis of epilepsy or PNES, the admission was considered nondiagnostic.

All participants underwent neuropsychologic and neuropsychiatric screening. Researchers assessed patients’ objective, global cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), a validated instrument. Patients responded to the Quality of Life in Epilepsy inventory (QOLIE-89) to provide a measure of subjective cognitive function. They also responded to the Hospital Anxiety and Depression Scale (HADS) to screen for mood disorders.

Dr. Foster and colleagues measured seizure frequency through patient self-report. Patients averaged their seizure frequency during the 12-month period before admission to the video EEG unit. They categorized it according to a 12-point system in which 0 denotes patients who are seizure-free and not taking AEDs and 12 denotes patients in status epilepticus. Patients with PNES used the same scale to report event frequency, although the system was not designed for this purpose.
 

Almost half of patients were prescribed polypharmacy

The researchers included 331 patients in their analysis. The population’s mean age was 39.3 years, and about 62% of patients were female. Approximately 47% of patients had epilepsy, 25.7% had PNES, 6.6% had comorbid epilepsy and PNES, and 20.5% had a nondiagnostic outcome. Among patients with epilepsy, most (54.5%) had temporal lobe epilepsy, followed by extratemporal focal epilepsy (32.1%) and generalized epilepsy (13.5%). The mean number of AEDs prescribed on admission was 1.6, and mean seizure or event frequency score was 7.2, which indicated 1-3 seizures per month. Mean HADS depression score was within the normal range (5.7), and mean HADS anxiety score was in the borderline range (8.2).

Approximately 45% of patients were prescribed AED polypharmacy on admission, 25.1% were prescribed AED monotherapy, and 29.9% were prescribed no AED. Levetiracetam, valproate, and carbamazepine were the most frequently prescribed AEDs. Most patients with epilepsy (73.1%) were on polypharmacy, compared with 17.6% of patients with PNES, 63.6% of patients with epilepsy and PNES, and 8.8% of nondiagnostic patients.

Older age and greater seizure frequency predicted impaired objective cognitive function. Comorbid epilepsy and PNES appeared to predict impaired objective cognitive function as well, but the data were inconclusive. No AED was a significant predictor of objective cognitive function. Higher depression and anxiety scores and greater seizure frequency predicted impaired subjective cognitive function. No AED predicted subjective cognitive function.
 

Future studies could address particular cognitive domains

Previous studies have suggested that treatment with topiramate predicts objective or subjective cognitive function, but Dr. Foster and colleagues did not observe this result. The current findings suggest that topiramate may have a less significant effect on cognition than the literature suggests, they wrote. In addition, more evidence is needed to fully understand the effects of clobazam, valproate, phenytoin, and gabapentin because the analysis was underpowered for these drugs.

Although NUCOG assesses global cognitive function reliably, its ability to measure particular cognitive subdomains is limited. “We aim to conduct future research investigating the complex associations between different cognitive functions, including processing speed, and specific AEDs in this heterogeneous population,” said Dr. Foster.

Despite the study’s large sample size, the researchers could not explore potential interactions between various predictor variables. “Epilepsy may interact with the aging process or with other medical conditions associated with aging, such as hypertension and diabetes, and this may increase the risk of cognitive decline,” said Dr. Foster. “Older age may also be associated with reduced capacity to metabolize drugs, increased sensitivity to the cognitive and neurological effects of drugs, less cognitive reserve, and increased likelihood of taking multiple medications, which, along with AEDs, may exert a cognitive effect.”

The current findings may reduce concerns about the effects of AEDs on cognitive function and encourage neurologists to pursue the proper dosing for optimal seizure control, wrote the authors. “However, it is possible that some individuals may be more susceptible than others to AED-related cognitive dysfunction,” said Dr. Foster. “We do not have a robust way to predict who these patients will be, and it is still good practice to make patients aware that some people experience adverse cognitive effects from AEDs. However, it needs to be emphasized that it is unlikely to be the sole reason for their cognitive impairment. Other issues, such as poor seizure control or unrecognized or undertreated mood disorders, are even more important factors for impaired cognition.”

Patients who report cognitive problems should be screened for mood disorders, Dr. Foster continued. “It would also be important to consider whether the patients’ cognitive complaints arise from subtle clinical or subclinical seizure activity and subsequent postictal periods. To investigate this [question] further, clinicians may arrange for prolonged EEG monitoring. This [monitoring] could be done in an ambulatory setting or during an inpatient admission.”

The study was conducted without external funding. Dr. Foster and other investigators reported research funding from professional associations and pharmaceutical companies that was unrelated to the study.

egreb@mdedge.com

SOURCE: Foster E et al. Neurology. 2020 Feb 3. doi: 10.1212/WNL.0000000000009061.

No antiepileptic drug (AED) is independently associated with cognitive dysfunction, according to research published online ahead of print Feb. 3 in Neurology. Optimizing AED therapy to reduce or prevent seizures is thus unlikely to affect cognition, according to the investigators.

Patients who take AEDs commonly report cognitive problems, but investigations into the cognitive effects of AEDs have yielded inconsistent results. “We were also interested in this association, as we often treat complex patients taking multiple or high-dose AEDs, and our patients often report cognitive dysfunction,” said Emma Foster, MBBS, an epilepsy fellow at Alfred Health and the Royal Melbourne Hospital in Victoria, Australia. “We were particularly interested to examine how much AEDs affect cognition relative to other factors. We commonly see patients in our tertiary epilepsy care unit who have had severe epilepsy for a long time or who have psychiatric disorders, and these factors may also contribute to cognitive dysfunction.”
 

Researchers analyzed patients admitted for video EEG monitoring

For their study, Dr. Foster and colleagues prospectively enrolled patients admitted to the Royal Melbourne Hospital’s video EEG monitoring unit between January 2009 and December 2016. Patients were included in the study if they were age 18 years or older, had been admitted for diagnostic or surgical evaluation, and had complete data for the relevant variables. Patients were prescribed AED monotherapy or polytherapy.

The researchers based epilepsy diagnoses on the 2014 International League Against Epilepsy criteria. Diagnoses of psychogenic nonepileptic seizures (PNES) were based on a consensus of epileptologists at weekly multidisciplinary clinical meetings, which was supported by evaluation of all available data. Some patients received a diagnosis of comorbid epilepsy and PNES. If data were insufficient to support a diagnosis of epilepsy or PNES, the admission was considered nondiagnostic.

All participants underwent neuropsychologic and neuropsychiatric screening. Researchers assessed patients’ objective, global cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), a validated instrument. Patients responded to the Quality of Life in Epilepsy inventory (QOLIE-89) to provide a measure of subjective cognitive function. They also responded to the Hospital Anxiety and Depression Scale (HADS) to screen for mood disorders.

Dr. Foster and colleagues measured seizure frequency through patient self-report. Patients averaged their seizure frequency during the 12-month period before admission to the video EEG unit. They categorized it according to a 12-point system in which 0 denotes patients who are seizure-free and not taking AEDs and 12 denotes patients in status epilepticus. Patients with PNES used the same scale to report event frequency, although the system was not designed for this purpose.
 

Almost half of patients were prescribed polypharmacy

The researchers included 331 patients in their analysis. The population’s mean age was 39.3 years, and about 62% of patients were female. Approximately 47% of patients had epilepsy, 25.7% had PNES, 6.6% had comorbid epilepsy and PNES, and 20.5% had a nondiagnostic outcome. Among patients with epilepsy, most (54.5%) had temporal lobe epilepsy, followed by extratemporal focal epilepsy (32.1%) and generalized epilepsy (13.5%). The mean number of AEDs prescribed on admission was 1.6, and mean seizure or event frequency score was 7.2, which indicated 1-3 seizures per month. Mean HADS depression score was within the normal range (5.7), and mean HADS anxiety score was in the borderline range (8.2).

Approximately 45% of patients were prescribed AED polypharmacy on admission, 25.1% were prescribed AED monotherapy, and 29.9% were prescribed no AED. Levetiracetam, valproate, and carbamazepine were the most frequently prescribed AEDs. Most patients with epilepsy (73.1%) were on polypharmacy, compared with 17.6% of patients with PNES, 63.6% of patients with epilepsy and PNES, and 8.8% of nondiagnostic patients.

Older age and greater seizure frequency predicted impaired objective cognitive function. Comorbid epilepsy and PNES appeared to predict impaired objective cognitive function as well, but the data were inconclusive. No AED was a significant predictor of objective cognitive function. Higher depression and anxiety scores and greater seizure frequency predicted impaired subjective cognitive function. No AED predicted subjective cognitive function.
 

Future studies could address particular cognitive domains

Previous studies have suggested that treatment with topiramate predicts objective or subjective cognitive function, but Dr. Foster and colleagues did not observe this result. The current findings suggest that topiramate may have a less significant effect on cognition than the literature suggests, they wrote. In addition, more evidence is needed to fully understand the effects of clobazam, valproate, phenytoin, and gabapentin because the analysis was underpowered for these drugs.

Although NUCOG assesses global cognitive function reliably, its ability to measure particular cognitive subdomains is limited. “We aim to conduct future research investigating the complex associations between different cognitive functions, including processing speed, and specific AEDs in this heterogeneous population,” said Dr. Foster.

Despite the study’s large sample size, the researchers could not explore potential interactions between various predictor variables. “Epilepsy may interact with the aging process or with other medical conditions associated with aging, such as hypertension and diabetes, and this may increase the risk of cognitive decline,” said Dr. Foster. “Older age may also be associated with reduced capacity to metabolize drugs, increased sensitivity to the cognitive and neurological effects of drugs, less cognitive reserve, and increased likelihood of taking multiple medications, which, along with AEDs, may exert a cognitive effect.”

The current findings may reduce concerns about the effects of AEDs on cognitive function and encourage neurologists to pursue the proper dosing for optimal seizure control, wrote the authors. “However, it is possible that some individuals may be more susceptible than others to AED-related cognitive dysfunction,” said Dr. Foster. “We do not have a robust way to predict who these patients will be, and it is still good practice to make patients aware that some people experience adverse cognitive effects from AEDs. However, it needs to be emphasized that it is unlikely to be the sole reason for their cognitive impairment. Other issues, such as poor seizure control or unrecognized or undertreated mood disorders, are even more important factors for impaired cognition.”

Patients who report cognitive problems should be screened for mood disorders, Dr. Foster continued. “It would also be important to consider whether the patients’ cognitive complaints arise from subtle clinical or subclinical seizure activity and subsequent postictal periods. To investigate this [question] further, clinicians may arrange for prolonged EEG monitoring. This [monitoring] could be done in an ambulatory setting or during an inpatient admission.”

The study was conducted without external funding. Dr. Foster and other investigators reported research funding from professional associations and pharmaceutical companies that was unrelated to the study.

egreb@mdedge.com

SOURCE: Foster E et al. Neurology. 2020 Feb 3. doi: 10.1212/WNL.0000000000009061.

No antiepileptic drug (AED) is independently associated with cognitive dysfunction, according to research published online ahead of print Feb. 3 in Neurology. Optimizing AED therapy to reduce or prevent seizures is thus unlikely to affect cognition, according to the investigators.

Patients who take AEDs commonly report cognitive problems, but investigations into the cognitive effects of AEDs have yielded inconsistent results. “We were also interested in this association, as we often treat complex patients taking multiple or high-dose AEDs, and our patients often report cognitive dysfunction,” said Emma Foster, MBBS, an epilepsy fellow at Alfred Health and the Royal Melbourne Hospital in Victoria, Australia. “We were particularly interested to examine how much AEDs affect cognition relative to other factors. We commonly see patients in our tertiary epilepsy care unit who have had severe epilepsy for a long time or who have psychiatric disorders, and these factors may also contribute to cognitive dysfunction.”
 

Researchers analyzed patients admitted for video EEG monitoring

For their study, Dr. Foster and colleagues prospectively enrolled patients admitted to the Royal Melbourne Hospital’s video EEG monitoring unit between January 2009 and December 2016. Patients were included in the study if they were age 18 years or older, had been admitted for diagnostic or surgical evaluation, and had complete data for the relevant variables. Patients were prescribed AED monotherapy or polytherapy.

The researchers based epilepsy diagnoses on the 2014 International League Against Epilepsy criteria. Diagnoses of psychogenic nonepileptic seizures (PNES) were based on a consensus of epileptologists at weekly multidisciplinary clinical meetings, which was supported by evaluation of all available data. Some patients received a diagnosis of comorbid epilepsy and PNES. If data were insufficient to support a diagnosis of epilepsy or PNES, the admission was considered nondiagnostic.

All participants underwent neuropsychologic and neuropsychiatric screening. Researchers assessed patients’ objective, global cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), a validated instrument. Patients responded to the Quality of Life in Epilepsy inventory (QOLIE-89) to provide a measure of subjective cognitive function. They also responded to the Hospital Anxiety and Depression Scale (HADS) to screen for mood disorders.

Dr. Foster and colleagues measured seizure frequency through patient self-report. Patients averaged their seizure frequency during the 12-month period before admission to the video EEG unit. They categorized it according to a 12-point system in which 0 denotes patients who are seizure-free and not taking AEDs and 12 denotes patients in status epilepticus. Patients with PNES used the same scale to report event frequency, although the system was not designed for this purpose.
 

Almost half of patients were prescribed polypharmacy

The researchers included 331 patients in their analysis. The population’s mean age was 39.3 years, and about 62% of patients were female. Approximately 47% of patients had epilepsy, 25.7% had PNES, 6.6% had comorbid epilepsy and PNES, and 20.5% had a nondiagnostic outcome. Among patients with epilepsy, most (54.5%) had temporal lobe epilepsy, followed by extratemporal focal epilepsy (32.1%) and generalized epilepsy (13.5%). The mean number of AEDs prescribed on admission was 1.6, and mean seizure or event frequency score was 7.2, which indicated 1-3 seizures per month. Mean HADS depression score was within the normal range (5.7), and mean HADS anxiety score was in the borderline range (8.2).

Approximately 45% of patients were prescribed AED polypharmacy on admission, 25.1% were prescribed AED monotherapy, and 29.9% were prescribed no AED. Levetiracetam, valproate, and carbamazepine were the most frequently prescribed AEDs. Most patients with epilepsy (73.1%) were on polypharmacy, compared with 17.6% of patients with PNES, 63.6% of patients with epilepsy and PNES, and 8.8% of nondiagnostic patients.

Older age and greater seizure frequency predicted impaired objective cognitive function. Comorbid epilepsy and PNES appeared to predict impaired objective cognitive function as well, but the data were inconclusive. No AED was a significant predictor of objective cognitive function. Higher depression and anxiety scores and greater seizure frequency predicted impaired subjective cognitive function. No AED predicted subjective cognitive function.
 

Future studies could address particular cognitive domains

Previous studies have suggested that treatment with topiramate predicts objective or subjective cognitive function, but Dr. Foster and colleagues did not observe this result. The current findings suggest that topiramate may have a less significant effect on cognition than the literature suggests, they wrote. In addition, more evidence is needed to fully understand the effects of clobazam, valproate, phenytoin, and gabapentin because the analysis was underpowered for these drugs.

Although NUCOG assesses global cognitive function reliably, its ability to measure particular cognitive subdomains is limited. “We aim to conduct future research investigating the complex associations between different cognitive functions, including processing speed, and specific AEDs in this heterogeneous population,” said Dr. Foster.

Despite the study’s large sample size, the researchers could not explore potential interactions between various predictor variables. “Epilepsy may interact with the aging process or with other medical conditions associated with aging, such as hypertension and diabetes, and this may increase the risk of cognitive decline,” said Dr. Foster. “Older age may also be associated with reduced capacity to metabolize drugs, increased sensitivity to the cognitive and neurological effects of drugs, less cognitive reserve, and increased likelihood of taking multiple medications, which, along with AEDs, may exert a cognitive effect.”

The current findings may reduce concerns about the effects of AEDs on cognitive function and encourage neurologists to pursue the proper dosing for optimal seizure control, wrote the authors. “However, it is possible that some individuals may be more susceptible than others to AED-related cognitive dysfunction,” said Dr. Foster. “We do not have a robust way to predict who these patients will be, and it is still good practice to make patients aware that some people experience adverse cognitive effects from AEDs. However, it needs to be emphasized that it is unlikely to be the sole reason for their cognitive impairment. Other issues, such as poor seizure control or unrecognized or undertreated mood disorders, are even more important factors for impaired cognition.”

Patients who report cognitive problems should be screened for mood disorders, Dr. Foster continued. “It would also be important to consider whether the patients’ cognitive complaints arise from subtle clinical or subclinical seizure activity and subsequent postictal periods. To investigate this [question] further, clinicians may arrange for prolonged EEG monitoring. This [monitoring] could be done in an ambulatory setting or during an inpatient admission.”

The study was conducted without external funding. Dr. Foster and other investigators reported research funding from professional associations and pharmaceutical companies that was unrelated to the study.

egreb@mdedge.com

SOURCE: Foster E et al. Neurology. 2020 Feb 3. doi: 10.1212/WNL.0000000000009061.

In 2017, roughly 3 years after evidence from several studies made endovascular thrombectomy first-line treatment for selected acute ischemic stroke patients, the treatment was available at barely more than one-third of all U.S. stroke centers, available within 30-minute access to just over 30% of Americans, and available within 15-minute access to one-fifth of U.S. residents, based on information in a comprehensive U.S. database.

Heba Sarraj

These numbers showed that “current direct EVT [endovascular thrombectomy] access in the United States is suboptimal under predominate EMS routing protocols,” Amrou Sarraj, MD, and his associates wrote in an article published online in Stroke on Feb. 12. “Only in eight states did the coverage exceed 25% of the population, and nine states had coverage for less than 10% of the population. These results reflect limited access to an effective treatment modality that would improve clinical outcomes in patients with large strokes and prevent potentially devastating disability,” wrote Dr. Sarraj, chief of the general neurology service at Memorial-Hermann Hospital in Houston and coauthors.

Their analysis of data collected in 2017 by the Medicare Provider Analysis and Review (MEDPAR) database, maintained by the Centers for Medicare & Medicaid Services, identified two apparently effective ways to improve EVT access for acute ischemic stroke patients: First, systematically divert patients to a nearby center that offers EVT even when it means bypassing a closer stroke center that does not perform EVT when the added travel time is less than 15 minutes. Second, convert selected stroke centers that currently do not perform EVT into centers that do. Between these two approaches, the strategy of having ambulances bypass stroke centers that do not perform EVT and continuing to ones that do generally has the greater potential to boost access, the authors found. They based their analysis exclusively on their calculations of expected consequences rather than actual experience.

The calculations showed that bypassing non-EVT centers when the added bypass time computed to less than 15 minutes linked with an anticipated overall U.S. gain in access of about 17%, or 52 million people, extending the ability of acute ischemic stroke patients able to quickly reach an EVT center to about 37% of the American public. The second approach to boost access, converting the top 10% of stroke centers based on case volume that currently do not provide EVT to centers that do offer it, would result in expanded access for about 23 million additional Americans, raising the total with access to about 27% of the public, the new report said.

As part of this analysis, the MEDPAR data identified 1,941 U.S. centers providing stroke services during 2017, of which 713 (37%) had performed at least one EVT procedure. By comparison, 2015 MEDPAR data showed 577 U.S. stroke centers performing EVT, indicating that during the 2-3 years following several reports in early 2015 on the net benefits of EVT for acute ischemic stroke patients, the number of U.S. stroke centers offering this treatment had grown by a relative 24%. Based on the locations of the stroke centers that made EVT available in 2017, Dr. Sarraj and coauthors calculated that the 713 EVT-capable stroke centers provided emergency access within a 15-minute ground-ambulance trip for 61 million Americans (20% of the U.S. population), and within a 30-minute ground-transport trip to 95 million residents (31%).

Boosting these numbers by implementing a systematic bypass of stroke patients past non-EVT stroke centers to nearby centers that are EVT capable “has the benefit of ease of implementation and requires less time and resources,” the authors said. However, they also noted the heterogeneity of circumstances based on variables like population density and stroke center distribution, which means that in some locations the most effective way to boost access would be by increasing the number of stroke centers that provide EVT.

In 2018, Dr. Sarraj and associates reported results from a similar analysis of MEDPAR data that used 30-minute and 60-minute ground-transport times as the criteria for their calculations.

The study received no commercial funding. Dr. Sarraj reported receiving research funding from Stryker Neurovascular outside of this work. One coauthor reported serving in roles for the University of Texas Health System for which the institution has been funded via various industry and government grants, and another coauthor reported receiving research funding from the Patient-Centered Outcomes Research Institute, the National Institutes of Health, Genentech, and CSL Behring, as well as consulting fees from Frazer Ltd.

mzoler@mdedge.com

SOURCE: Sarraj A et al. Stroke. 2020 Feb 12. doi: 10.1161/STROKEAHA.120.028850.

In 2017, roughly 3 years after evidence from several studies made endovascular thrombectomy first-line treatment for selected acute ischemic stroke patients, the treatment was available at barely more than one-third of all U.S. stroke centers, available within 30-minute access to just over 30% of Americans, and available within 15-minute access to one-fifth of U.S. residents, based on information in a comprehensive U.S. database.

Heba Sarraj

These numbers showed that “current direct EVT [endovascular thrombectomy] access in the United States is suboptimal under predominate EMS routing protocols,” Amrou Sarraj, MD, and his associates wrote in an article published online in Stroke on Feb. 12. “Only in eight states did the coverage exceed 25% of the population, and nine states had coverage for less than 10% of the population. These results reflect limited access to an effective treatment modality that would improve clinical outcomes in patients with large strokes and prevent potentially devastating disability,” wrote Dr. Sarraj, chief of the general neurology service at Memorial-Hermann Hospital in Houston and coauthors.

Their analysis of data collected in 2017 by the Medicare Provider Analysis and Review (MEDPAR) database, maintained by the Centers for Medicare & Medicaid Services, identified two apparently effective ways to improve EVT access for acute ischemic stroke patients: First, systematically divert patients to a nearby center that offers EVT even when it means bypassing a closer stroke center that does not perform EVT when the added travel time is less than 15 minutes. Second, convert selected stroke centers that currently do not perform EVT into centers that do. Between these two approaches, the strategy of having ambulances bypass stroke centers that do not perform EVT and continuing to ones that do generally has the greater potential to boost access, the authors found. They based their analysis exclusively on their calculations of expected consequences rather than actual experience.

The calculations showed that bypassing non-EVT centers when the added bypass time computed to less than 15 minutes linked with an anticipated overall U.S. gain in access of about 17%, or 52 million people, extending the ability of acute ischemic stroke patients able to quickly reach an EVT center to about 37% of the American public. The second approach to boost access, converting the top 10% of stroke centers based on case volume that currently do not provide EVT to centers that do offer it, would result in expanded access for about 23 million additional Americans, raising the total with access to about 27% of the public, the new report said.

As part of this analysis, the MEDPAR data identified 1,941 U.S. centers providing stroke services during 2017, of which 713 (37%) had performed at least one EVT procedure. By comparison, 2015 MEDPAR data showed 577 U.S. stroke centers performing EVT, indicating that during the 2-3 years following several reports in early 2015 on the net benefits of EVT for acute ischemic stroke patients, the number of U.S. stroke centers offering this treatment had grown by a relative 24%. Based on the locations of the stroke centers that made EVT available in 2017, Dr. Sarraj and coauthors calculated that the 713 EVT-capable stroke centers provided emergency access within a 15-minute ground-ambulance trip for 61 million Americans (20% of the U.S. population), and within a 30-minute ground-transport trip to 95 million residents (31%).

Boosting these numbers by implementing a systematic bypass of stroke patients past non-EVT stroke centers to nearby centers that are EVT capable “has the benefit of ease of implementation and requires less time and resources,” the authors said. However, they also noted the heterogeneity of circumstances based on variables like population density and stroke center distribution, which means that in some locations the most effective way to boost access would be by increasing the number of stroke centers that provide EVT.

In 2018, Dr. Sarraj and associates reported results from a similar analysis of MEDPAR data that used 30-minute and 60-minute ground-transport times as the criteria for their calculations.

The study received no commercial funding. Dr. Sarraj reported receiving research funding from Stryker Neurovascular outside of this work. One coauthor reported serving in roles for the University of Texas Health System for which the institution has been funded via various industry and government grants, and another coauthor reported receiving research funding from the Patient-Centered Outcomes Research Institute, the National Institutes of Health, Genentech, and CSL Behring, as well as consulting fees from Frazer Ltd.

mzoler@mdedge.com

SOURCE: Sarraj A et al. Stroke. 2020 Feb 12. doi: 10.1161/STROKEAHA.120.028850.

In 2017, roughly 3 years after evidence from several studies made endovascular thrombectomy first-line treatment for selected acute ischemic stroke patients, the treatment was available at barely more than one-third of all U.S. stroke centers, available within 30-minute access to just over 30% of Americans, and available within 15-minute access to one-fifth of U.S. residents, based on information in a comprehensive U.S. database.

Heba Sarraj

These numbers showed that “current direct EVT [endovascular thrombectomy] access in the United States is suboptimal under predominate EMS routing protocols,” Amrou Sarraj, MD, and his associates wrote in an article published online in Stroke on Feb. 12. “Only in eight states did the coverage exceed 25% of the population, and nine states had coverage for less than 10% of the population. These results reflect limited access to an effective treatment modality that would improve clinical outcomes in patients with large strokes and prevent potentially devastating disability,” wrote Dr. Sarraj, chief of the general neurology service at Memorial-Hermann Hospital in Houston and coauthors.

Their analysis of data collected in 2017 by the Medicare Provider Analysis and Review (MEDPAR) database, maintained by the Centers for Medicare & Medicaid Services, identified two apparently effective ways to improve EVT access for acute ischemic stroke patients: First, systematically divert patients to a nearby center that offers EVT even when it means bypassing a closer stroke center that does not perform EVT when the added travel time is less than 15 minutes. Second, convert selected stroke centers that currently do not perform EVT into centers that do. Between these two approaches, the strategy of having ambulances bypass stroke centers that do not perform EVT and continuing to ones that do generally has the greater potential to boost access, the authors found. They based their analysis exclusively on their calculations of expected consequences rather than actual experience.

The calculations showed that bypassing non-EVT centers when the added bypass time computed to less than 15 minutes linked with an anticipated overall U.S. gain in access of about 17%, or 52 million people, extending the ability of acute ischemic stroke patients able to quickly reach an EVT center to about 37% of the American public. The second approach to boost access, converting the top 10% of stroke centers based on case volume that currently do not provide EVT to centers that do offer it, would result in expanded access for about 23 million additional Americans, raising the total with access to about 27% of the public, the new report said.

As part of this analysis, the MEDPAR data identified 1,941 U.S. centers providing stroke services during 2017, of which 713 (37%) had performed at least one EVT procedure. By comparison, 2015 MEDPAR data showed 577 U.S. stroke centers performing EVT, indicating that during the 2-3 years following several reports in early 2015 on the net benefits of EVT for acute ischemic stroke patients, the number of U.S. stroke centers offering this treatment had grown by a relative 24%. Based on the locations of the stroke centers that made EVT available in 2017, Dr. Sarraj and coauthors calculated that the 713 EVT-capable stroke centers provided emergency access within a 15-minute ground-ambulance trip for 61 million Americans (20% of the U.S. population), and within a 30-minute ground-transport trip to 95 million residents (31%).

Boosting these numbers by implementing a systematic bypass of stroke patients past non-EVT stroke centers to nearby centers that are EVT capable “has the benefit of ease of implementation and requires less time and resources,” the authors said. However, they also noted the heterogeneity of circumstances based on variables like population density and stroke center distribution, which means that in some locations the most effective way to boost access would be by increasing the number of stroke centers that provide EVT.

In 2018, Dr. Sarraj and associates reported results from a similar analysis of MEDPAR data that used 30-minute and 60-minute ground-transport times as the criteria for their calculations.

The study received no commercial funding. Dr. Sarraj reported receiving research funding from Stryker Neurovascular outside of this work. One coauthor reported serving in roles for the University of Texas Health System for which the institution has been funded via various industry and government grants, and another coauthor reported receiving research funding from the Patient-Centered Outcomes Research Institute, the National Institutes of Health, Genentech, and CSL Behring, as well as consulting fees from Frazer Ltd.

mzoler@mdedge.com

SOURCE: Sarraj A et al. Stroke. 2020 Feb 12. doi: 10.1161/STROKEAHA.120.028850.

The American Academy of Neurology (AAN) has issued a new guideline for the treatment of sleep problems in children and teenagers with autism spectrum disorders (ASD). The guideline was published online ahead of print Feb. 12 in Neurology.

“While up to 40% of children and teens in the general population will have sleep problems at some point during their childhood, such problems usually lessen with age,” lead author Ashura Williams Buckley, MD, director of the Sleep and Neurodevelopment Service at the National Institute of Mental Health in Bethesda, Md., said in a press release. “For children and teens with autism, sleep problems are more common and more likely to persist, resulting in poor health and poor quality of life. Some sleep problems may be directly related to autism, but others are not. Regardless, autism symptoms may make sleep problems worse.”
 

Few evidence-based treatments are available

Dr. Williams Buckley and colleagues developed the current guideline to evaluate which pharmacologic, behavioral, and complementary and alternative medicine (CAM) interventions improve bedtime resistance, sleep onset latency, sleep continuity, total sleep time, and daytime behavior in children and adolescents with ASD. The panel evaluated 900 abstracts of articles that had been included in systematic reviews, as well as 1,087 additional abstracts. One hundred thirty-nine articles were potentially relevant, 12 met criteria for data extraction, and eight were rated class III or higher and were included in the panel’s review.

The authors observed what they called a dearth of evidence-based treatments for sleep dysregulation in ASD. Evidence indicates that melatonin, with or without cognitive–behavioral therapy (CBT), improves several sleep outcomes, compared with placebo. “Evidence for other interventions is largely lacking,” wrote Dr. Williams Buckley and colleagues. They observed a lack of long-term safety data for melatonin in children, which they considered concerning, because melatonin affects the hypothalamic–gonadal axis and can potentially influence pubertal development.
 

Screening for comorbid conditions and concomitant medications

The guideline recommends that clinicians assess children with ASD and sleep disturbances for coexisting conditions and concomitant medications that could be contributing to these sleep disturbances. They should ensure that children receive appropriate treatment for coexisting conditions and adjust or discontinue potentially problematic medications appropriately, according to the guideline.

Furthermore, clinicians should counsel parents or guardians about behavioral strategies as a first-line treatment for improving sleep function. These strategies could be administered alone or with pharmacologic or neutraceutical approaches as needed, according to the authors. Suggested behavioral approaches include unmodified extinction (i.e., imposing a bedtime and ignoring a child’s protests), graduated extinction (i.e., ignoring protests for a specified period before responding), positive routines (i.e., establishing pre-bedtime calming rituals), and bedtime fading (i.e., putting a child to bed close to the time he or she begins to fall asleep).

If a child’s contributing coexisting conditions and medications have been addressed and behavioral strategies have not been helpful, clinicians should offer melatonin, according to the guideline. Because over-the-counter formulations contain variable concentrations of melatonin, clinicians should write a prescription for it or recommend high-purity pharmaceutical grade melatonin. The initial dose should be 1-3 mg/day at 60-30 minutes before bedtime. The dose can be titrated to 10 mg/day. Clinicians also should counsel children and their parents about potential adverse events of melatonin and the lack of long-term safety data, according to the guideline.

In addition, clinicians should advise children and parents that no evidence supports the routine use of weighted blankets or specialized mattress technology for improving sleep. Parents who ask about weighted blankets should be told that the reviewed trial reported no serious adverse events with this intervention, and that blankets could be a reasonable nonpharmacologic approach for some patients, according to the guideline.
 

Optimal outcome measures are undefined

Dr. Williams Buckley and colleagues also suggested areas for future research. Investigators have not yet defined optimal outcome measures (e.g., questionnaires, polysomnography, and actigraphy) that balance tolerability and accuracy, they wrote. Clinically important differences for most measures also have yet to be determined. Researchers should investigate whether long-term adverse events are associated with chronic melatonin use and study patients with ASD and comorbid mood disorders, wrote the authors. “Research tying the underlying neurobiology in early-life sleep disruption to behavior might help clinicians and researchers understand which treatments might work for which people with ASD,” they concluded.

The AAN supported the development of the guideline. Dr. Williams Buckley had no conflicts of interest. Six authors had conflicts of interest that the AAN deemed not significant enough to prevent their participation in the development of the guideline.

egreb@mdedge.com

SOURCE: Williams Buckley A et al. Neurology. 2020;94:393-405. doi: 10.1212/WNL0000000000009033.

The American Academy of Neurology (AAN) has issued a new guideline for the treatment of sleep problems in children and teenagers with autism spectrum disorders (ASD). The guideline was published online ahead of print Feb. 12 in Neurology.

“While up to 40% of children and teens in the general population will have sleep problems at some point during their childhood, such problems usually lessen with age,” lead author Ashura Williams Buckley, MD, director of the Sleep and Neurodevelopment Service at the National Institute of Mental Health in Bethesda, Md., said in a press release. “For children and teens with autism, sleep problems are more common and more likely to persist, resulting in poor health and poor quality of life. Some sleep problems may be directly related to autism, but others are not. Regardless, autism symptoms may make sleep problems worse.”
 

Few evidence-based treatments are available

Dr. Williams Buckley and colleagues developed the current guideline to evaluate which pharmacologic, behavioral, and complementary and alternative medicine (CAM) interventions improve bedtime resistance, sleep onset latency, sleep continuity, total sleep time, and daytime behavior in children and adolescents with ASD. The panel evaluated 900 abstracts of articles that had been included in systematic reviews, as well as 1,087 additional abstracts. One hundred thirty-nine articles were potentially relevant, 12 met criteria for data extraction, and eight were rated class III or higher and were included in the panel’s review.

The authors observed what they called a dearth of evidence-based treatments for sleep dysregulation in ASD. Evidence indicates that melatonin, with or without cognitive–behavioral therapy (CBT), improves several sleep outcomes, compared with placebo. “Evidence for other interventions is largely lacking,” wrote Dr. Williams Buckley and colleagues. They observed a lack of long-term safety data for melatonin in children, which they considered concerning, because melatonin affects the hypothalamic–gonadal axis and can potentially influence pubertal development.
 

Screening for comorbid conditions and concomitant medications

The guideline recommends that clinicians assess children with ASD and sleep disturbances for coexisting conditions and concomitant medications that could be contributing to these sleep disturbances. They should ensure that children receive appropriate treatment for coexisting conditions and adjust or discontinue potentially problematic medications appropriately, according to the guideline.

Furthermore, clinicians should counsel parents or guardians about behavioral strategies as a first-line treatment for improving sleep function. These strategies could be administered alone or with pharmacologic or neutraceutical approaches as needed, according to the authors. Suggested behavioral approaches include unmodified extinction (i.e., imposing a bedtime and ignoring a child’s protests), graduated extinction (i.e., ignoring protests for a specified period before responding), positive routines (i.e., establishing pre-bedtime calming rituals), and bedtime fading (i.e., putting a child to bed close to the time he or she begins to fall asleep).

If a child’s contributing coexisting conditions and medications have been addressed and behavioral strategies have not been helpful, clinicians should offer melatonin, according to the guideline. Because over-the-counter formulations contain variable concentrations of melatonin, clinicians should write a prescription for it or recommend high-purity pharmaceutical grade melatonin. The initial dose should be 1-3 mg/day at 60-30 minutes before bedtime. The dose can be titrated to 10 mg/day. Clinicians also should counsel children and their parents about potential adverse events of melatonin and the lack of long-term safety data, according to the guideline.

In addition, clinicians should advise children and parents that no evidence supports the routine use of weighted blankets or specialized mattress technology for improving sleep. Parents who ask about weighted blankets should be told that the reviewed trial reported no serious adverse events with this intervention, and that blankets could be a reasonable nonpharmacologic approach for some patients, according to the guideline.
 

Optimal outcome measures are undefined

Dr. Williams Buckley and colleagues also suggested areas for future research. Investigators have not yet defined optimal outcome measures (e.g., questionnaires, polysomnography, and actigraphy) that balance tolerability and accuracy, they wrote. Clinically important differences for most measures also have yet to be determined. Researchers should investigate whether long-term adverse events are associated with chronic melatonin use and study patients with ASD and comorbid mood disorders, wrote the authors. “Research tying the underlying neurobiology in early-life sleep disruption to behavior might help clinicians and researchers understand which treatments might work for which people with ASD,” they concluded.

The AAN supported the development of the guideline. Dr. Williams Buckley had no conflicts of interest. Six authors had conflicts of interest that the AAN deemed not significant enough to prevent their participation in the development of the guideline.

egreb@mdedge.com

SOURCE: Williams Buckley A et al. Neurology. 2020;94:393-405. doi: 10.1212/WNL0000000000009033.

The American Academy of Neurology (AAN) has issued a new guideline for the treatment of sleep problems in children and teenagers with autism spectrum disorders (ASD). The guideline was published online ahead of print Feb. 12 in Neurology.

“While up to 40% of children and teens in the general population will have sleep problems at some point during their childhood, such problems usually lessen with age,” lead author Ashura Williams Buckley, MD, director of the Sleep and Neurodevelopment Service at the National Institute of Mental Health in Bethesda, Md., said in a press release. “For children and teens with autism, sleep problems are more common and more likely to persist, resulting in poor health and poor quality of life. Some sleep problems may be directly related to autism, but others are not. Regardless, autism symptoms may make sleep problems worse.”
 

Few evidence-based treatments are available

Dr. Williams Buckley and colleagues developed the current guideline to evaluate which pharmacologic, behavioral, and complementary and alternative medicine (CAM) interventions improve bedtime resistance, sleep onset latency, sleep continuity, total sleep time, and daytime behavior in children and adolescents with ASD. The panel evaluated 900 abstracts of articles that had been included in systematic reviews, as well as 1,087 additional abstracts. One hundred thirty-nine articles were potentially relevant, 12 met criteria for data extraction, and eight were rated class III or higher and were included in the panel’s review.

The authors observed what they called a dearth of evidence-based treatments for sleep dysregulation in ASD. Evidence indicates that melatonin, with or without cognitive–behavioral therapy (CBT), improves several sleep outcomes, compared with placebo. “Evidence for other interventions is largely lacking,” wrote Dr. Williams Buckley and colleagues. They observed a lack of long-term safety data for melatonin in children, which they considered concerning, because melatonin affects the hypothalamic–gonadal axis and can potentially influence pubertal development.
 

Screening for comorbid conditions and concomitant medications

The guideline recommends that clinicians assess children with ASD and sleep disturbances for coexisting conditions and concomitant medications that could be contributing to these sleep disturbances. They should ensure that children receive appropriate treatment for coexisting conditions and adjust or discontinue potentially problematic medications appropriately, according to the guideline.

Furthermore, clinicians should counsel parents or guardians about behavioral strategies as a first-line treatment for improving sleep function. These strategies could be administered alone or with pharmacologic or neutraceutical approaches as needed, according to the authors. Suggested behavioral approaches include unmodified extinction (i.e., imposing a bedtime and ignoring a child’s protests), graduated extinction (i.e., ignoring protests for a specified period before responding), positive routines (i.e., establishing pre-bedtime calming rituals), and bedtime fading (i.e., putting a child to bed close to the time he or she begins to fall asleep).

If a child’s contributing coexisting conditions and medications have been addressed and behavioral strategies have not been helpful, clinicians should offer melatonin, according to the guideline. Because over-the-counter formulations contain variable concentrations of melatonin, clinicians should write a prescription for it or recommend high-purity pharmaceutical grade melatonin. The initial dose should be 1-3 mg/day at 60-30 minutes before bedtime. The dose can be titrated to 10 mg/day. Clinicians also should counsel children and their parents about potential adverse events of melatonin and the lack of long-term safety data, according to the guideline.

In addition, clinicians should advise children and parents that no evidence supports the routine use of weighted blankets or specialized mattress technology for improving sleep. Parents who ask about weighted blankets should be told that the reviewed trial reported no serious adverse events with this intervention, and that blankets could be a reasonable nonpharmacologic approach for some patients, according to the guideline.
 

Optimal outcome measures are undefined

Dr. Williams Buckley and colleagues also suggested areas for future research. Investigators have not yet defined optimal outcome measures (e.g., questionnaires, polysomnography, and actigraphy) that balance tolerability and accuracy, they wrote. Clinically important differences for most measures also have yet to be determined. Researchers should investigate whether long-term adverse events are associated with chronic melatonin use and study patients with ASD and comorbid mood disorders, wrote the authors. “Research tying the underlying neurobiology in early-life sleep disruption to behavior might help clinicians and researchers understand which treatments might work for which people with ASD,” they concluded.

The AAN supported the development of the guideline. Dr. Williams Buckley had no conflicts of interest. Six authors had conflicts of interest that the AAN deemed not significant enough to prevent their participation in the development of the guideline.

egreb@mdedge.com

SOURCE: Williams Buckley A et al. Neurology. 2020;94:393-405. doi: 10.1212/WNL0000000000009033.

In its first year of operation, a mobile stroke unit in Melbourne demonstrated substantial savings in time to commencement of both thrombolysis and endovascular thrombectomy (EVT), results from a prospective study showed.

“While previously published data from MSU [mobile stroke unit] services in Europe and North America show substantial reductions in time to thrombolysis of approximately 30-45 minutes, little is known about the clinical impact on EVT,” first author Henry Zhao, MBBS, and colleagues wrote in a study published in Stroke.

Launched in November 2017, the Melbourne MSU is based at a large comprehensive stroke center and operates with a 20-km radius, servicing about 1.7 million people within the city of Melbourne. It is staffed with an onboard neurologist or senior stroke fellow who provides primary assessment and treatment decisions, a stroke advanced practice nurse who provides clinical support and treatment administration, a clinician who provides CT imaging, and advanced life support and mobile intensive care paramedics who provide transport logistics and paramedicine support. For the current analysis, MSU patients who received reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment, which the researchers used quantile regression analysis to determine. Time savings were subsequently converted to disability-adjusted life years (DALY) avoiding using published estimates.

Dr. Zhao of the Melbourne Brain Centre and department of neurology at Royal Melbourne Hospital and his colleagues reported that, in its first year of operation, the Melbourne MSU administered prehospital thrombolysis to 100 patients with a mean age of nearly 74 years. More than half of the patients (62%) were male. Compared with controls, the median time savings per MSU patient was 26 minutes for dispatch to hospital arrival and 15 minutes for hospital arrival to thrombolysis (P less than .0010 for both associations). The calculated overall time saving from dispatch to thrombolysis was 42.5 minutes.

Over the same time period, 41 MSU patients with a mean age of 76 years received EVT dispatch-to-treatment time saving of 51 minutes (P less than 0.001). This included a median time saving of 17 minutes for EVT hospital arrival to arterial puncture for MSU patients (P = .001). Overall estimated median DALYs saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT.

“The benefit in EVT patients was primarily driven by prehospital MSU diagnosis of large vessel occlusion, which enabled bypass of a local non-EVT center directly to a comprehensive stroke center in almost 50% of patients with large vessel occlusion,” the researchers wrote. “Even when patients were located close to an EVT center, MSU pre-notification and facilitated workflows achieved a reduction in hospital arrival to arterial puncture by one-third. Furthermore, the time saving was seen despite the majority of EVT patients receiving repeat imaging in hospital to visualize the extracranial circulation.”

The study is scheduled to be presented at the International Stroke Conference on Feb. 20.

The Melbourne MSU received funding from the Australian Commonwealth Government, Victorian State Government, Royal Melbourne Hospital Neurosciences Foundation, Stroke Foundation, the Florey Institute of Neurosciences and Mental Health, the University of Melbourne, Boehringer Ingelheim, and private donation. Dr. Zhao disclosed that he has received grants from the Australian Commonwealth Government and the University of Melbourne and personal fees from Boehringer Ingelheim.

dbrunk@mdedge.com

SOURCE: Zhao H et al. Stroke. 2020 Feb 12. doi: 10.1161/strokeaha.119.027843.

In its first year of operation, a mobile stroke unit in Melbourne demonstrated substantial savings in time to commencement of both thrombolysis and endovascular thrombectomy (EVT), results from a prospective study showed.

“While previously published data from MSU [mobile stroke unit] services in Europe and North America show substantial reductions in time to thrombolysis of approximately 30-45 minutes, little is known about the clinical impact on EVT,” first author Henry Zhao, MBBS, and colleagues wrote in a study published in Stroke.

Launched in November 2017, the Melbourne MSU is based at a large comprehensive stroke center and operates with a 20-km radius, servicing about 1.7 million people within the city of Melbourne. It is staffed with an onboard neurologist or senior stroke fellow who provides primary assessment and treatment decisions, a stroke advanced practice nurse who provides clinical support and treatment administration, a clinician who provides CT imaging, and advanced life support and mobile intensive care paramedics who provide transport logistics and paramedicine support. For the current analysis, MSU patients who received reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment, which the researchers used quantile regression analysis to determine. Time savings were subsequently converted to disability-adjusted life years (DALY) avoiding using published estimates.

Dr. Zhao of the Melbourne Brain Centre and department of neurology at Royal Melbourne Hospital and his colleagues reported that, in its first year of operation, the Melbourne MSU administered prehospital thrombolysis to 100 patients with a mean age of nearly 74 years. More than half of the patients (62%) were male. Compared with controls, the median time savings per MSU patient was 26 minutes for dispatch to hospital arrival and 15 minutes for hospital arrival to thrombolysis (P less than .0010 for both associations). The calculated overall time saving from dispatch to thrombolysis was 42.5 minutes.

Over the same time period, 41 MSU patients with a mean age of 76 years received EVT dispatch-to-treatment time saving of 51 minutes (P less than 0.001). This included a median time saving of 17 minutes for EVT hospital arrival to arterial puncture for MSU patients (P = .001). Overall estimated median DALYs saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT.

“The benefit in EVT patients was primarily driven by prehospital MSU diagnosis of large vessel occlusion, which enabled bypass of a local non-EVT center directly to a comprehensive stroke center in almost 50% of patients with large vessel occlusion,” the researchers wrote. “Even when patients were located close to an EVT center, MSU pre-notification and facilitated workflows achieved a reduction in hospital arrival to arterial puncture by one-third. Furthermore, the time saving was seen despite the majority of EVT patients receiving repeat imaging in hospital to visualize the extracranial circulation.”

The study is scheduled to be presented at the International Stroke Conference on Feb. 20.

The Melbourne MSU received funding from the Australian Commonwealth Government, Victorian State Government, Royal Melbourne Hospital Neurosciences Foundation, Stroke Foundation, the Florey Institute of Neurosciences and Mental Health, the University of Melbourne, Boehringer Ingelheim, and private donation. Dr. Zhao disclosed that he has received grants from the Australian Commonwealth Government and the University of Melbourne and personal fees from Boehringer Ingelheim.

dbrunk@mdedge.com

SOURCE: Zhao H et al. Stroke. 2020 Feb 12. doi: 10.1161/strokeaha.119.027843.

In its first year of operation, a mobile stroke unit in Melbourne demonstrated substantial savings in time to commencement of both thrombolysis and endovascular thrombectomy (EVT), results from a prospective study showed.

“While previously published data from MSU [mobile stroke unit] services in Europe and North America show substantial reductions in time to thrombolysis of approximately 30-45 minutes, little is known about the clinical impact on EVT,” first author Henry Zhao, MBBS, and colleagues wrote in a study published in Stroke.

Launched in November 2017, the Melbourne MSU is based at a large comprehensive stroke center and operates with a 20-km radius, servicing about 1.7 million people within the city of Melbourne. It is staffed with an onboard neurologist or senior stroke fellow who provides primary assessment and treatment decisions, a stroke advanced practice nurse who provides clinical support and treatment administration, a clinician who provides CT imaging, and advanced life support and mobile intensive care paramedics who provide transport logistics and paramedicine support. For the current analysis, MSU patients who received reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment, which the researchers used quantile regression analysis to determine. Time savings were subsequently converted to disability-adjusted life years (DALY) avoiding using published estimates.

Dr. Zhao of the Melbourne Brain Centre and department of neurology at Royal Melbourne Hospital and his colleagues reported that, in its first year of operation, the Melbourne MSU administered prehospital thrombolysis to 100 patients with a mean age of nearly 74 years. More than half of the patients (62%) were male. Compared with controls, the median time savings per MSU patient was 26 minutes for dispatch to hospital arrival and 15 minutes for hospital arrival to thrombolysis (P less than .0010 for both associations). The calculated overall time saving from dispatch to thrombolysis was 42.5 minutes.

Over the same time period, 41 MSU patients with a mean age of 76 years received EVT dispatch-to-treatment time saving of 51 minutes (P less than 0.001). This included a median time saving of 17 minutes for EVT hospital arrival to arterial puncture for MSU patients (P = .001). Overall estimated median DALYs saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT.

“The benefit in EVT patients was primarily driven by prehospital MSU diagnosis of large vessel occlusion, which enabled bypass of a local non-EVT center directly to a comprehensive stroke center in almost 50% of patients with large vessel occlusion,” the researchers wrote. “Even when patients were located close to an EVT center, MSU pre-notification and facilitated workflows achieved a reduction in hospital arrival to arterial puncture by one-third. Furthermore, the time saving was seen despite the majority of EVT patients receiving repeat imaging in hospital to visualize the extracranial circulation.”

The study is scheduled to be presented at the International Stroke Conference on Feb. 20.

The Melbourne MSU received funding from the Australian Commonwealth Government, Victorian State Government, Royal Melbourne Hospital Neurosciences Foundation, Stroke Foundation, the Florey Institute of Neurosciences and Mental Health, the University of Melbourne, Boehringer Ingelheim, and private donation. Dr. Zhao disclosed that he has received grants from the Australian Commonwealth Government and the University of Melbourne and personal fees from Boehringer Ingelheim.

dbrunk@mdedge.com

SOURCE: Zhao H et al. Stroke. 2020 Feb 12. doi: 10.1161/strokeaha.119.027843.

A network meta-analysis of migraine treatments in children found little evidence that prophylactic medicines work in this population.

Marta Ortiz/iStock/Getty Images Plus

Clinicians hoped that medications used in adults – such as antidepressants, antiepileptics, antihypertensive agents, calcium channel blockers, and food supplements – would find similar success in children. Unfortunately, researchers found only short-term signs of efficacy over placebo, with no benefit lasting more than 6 months.

The study, conducted by a team led by Cosima Locher, PhD, of Boston Children’s Hospital, included 23 double-blind, randomized, controlled trials with a total of 2,217 patients; the mean age was 11 years. They compared 12 pharmacologic agents with each other or with placebo in the study, published online in JAMA Pediatrics.

In a main efficacy analysis that included 19 studies, only two treatments outperformed placebo: propranolol (standardized mean difference, 0.60; 95% confidence interval, 0.03-1.17) and topiramate (SMD, 0.59; 95% CI, 0.03-1.15). There were no statistically significant between-treatment differences.

The results had an overall low to moderate certainty.

When propranolol was compared to placebo, the 95% prediction interval (–0.62 to 1.82) was wider than the significant confidence interval (0.03-1.17), and comprised both beneficial and detrimental effects. A similar result was found with topiramate, with a prediction interval of –0.62 to 1.80 extending into nonsignificant effects (95% CI, 0.03-1.15). In both cases, significant effects were found only when the prediction interval was 70%.

In a long-term analysis (greater than 6 months), no treatment outperformed placebo.

The treatments generally were acceptable. The researchers found no significant difference in tolerability between any of the treatments and each other or placebo. Safety data analyzed from 13 trials revealed no significant differences between treatments and placebo.

“Because specific effects of drugs are associated with the size of the placebo effect, the lack of drug efficacy in our NMA [network meta-analysis] could be owing to a comparatively high placebo effect in children. In fact, there is indirect evidence [from other studies] that the placebo effect is more pronounced in children and adolescents than in adults,” Dr. Locher and associates said. They suggested that studies were needed to quantify the placebo effect in pediatric migraine, and if it was large, to develop innovative therapies making use of this.

The findings should lead to some changes in practice, Boris Zernikow, MD, PhD, of Children’s and Adolescents’ Hospital Datteln (Germany) wrote in an accompanying editorial.

Pharmacological prophylactic treatment of childhood migraine should be an exception rather than the rule, and nonpharmacologic approaches should be emphasized, particularly because the placebo effect is magnified in children, he said.

Many who suffer migraines in childhood will continue to be affected in adulthood, so pediatric intervention is a good opportunity to instill effective strategies. These include: using abortive medication early in an attack and using antimigraine medications for only that specific type of headache; engaging in physical activity to reduce migraine attacks; getting sufficient sleep; and learning relaxation and other psychological approaches to counter migraines.

Dr. Zernikow had no relevant financial disclosures. One study author received grants from Amgen and other support from Grunenthal and Akelos. The study received funding from the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment; the Swiss National Science Foundation; the Schweizer-Arau-Foundation; and the Theophrastus Foundation.

SOURCES: Locher C et al. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5856; Zernikow B. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5907.

A network meta-analysis of migraine treatments in children found little evidence that prophylactic medicines work in this population.

Marta Ortiz/iStock/Getty Images Plus

Clinicians hoped that medications used in adults – such as antidepressants, antiepileptics, antihypertensive agents, calcium channel blockers, and food supplements – would find similar success in children. Unfortunately, researchers found only short-term signs of efficacy over placebo, with no benefit lasting more than 6 months.

The study, conducted by a team led by Cosima Locher, PhD, of Boston Children’s Hospital, included 23 double-blind, randomized, controlled trials with a total of 2,217 patients; the mean age was 11 years. They compared 12 pharmacologic agents with each other or with placebo in the study, published online in JAMA Pediatrics.

In a main efficacy analysis that included 19 studies, only two treatments outperformed placebo: propranolol (standardized mean difference, 0.60; 95% confidence interval, 0.03-1.17) and topiramate (SMD, 0.59; 95% CI, 0.03-1.15). There were no statistically significant between-treatment differences.

The results had an overall low to moderate certainty.

When propranolol was compared to placebo, the 95% prediction interval (–0.62 to 1.82) was wider than the significant confidence interval (0.03-1.17), and comprised both beneficial and detrimental effects. A similar result was found with topiramate, with a prediction interval of –0.62 to 1.80 extending into nonsignificant effects (95% CI, 0.03-1.15). In both cases, significant effects were found only when the prediction interval was 70%.

In a long-term analysis (greater than 6 months), no treatment outperformed placebo.

The treatments generally were acceptable. The researchers found no significant difference in tolerability between any of the treatments and each other or placebo. Safety data analyzed from 13 trials revealed no significant differences between treatments and placebo.

“Because specific effects of drugs are associated with the size of the placebo effect, the lack of drug efficacy in our NMA [network meta-analysis] could be owing to a comparatively high placebo effect in children. In fact, there is indirect evidence [from other studies] that the placebo effect is more pronounced in children and adolescents than in adults,” Dr. Locher and associates said. They suggested that studies were needed to quantify the placebo effect in pediatric migraine, and if it was large, to develop innovative therapies making use of this.

The findings should lead to some changes in practice, Boris Zernikow, MD, PhD, of Children’s and Adolescents’ Hospital Datteln (Germany) wrote in an accompanying editorial.

Pharmacological prophylactic treatment of childhood migraine should be an exception rather than the rule, and nonpharmacologic approaches should be emphasized, particularly because the placebo effect is magnified in children, he said.

Many who suffer migraines in childhood will continue to be affected in adulthood, so pediatric intervention is a good opportunity to instill effective strategies. These include: using abortive medication early in an attack and using antimigraine medications for only that specific type of headache; engaging in physical activity to reduce migraine attacks; getting sufficient sleep; and learning relaxation and other psychological approaches to counter migraines.

Dr. Zernikow had no relevant financial disclosures. One study author received grants from Amgen and other support from Grunenthal and Akelos. The study received funding from the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment; the Swiss National Science Foundation; the Schweizer-Arau-Foundation; and the Theophrastus Foundation.

SOURCES: Locher C et al. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5856; Zernikow B. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5907.

A network meta-analysis of migraine treatments in children found little evidence that prophylactic medicines work in this population.

Marta Ortiz/iStock/Getty Images Plus

Clinicians hoped that medications used in adults – such as antidepressants, antiepileptics, antihypertensive agents, calcium channel blockers, and food supplements – would find similar success in children. Unfortunately, researchers found only short-term signs of efficacy over placebo, with no benefit lasting more than 6 months.

The study, conducted by a team led by Cosima Locher, PhD, of Boston Children’s Hospital, included 23 double-blind, randomized, controlled trials with a total of 2,217 patients; the mean age was 11 years. They compared 12 pharmacologic agents with each other or with placebo in the study, published online in JAMA Pediatrics.

In a main efficacy analysis that included 19 studies, only two treatments outperformed placebo: propranolol (standardized mean difference, 0.60; 95% confidence interval, 0.03-1.17) and topiramate (SMD, 0.59; 95% CI, 0.03-1.15). There were no statistically significant between-treatment differences.

The results had an overall low to moderate certainty.

When propranolol was compared to placebo, the 95% prediction interval (–0.62 to 1.82) was wider than the significant confidence interval (0.03-1.17), and comprised both beneficial and detrimental effects. A similar result was found with topiramate, with a prediction interval of –0.62 to 1.80 extending into nonsignificant effects (95% CI, 0.03-1.15). In both cases, significant effects were found only when the prediction interval was 70%.

In a long-term analysis (greater than 6 months), no treatment outperformed placebo.

The treatments generally were acceptable. The researchers found no significant difference in tolerability between any of the treatments and each other or placebo. Safety data analyzed from 13 trials revealed no significant differences between treatments and placebo.

“Because specific effects of drugs are associated with the size of the placebo effect, the lack of drug efficacy in our NMA [network meta-analysis] could be owing to a comparatively high placebo effect in children. In fact, there is indirect evidence [from other studies] that the placebo effect is more pronounced in children and adolescents than in adults,” Dr. Locher and associates said. They suggested that studies were needed to quantify the placebo effect in pediatric migraine, and if it was large, to develop innovative therapies making use of this.

The findings should lead to some changes in practice, Boris Zernikow, MD, PhD, of Children’s and Adolescents’ Hospital Datteln (Germany) wrote in an accompanying editorial.

Pharmacological prophylactic treatment of childhood migraine should be an exception rather than the rule, and nonpharmacologic approaches should be emphasized, particularly because the placebo effect is magnified in children, he said.

Many who suffer migraines in childhood will continue to be affected in adulthood, so pediatric intervention is a good opportunity to instill effective strategies. These include: using abortive medication early in an attack and using antimigraine medications for only that specific type of headache; engaging in physical activity to reduce migraine attacks; getting sufficient sleep; and learning relaxation and other psychological approaches to counter migraines.

Dr. Zernikow had no relevant financial disclosures. One study author received grants from Amgen and other support from Grunenthal and Akelos. The study received funding from the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment; the Swiss National Science Foundation; the Schweizer-Arau-Foundation; and the Theophrastus Foundation.

SOURCES: Locher C et al. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5856; Zernikow B. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5907.

After 12 months of receiving palliative care in an outpatient setting in addition to standard care, patients with Parkinson’s disease and related disorders (PDRD) had improved quality of life (QoL), compared with patients who received standard care alone, according to results from a randomized clinical trial in JAMA Neurology.

The benefits of palliative care even extended to patients’ caregivers, who also appeared to benefit from outpatient palliative care at the 12-month mark, according to lead author Benzi M. Kluger, MD, of the department of neurology, University of Colorado at Denver, Aurora, and colleagues.

Between November 2015 and September 2017, Dr. Kluger and colleagues included 210 patients into the trial from three participating academic tertiary care centers who had “moderate to high palliative care needs” as assessed by the Palliative Care Needs Assessment Tool, which the researchers said are “common reasons for referral” and “reflect a desire to meet patient-centered needs rather than disease-centered markers.” Patients were primarily non-Hispanic white men with a mean age of about 70 years. The researchers also included 175 caregivers in the trial, most of whom were women, spouses to the patients, and in their caregiver role for over 5.5 years.

Patients with PDRD were randomized to receive standard care – usual care through their primary care physician and a neurologist – or “integrated outpatient palliative care,” from a team consisting of a palliative neurologist, nurse, social worker, chaplain, and board-certified palliative medicine physician. The goal of palliative care was addressing “nonmotor symptoms, goals of care, anticipatory guidance, difficult emotions, and caregiver support,” which patients received every 3 months through an in-person outpatient visit or telemedicine.

Quality of life for patients was measured through the Quality of Life in Alzheimer’s Disease (QoL-AD) scale, and caregiver burden was assessed with the Zarit Burden Interview (ZBI-12). The researchers also measured symptom burden and other QoL measures using the Edmonton Symptom Assessment Scale–Revised for Parkinson’s Disease, Parkinson’s Disease Questionnaire, Hospital Anxiety and Depression Scale, Prolonged Grief Disorder questionnaire, and Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being.

Overall, 87 of 105 (82.1%) of patients in the palliative care group went to all their outpatient palliative care visits, and 19 of 106 (17.9%) patients received palliative care through telemedicine. Patients in the palliative care group also attended more neurology visits (4.66 visits) than those in the standard care (3.16 visits) group.

Quality of life significantly improved for patients in the palliative care group, compared with patients receiving standard care only at 6 months (0.66 vs. –0.84; between-group difference, 1.87; 95% confidence interval, 0.47-3.27; P = .009) and at 12 months (0.68 vs. –0.42; between-group difference, 1.36; 95% CI, −0.01 to 2.73; P = .05). These results remained significant at 6 months and 12 months after researchers used multiple imputation to fill in missing data. While there was no significant difference in caregiver burden between groups at 6 months, there was a statistically significant difference at 12 months favoring the palliative care group (between-group difference, −2.60; 95% CI, −4.58 to −0.61; P = .01).

Patients receiving palliative care also had better nonmotor symptom burden, motor symptom severity, and were more likely to complete advance directives, compared with patients receiving standard care alone. “We hypothesize that motor improvements may have reflected an unanticipated benefit of our palliative care team’s general goal of encouraging activities that promoted joy, meaning, and connection,” Dr. Kluger and colleagues said. Researchers also noted that the intervention patients with greater need for palliative care tended to benefit more than patients with patients with lower palliative care needs.

“Because the palliative care intervention is time-intensive and resource-intensive, future studies should optimize triage tools and consider alternative models of care delivery, such as telemedicine or care navigators, to provide key aspects of the intervention at lower cost,” they said.

In a related editorial, Bastiaan R. Bloem, MD, PhD, from the Center of Expertise for Parkinson & Movement Disorders, at Radboud University Medical Center, in the Netherlands, and colleagues acknowledged that the study by Kluger et al. is “timely and practical” because it introduces a system for outpatient palliative care for patients with PDRD at a time when there is “growing awareness that palliative care may also benefit persons with neurodegenerative diseases like Parkinson’s disease.”

The study is also important because it highlights that patients at varying stages of disease, including mild disease, may benefit from an integrated outpatient palliative model, which is not usually considered when determining candidates for palliative care in other scenarios, such as in patients with cancer. Future studies are warranted to assess how palliative care models can be implemented in different disease states and health care settings, they said.

“These new studies should continue to highlight the fact that palliative care is not about terminal diseases and dying,” Dr. Bloem and colleagues concluded. “As Kluger and colleagues indicate in their important clinical trial, palliative care is about how to live well.”

Six authors reported receiving a grant from the Patient-Centered Outcomes Research Institute, which was the funding source for the study. Two authors reported receiving grants from the University Hospital Foundation during the study. One author reported receiving grants from Allergan and Merz Pharma and is a consultant for GE Pharmaceuticals and Sunovion Pharmaceuticals; another reported receiving grants from the Archstone Foundation, the California Health Care Foundation, the Cambia Health Foundation, the Gordon and Betty Moore Foundation, the National Institute of Nursing Research, the Stupski Foundation, and the UniHealth Foundation. Dr. Bloem and a colleague reported their institution received a center of excellence grant from the Parkinson’s Foundation.

SOURCE: Kluger B et al. JAMA Neurol. doi: 10.1001/jamaneurol.2019.4992.

After 12 months of receiving palliative care in an outpatient setting in addition to standard care, patients with Parkinson’s disease and related disorders (PDRD) had improved quality of life (QoL), compared with patients who received standard care alone, according to results from a randomized clinical trial in JAMA Neurology.

The benefits of palliative care even extended to patients’ caregivers, who also appeared to benefit from outpatient palliative care at the 12-month mark, according to lead author Benzi M. Kluger, MD, of the department of neurology, University of Colorado at Denver, Aurora, and colleagues.

Between November 2015 and September 2017, Dr. Kluger and colleagues included 210 patients into the trial from three participating academic tertiary care centers who had “moderate to high palliative care needs” as assessed by the Palliative Care Needs Assessment Tool, which the researchers said are “common reasons for referral” and “reflect a desire to meet patient-centered needs rather than disease-centered markers.” Patients were primarily non-Hispanic white men with a mean age of about 70 years. The researchers also included 175 caregivers in the trial, most of whom were women, spouses to the patients, and in their caregiver role for over 5.5 years.

Patients with PDRD were randomized to receive standard care – usual care through their primary care physician and a neurologist – or “integrated outpatient palliative care,” from a team consisting of a palliative neurologist, nurse, social worker, chaplain, and board-certified palliative medicine physician. The goal of palliative care was addressing “nonmotor symptoms, goals of care, anticipatory guidance, difficult emotions, and caregiver support,” which patients received every 3 months through an in-person outpatient visit or telemedicine.

Quality of life for patients was measured through the Quality of Life in Alzheimer’s Disease (QoL-AD) scale, and caregiver burden was assessed with the Zarit Burden Interview (ZBI-12). The researchers also measured symptom burden and other QoL measures using the Edmonton Symptom Assessment Scale–Revised for Parkinson’s Disease, Parkinson’s Disease Questionnaire, Hospital Anxiety and Depression Scale, Prolonged Grief Disorder questionnaire, and Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being.

Overall, 87 of 105 (82.1%) of patients in the palliative care group went to all their outpatient palliative care visits, and 19 of 106 (17.9%) patients received palliative care through telemedicine. Patients in the palliative care group also attended more neurology visits (4.66 visits) than those in the standard care (3.16 visits) group.

Quality of life significantly improved for patients in the palliative care group, compared with patients receiving standard care only at 6 months (0.66 vs. –0.84; between-group difference, 1.87; 95% confidence interval, 0.47-3.27; P = .009) and at 12 months (0.68 vs. –0.42; between-group difference, 1.36; 95% CI, −0.01 to 2.73; P = .05). These results remained significant at 6 months and 12 months after researchers used multiple imputation to fill in missing data. While there was no significant difference in caregiver burden between groups at 6 months, there was a statistically significant difference at 12 months favoring the palliative care group (between-group difference, −2.60; 95% CI, −4.58 to −0.61; P = .01).

Patients receiving palliative care also had better nonmotor symptom burden, motor symptom severity, and were more likely to complete advance directives, compared with patients receiving standard care alone. “We hypothesize that motor improvements may have reflected an unanticipated benefit of our palliative care team’s general goal of encouraging activities that promoted joy, meaning, and connection,” Dr. Kluger and colleagues said. Researchers also noted that the intervention patients with greater need for palliative care tended to benefit more than patients with patients with lower palliative care needs.

“Because the palliative care intervention is time-intensive and resource-intensive, future studies should optimize triage tools and consider alternative models of care delivery, such as telemedicine or care navigators, to provide key aspects of the intervention at lower cost,” they said.

In a related editorial, Bastiaan R. Bloem, MD, PhD, from the Center of Expertise for Parkinson & Movement Disorders, at Radboud University Medical Center, in the Netherlands, and colleagues acknowledged that the study by Kluger et al. is “timely and practical” because it introduces a system for outpatient palliative care for patients with PDRD at a time when there is “growing awareness that palliative care may also benefit persons with neurodegenerative diseases like Parkinson’s disease.”

The study is also important because it highlights that patients at varying stages of disease, including mild disease, may benefit from an integrated outpatient palliative model, which is not usually considered when determining candidates for palliative care in other scenarios, such as in patients with cancer. Future studies are warranted to assess how palliative care models can be implemented in different disease states and health care settings, they said.

“These new studies should continue to highlight the fact that palliative care is not about terminal diseases and dying,” Dr. Bloem and colleagues concluded. “As Kluger and colleagues indicate in their important clinical trial, palliative care is about how to live well.”

Six authors reported receiving a grant from the Patient-Centered Outcomes Research Institute, which was the funding source for the study. Two authors reported receiving grants from the University Hospital Foundation during the study. One author reported receiving grants from Allergan and Merz Pharma and is a consultant for GE Pharmaceuticals and Sunovion Pharmaceuticals; another reported receiving grants from the Archstone Foundation, the California Health Care Foundation, the Cambia Health Foundation, the Gordon and Betty Moore Foundation, the National Institute of Nursing Research, the Stupski Foundation, and the UniHealth Foundation. Dr. Bloem and a colleague reported their institution received a center of excellence grant from the Parkinson’s Foundation.

SOURCE: Kluger B et al. JAMA Neurol. doi: 10.1001/jamaneurol.2019.4992.

After 12 months of receiving palliative care in an outpatient setting in addition to standard care, patients with Parkinson’s disease and related disorders (PDRD) had improved quality of life (QoL), compared with patients who received standard care alone, according to results from a randomized clinical trial in JAMA Neurology.

The benefits of palliative care even extended to patients’ caregivers, who also appeared to benefit from outpatient palliative care at the 12-month mark, according to lead author Benzi M. Kluger, MD, of the department of neurology, University of Colorado at Denver, Aurora, and colleagues.

Between November 2015 and September 2017, Dr. Kluger and colleagues included 210 patients into the trial from three participating academic tertiary care centers who had “moderate to high palliative care needs” as assessed by the Palliative Care Needs Assessment Tool, which the researchers said are “common reasons for referral” and “reflect a desire to meet patient-centered needs rather than disease-centered markers.” Patients were primarily non-Hispanic white men with a mean age of about 70 years. The researchers also included 175 caregivers in the trial, most of whom were women, spouses to the patients, and in their caregiver role for over 5.5 years.

Patients with PDRD were randomized to receive standard care – usual care through their primary care physician and a neurologist – or “integrated outpatient palliative care,” from a team consisting of a palliative neurologist, nurse, social worker, chaplain, and board-certified palliative medicine physician. The goal of palliative care was addressing “nonmotor symptoms, goals of care, anticipatory guidance, difficult emotions, and caregiver support,” which patients received every 3 months through an in-person outpatient visit or telemedicine.

Quality of life for patients was measured through the Quality of Life in Alzheimer’s Disease (QoL-AD) scale, and caregiver burden was assessed with the Zarit Burden Interview (ZBI-12). The researchers also measured symptom burden and other QoL measures using the Edmonton Symptom Assessment Scale–Revised for Parkinson’s Disease, Parkinson’s Disease Questionnaire, Hospital Anxiety and Depression Scale, Prolonged Grief Disorder questionnaire, and Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being.

Overall, 87 of 105 (82.1%) of patients in the palliative care group went to all their outpatient palliative care visits, and 19 of 106 (17.9%) patients received palliative care through telemedicine. Patients in the palliative care group also attended more neurology visits (4.66 visits) than those in the standard care (3.16 visits) group.

Quality of life significantly improved for patients in the palliative care group, compared with patients receiving standard care only at 6 months (0.66 vs. –0.84; between-group difference, 1.87; 95% confidence interval, 0.47-3.27; P = .009) and at 12 months (0.68 vs. –0.42; between-group difference, 1.36; 95% CI, −0.01 to 2.73; P = .05). These results remained significant at 6 months and 12 months after researchers used multiple imputation to fill in missing data. While there was no significant difference in caregiver burden between groups at 6 months, there was a statistically significant difference at 12 months favoring the palliative care group (between-group difference, −2.60; 95% CI, −4.58 to −0.61; P = .01).

Patients receiving palliative care also had better nonmotor symptom burden, motor symptom severity, and were more likely to complete advance directives, compared with patients receiving standard care alone. “We hypothesize that motor improvements may have reflected an unanticipated benefit of our palliative care team’s general goal of encouraging activities that promoted joy, meaning, and connection,” Dr. Kluger and colleagues said. Researchers also noted that the intervention patients with greater need for palliative care tended to benefit more than patients with patients with lower palliative care needs.

“Because the palliative care intervention is time-intensive and resource-intensive, future studies should optimize triage tools and consider alternative models of care delivery, such as telemedicine or care navigators, to provide key aspects of the intervention at lower cost,” they said.

In a related editorial, Bastiaan R. Bloem, MD, PhD, from the Center of Expertise for Parkinson & Movement Disorders, at Radboud University Medical Center, in the Netherlands, and colleagues acknowledged that the study by Kluger et al. is “timely and practical” because it introduces a system for outpatient palliative care for patients with PDRD at a time when there is “growing awareness that palliative care may also benefit persons with neurodegenerative diseases like Parkinson’s disease.”

The study is also important because it highlights that patients at varying stages of disease, including mild disease, may benefit from an integrated outpatient palliative model, which is not usually considered when determining candidates for palliative care in other scenarios, such as in patients with cancer. Future studies are warranted to assess how palliative care models can be implemented in different disease states and health care settings, they said.

“These new studies should continue to highlight the fact that palliative care is not about terminal diseases and dying,” Dr. Bloem and colleagues concluded. “As Kluger and colleagues indicate in their important clinical trial, palliative care is about how to live well.”

Six authors reported receiving a grant from the Patient-Centered Outcomes Research Institute, which was the funding source for the study. Two authors reported receiving grants from the University Hospital Foundation during the study. One author reported receiving grants from Allergan and Merz Pharma and is a consultant for GE Pharmaceuticals and Sunovion Pharmaceuticals; another reported receiving grants from the Archstone Foundation, the California Health Care Foundation, the Cambia Health Foundation, the Gordon and Betty Moore Foundation, the National Institute of Nursing Research, the Stupski Foundation, and the UniHealth Foundation. Dr. Bloem and a colleague reported their institution received a center of excellence grant from the Parkinson’s Foundation.

SOURCE: Kluger B et al. JAMA Neurol. doi: 10.1001/jamaneurol.2019.4992.

Apolipoprotein E epsilon 4 (APOE4) directly and independently exacerbates accumulation of alpha-synuclein in patients with Lewy body dementia, whereas APOE2 may have a protective effect, based on two recent studies involving mouse models and human patients.

These insights confirm the importance of APOE in synucleinopathies, and may lead to new treatments, according to Eliezer Masliah, MD, director of the division of neuroscience at the National Institute on Aging.

“These [studies] definitely implicate a role of APOE4,” Dr. Masliah said in an interview.

According to Dr. Masliah, previous studies linked the APOE4 genotype with cognitive decline in synucleinopathies, but underlying molecular mechanisms remained unknown.

“We [now] have more direct confirmation [based on] different experimental animal models,” Dr. Masliah said. “It also means that APOE4 could be a therapeutic target for dementia with Lewy bodies.”

The two studies were published simultaneously in Science Translational Medicine. The first study was conducted by Albert A. Davis, MD, PhD, of Washington University, St. Louis, and colleagues; the second was led by Na Zhao, MD, PhD, of the Mayo Clinic in Jacksonville, Fla.

“The studies are very synergistic, but used different techniques,” said Dr. Masliah, who was not involved in the studies.

Both studies involved mice that expressed a human variant of APOE: APOE2, APOE3, or APOE4. Three independent techniques were used to concurrently overexpress alpha-synuclein; Dr. Davis and colleagues used a transgenic approach, as well as striatal injection of alpha-synuclein preformed fibrils, whereas Dr. Zhao and colleagues turned to a viral vector. Regardless of technique, each APOE variant had a distinct impact on the level of alpha-synuclein accumulation.

“In a nutshell, [Dr. Davis and colleagues] found that those mice that have synuclein and APOE4 have a much more rapid progression of the disease,” Dr. Masliah said. “They become Parkinsonian much faster, but also, they become cognitively impaired much faster, and they have more synuclein in the brain. Remarkably, on the opposite side, those that were expressing APOE2, which we know is a protective allele, actually were far less impaired. So that’s really a remarkable finding.”

The study at the Mayo Clinic echoed these findings.

“Essentially, [Dr. Zhao and colleagues] had very similar results,” Dr. Masliah said. “[In mice expressing] APOE4, synuclein accumulation was worse and pathology was worse, and with APOE2, there was relative protection.”

Both studies found that the exacerbating effect of APOE4 translated to human patients.

Dr. Davis and colleagues evaluated data from 251 patients in the Parkinson’s Progression Markers Initiative. A multivariate model showed that patients with the APOE4 genotype had faster cognitive decline, an impact that was independent of other variables, including cerebrospinal fluid concentrations of amyloid beta and tau protein (P = .0119). This finding was further supported by additional analyses involving 177 patients with Parkinson’s disease from the Washington University Movement Disorders Center, and another 1,030 patients enrolled in the NeuroGenetics Research Consortium study.

Dr. Zhao and colleagues evaluated postmortem samples from patients with Lewy body dementia who had minimal amyloid pathology. Comparing 22 APOE4 carriers versus 22 age- and sex-matched noncarriers, they found that carriers had significantly greater accumulations of alpha-synuclein (P less than .05).

According to the investigators, these findings could have both prognostic and therapeutic implications.

“[I]t is intriguing to speculate whether APOE and other potential genetic risk or resilience genes could be useful as screening tools to stratify risk for individual patients,” Dr. Davis and colleagues wrote in their paper. They went on to suggest that APOE genotyping may one day be used to personalize treatments for patients with neurodegenerative disease.

According to Dr. Masliah, several treatment strategies are under investigation.

“There are some pharmaceutical companies and also some academic groups that have been developing antibodies against APOE4 for Alzheimer’s disease, but certainly that could also be used for dementia with Lewy bodies,” he said. “There are other ways. One could [be] to suppress the expression of APOE4 with antisense or other technologies.

“There is also a very innovative technology that has been developed by the group at the Gladstone Institutes in San Francisco, which is to switch APOE4 to APOE3.” This technique, Dr. Masliah explained, is accomplished by breaking a disulfide bond in APOE4, which opens the structure into an isoform that mimics APOE3. “They have developed small molecules that actually can break that bond and essentially chemically switch APOE4 to APOE3,” he said.

Although multiple techniques are feasible, Dr. Masliah stressed that these therapeutic efforts are still in their infancy.

“We need to better understand the mechanisms as to how APOE4 and alpha-synuclein interact,” he said. “I think we need a lot more work in this area.”

The Davis study was funded by the American Academy of Neurology/American Brain Foundation, the BrightFocus Foundation, the Mary E. Groff Charitable Trust, and others; the investigators reported additional relationships with Biogen, Alector, Parabon, and others. The Zhao study was funded by the National Institutes of Health and the Lewy Body Dementia Center Without Walls; the investigators reported no competing interests. Dr. Masliah reported no conflicts of interest.

SOURCES: Davis AA et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay3069; Zhao N et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay1809.

Apolipoprotein E epsilon 4 (APOE4) directly and independently exacerbates accumulation of alpha-synuclein in patients with Lewy body dementia, whereas APOE2 may have a protective effect, based on two recent studies involving mouse models and human patients.

These insights confirm the importance of APOE in synucleinopathies, and may lead to new treatments, according to Eliezer Masliah, MD, director of the division of neuroscience at the National Institute on Aging.

“These [studies] definitely implicate a role of APOE4,” Dr. Masliah said in an interview.

According to Dr. Masliah, previous studies linked the APOE4 genotype with cognitive decline in synucleinopathies, but underlying molecular mechanisms remained unknown.

“We [now] have more direct confirmation [based on] different experimental animal models,” Dr. Masliah said. “It also means that APOE4 could be a therapeutic target for dementia with Lewy bodies.”

The two studies were published simultaneously in Science Translational Medicine. The first study was conducted by Albert A. Davis, MD, PhD, of Washington University, St. Louis, and colleagues; the second was led by Na Zhao, MD, PhD, of the Mayo Clinic in Jacksonville, Fla.

“The studies are very synergistic, but used different techniques,” said Dr. Masliah, who was not involved in the studies.

Both studies involved mice that expressed a human variant of APOE: APOE2, APOE3, or APOE4. Three independent techniques were used to concurrently overexpress alpha-synuclein; Dr. Davis and colleagues used a transgenic approach, as well as striatal injection of alpha-synuclein preformed fibrils, whereas Dr. Zhao and colleagues turned to a viral vector. Regardless of technique, each APOE variant had a distinct impact on the level of alpha-synuclein accumulation.

“In a nutshell, [Dr. Davis and colleagues] found that those mice that have synuclein and APOE4 have a much more rapid progression of the disease,” Dr. Masliah said. “They become Parkinsonian much faster, but also, they become cognitively impaired much faster, and they have more synuclein in the brain. Remarkably, on the opposite side, those that were expressing APOE2, which we know is a protective allele, actually were far less impaired. So that’s really a remarkable finding.”

The study at the Mayo Clinic echoed these findings.

“Essentially, [Dr. Zhao and colleagues] had very similar results,” Dr. Masliah said. “[In mice expressing] APOE4, synuclein accumulation was worse and pathology was worse, and with APOE2, there was relative protection.”

Both studies found that the exacerbating effect of APOE4 translated to human patients.

Dr. Davis and colleagues evaluated data from 251 patients in the Parkinson’s Progression Markers Initiative. A multivariate model showed that patients with the APOE4 genotype had faster cognitive decline, an impact that was independent of other variables, including cerebrospinal fluid concentrations of amyloid beta and tau protein (P = .0119). This finding was further supported by additional analyses involving 177 patients with Parkinson’s disease from the Washington University Movement Disorders Center, and another 1,030 patients enrolled in the NeuroGenetics Research Consortium study.

Dr. Zhao and colleagues evaluated postmortem samples from patients with Lewy body dementia who had minimal amyloid pathology. Comparing 22 APOE4 carriers versus 22 age- and sex-matched noncarriers, they found that carriers had significantly greater accumulations of alpha-synuclein (P less than .05).

According to the investigators, these findings could have both prognostic and therapeutic implications.

“[I]t is intriguing to speculate whether APOE and other potential genetic risk or resilience genes could be useful as screening tools to stratify risk for individual patients,” Dr. Davis and colleagues wrote in their paper. They went on to suggest that APOE genotyping may one day be used to personalize treatments for patients with neurodegenerative disease.

According to Dr. Masliah, several treatment strategies are under investigation.

“There are some pharmaceutical companies and also some academic groups that have been developing antibodies against APOE4 for Alzheimer’s disease, but certainly that could also be used for dementia with Lewy bodies,” he said. “There are other ways. One could [be] to suppress the expression of APOE4 with antisense or other technologies.

“There is also a very innovative technology that has been developed by the group at the Gladstone Institutes in San Francisco, which is to switch APOE4 to APOE3.” This technique, Dr. Masliah explained, is accomplished by breaking a disulfide bond in APOE4, which opens the structure into an isoform that mimics APOE3. “They have developed small molecules that actually can break that bond and essentially chemically switch APOE4 to APOE3,” he said.

Although multiple techniques are feasible, Dr. Masliah stressed that these therapeutic efforts are still in their infancy.

“We need to better understand the mechanisms as to how APOE4 and alpha-synuclein interact,” he said. “I think we need a lot more work in this area.”

The Davis study was funded by the American Academy of Neurology/American Brain Foundation, the BrightFocus Foundation, the Mary E. Groff Charitable Trust, and others; the investigators reported additional relationships with Biogen, Alector, Parabon, and others. The Zhao study was funded by the National Institutes of Health and the Lewy Body Dementia Center Without Walls; the investigators reported no competing interests. Dr. Masliah reported no conflicts of interest.

SOURCES: Davis AA et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay3069; Zhao N et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay1809.

Apolipoprotein E epsilon 4 (APOE4) directly and independently exacerbates accumulation of alpha-synuclein in patients with Lewy body dementia, whereas APOE2 may have a protective effect, based on two recent studies involving mouse models and human patients.

These insights confirm the importance of APOE in synucleinopathies, and may lead to new treatments, according to Eliezer Masliah, MD, director of the division of neuroscience at the National Institute on Aging.

“These [studies] definitely implicate a role of APOE4,” Dr. Masliah said in an interview.

According to Dr. Masliah, previous studies linked the APOE4 genotype with cognitive decline in synucleinopathies, but underlying molecular mechanisms remained unknown.

“We [now] have more direct confirmation [based on] different experimental animal models,” Dr. Masliah said. “It also means that APOE4 could be a therapeutic target for dementia with Lewy bodies.”

The two studies were published simultaneously in Science Translational Medicine. The first study was conducted by Albert A. Davis, MD, PhD, of Washington University, St. Louis, and colleagues; the second was led by Na Zhao, MD, PhD, of the Mayo Clinic in Jacksonville, Fla.

“The studies are very synergistic, but used different techniques,” said Dr. Masliah, who was not involved in the studies.

Both studies involved mice that expressed a human variant of APOE: APOE2, APOE3, or APOE4. Three independent techniques were used to concurrently overexpress alpha-synuclein; Dr. Davis and colleagues used a transgenic approach, as well as striatal injection of alpha-synuclein preformed fibrils, whereas Dr. Zhao and colleagues turned to a viral vector. Regardless of technique, each APOE variant had a distinct impact on the level of alpha-synuclein accumulation.

“In a nutshell, [Dr. Davis and colleagues] found that those mice that have synuclein and APOE4 have a much more rapid progression of the disease,” Dr. Masliah said. “They become Parkinsonian much faster, but also, they become cognitively impaired much faster, and they have more synuclein in the brain. Remarkably, on the opposite side, those that were expressing APOE2, which we know is a protective allele, actually were far less impaired. So that’s really a remarkable finding.”

The study at the Mayo Clinic echoed these findings.

“Essentially, [Dr. Zhao and colleagues] had very similar results,” Dr. Masliah said. “[In mice expressing] APOE4, synuclein accumulation was worse and pathology was worse, and with APOE2, there was relative protection.”

Both studies found that the exacerbating effect of APOE4 translated to human patients.

Dr. Davis and colleagues evaluated data from 251 patients in the Parkinson’s Progression Markers Initiative. A multivariate model showed that patients with the APOE4 genotype had faster cognitive decline, an impact that was independent of other variables, including cerebrospinal fluid concentrations of amyloid beta and tau protein (P = .0119). This finding was further supported by additional analyses involving 177 patients with Parkinson’s disease from the Washington University Movement Disorders Center, and another 1,030 patients enrolled in the NeuroGenetics Research Consortium study.

Dr. Zhao and colleagues evaluated postmortem samples from patients with Lewy body dementia who had minimal amyloid pathology. Comparing 22 APOE4 carriers versus 22 age- and sex-matched noncarriers, they found that carriers had significantly greater accumulations of alpha-synuclein (P less than .05).

According to the investigators, these findings could have both prognostic and therapeutic implications.

“[I]t is intriguing to speculate whether APOE and other potential genetic risk or resilience genes could be useful as screening tools to stratify risk for individual patients,” Dr. Davis and colleagues wrote in their paper. They went on to suggest that APOE genotyping may one day be used to personalize treatments for patients with neurodegenerative disease.

According to Dr. Masliah, several treatment strategies are under investigation.

“There are some pharmaceutical companies and also some academic groups that have been developing antibodies against APOE4 for Alzheimer’s disease, but certainly that could also be used for dementia with Lewy bodies,” he said. “There are other ways. One could [be] to suppress the expression of APOE4 with antisense or other technologies.

“There is also a very innovative technology that has been developed by the group at the Gladstone Institutes in San Francisco, which is to switch APOE4 to APOE3.” This technique, Dr. Masliah explained, is accomplished by breaking a disulfide bond in APOE4, which opens the structure into an isoform that mimics APOE3. “They have developed small molecules that actually can break that bond and essentially chemically switch APOE4 to APOE3,” he said.

Although multiple techniques are feasible, Dr. Masliah stressed that these therapeutic efforts are still in their infancy.

“We need to better understand the mechanisms as to how APOE4 and alpha-synuclein interact,” he said. “I think we need a lot more work in this area.”

The Davis study was funded by the American Academy of Neurology/American Brain Foundation, the BrightFocus Foundation, the Mary E. Groff Charitable Trust, and others; the investigators reported additional relationships with Biogen, Alector, Parabon, and others. The Zhao study was funded by the National Institutes of Health and the Lewy Body Dementia Center Without Walls; the investigators reported no competing interests. Dr. Masliah reported no conflicts of interest.

SOURCES: Davis AA et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay3069; Zhao N et al. Sci Transl Med. 2020 Feb 5. doi: 10.1126/scitranslmed.aay1809.

Serum levels of neurofilament light (NfL) are elevated as long as 6 years before the clinical onset of multiple sclerosis (MS), according to research published in the January issue of JAMA Neurology. These results lend weight to the idea that MS has a prodromal phase, and this phase appears to be associated with neurodegeneration, according to the authors.

Patients often have CNS lesions of various stages of development at the time of their first demyelinating event, and this finding was one basis for neurologists’ hypothesis of a prodromal phase of MS. The finding that one-third of patients with radiologically isolated syndrome develop MS within 5 years also lends credence to this idea. Diagnosing MS early would enable early treatment that could prevent demyelination and the progression of neurodegeneration.
 

Researchers compared presymptomatic and symptomatic samples

With this idea in mind, Kjetil Bjornevik, MD, PhD, a member of the neuroepidemiology research group at Harvard TH Chan School of Public Health in Boston, and colleagues evaluated whether serum levels of NfL, a marker of ongoing neuroaxonal degeneration, were increased in the years before and around the time of clinical onset of MS. For their study population, the investigators chose active-duty U.S. military personnel who have at least one serum sample stored in the U.S. Department of Defense Serum Repository. Samples are collected after routine HIV type 1 antibody testing.

Within this population, Dr. Bjornevik and colleagues identified patients with MS who had at least one presymptomatic serum sample. The date of clinical MS onset was defined as the date of the first neurologic symptoms attributable to MS documented in the medical record. The investigators randomly selected two control individuals from the population and matched them to each case by age, sex, race or ethnicity, and dates of sample collection. Eligible controls were on active duty on the date of onset of the matched case.

Dr. Bjornevik and colleagues identified 245 patients with MS. Among this sample, the researchers selected two groups that each included 30 cases and 30 controls. The first group included patients who had provided at least one serum sample before MS onset and one sample within 2 years after MS onset. The second group included cases with at least two presymptomatic serum samples, one of which was collected more than 5 years before MS diagnosis, and the other of which was collected between 2 and 5 years before diagnosis. The investigators handled pairs of serum samples in the same way and assayed them in the same batch. The order of the samples in each pair was arranged at random.
 

Levels were higher in cases than in controls

About 77% of the population was male. Sixty percent of participants were white, 28% were black, and 6.7% were Hispanic. The population’s mean age at first sample collection was approximately 27 years. Mean age at MS onset was approximately 31 years.

For patients who provided samples before and after the clinical onset of MS, serum NfL levels were higher than in matched controls at both points. Most patients who passed from the presymptomatic stage to the symptomatic stage had a significant increase in serum NfL level (i.e., from a median of 25.0 pg/mL to a median of 45.1 pg/mL). Serum NfL levels at the two time points in controls did not differ significantly. For any given patient, an increase in serum NfL level from the presymptomatic measurement to the symptomatic measurement was associated with an increased risk of MS.

In patients with two presymptomatic samples, serum NfL levels were significantly higher in both samples than in the corresponding samples from matched controls. In cases, the earlier sample was collected at a median of 6 years before clinical onset of MS, and the later sample was collected at a median of 1 year before clinical onset. The serum NfL levels increased significantly between the two points for cases (i.e., a median increase of 1.3 pg/mL per year), but there was no significant difference in serum NfL level between the two samples in controls. A within-patient increase in presymptomatic serum NfL level was associated with an increased risk of MS.
 

Population included few women

“Our study differs from previous studies on the prodromal phase of MS because these have used indirect markers of this phase, which included unspecific symptoms or disturbances occurring before the clinical onset, compared with a marker of neurodegeneration,” wrote Dr. Bjornevik and colleagues. Initiation of treatment with disease-modifying therapy is associated with reductions in serum NfL levels, and this association could explain why some patients in the current study had higher NfL levels before MS onset than afterward. Furthermore, serum NfL levels are highly associated with levels of NfL in cerebrospinal fluid. “Thus, our findings of a presymptomatic increase in serum NfL not only suggest the presence of a prodromal phase in MS, but also that this phase is associated with neurodegeneration,” wrote the investigators.

The study’s well-defined population helped to minimize selection bias, and the blinded, randomized method of analyzing the serum samples eliminated artifactual differences in serum NfL concentrations. But the small sample size precluded analyses that could have influenced clinical practice, wrote Dr. Bjornevik and colleagues. For example, the researchers could not evaluate distinct cutoffs in serum NfL level that could mark the beginning of the prodromal phase of MS. Nor could they determine whether presymptomatic serum NfL levels varied with age at clinical onset, sex, or race. The small number of women in the sample was another limitation of the study.

The Swiss National Research Foundation and the National Institute of Neurologic Disorders and Stroke funded the study. Several of the investigators received fees from various drug companies that were unrelated to the study, and one researcher received grants from the National Institutes of Health during the study.

egreb@mdedge.com

SOURCE: Bjornevik K et al. JAMA Neurol. 2020;77(1):58-64.

Serum levels of neurofilament light (NfL) are elevated as long as 6 years before the clinical onset of multiple sclerosis (MS), according to research published in the January issue of JAMA Neurology. These results lend weight to the idea that MS has a prodromal phase, and this phase appears to be associated with neurodegeneration, according to the authors.

Patients often have CNS lesions of various stages of development at the time of their first demyelinating event, and this finding was one basis for neurologists’ hypothesis of a prodromal phase of MS. The finding that one-third of patients with radiologically isolated syndrome develop MS within 5 years also lends credence to this idea. Diagnosing MS early would enable early treatment that could prevent demyelination and the progression of neurodegeneration.
 

Researchers compared presymptomatic and symptomatic samples

With this idea in mind, Kjetil Bjornevik, MD, PhD, a member of the neuroepidemiology research group at Harvard TH Chan School of Public Health in Boston, and colleagues evaluated whether serum levels of NfL, a marker of ongoing neuroaxonal degeneration, were increased in the years before and around the time of clinical onset of MS. For their study population, the investigators chose active-duty U.S. military personnel who have at least one serum sample stored in the U.S. Department of Defense Serum Repository. Samples are collected after routine HIV type 1 antibody testing.

Within this population, Dr. Bjornevik and colleagues identified patients with MS who had at least one presymptomatic serum sample. The date of clinical MS onset was defined as the date of the first neurologic symptoms attributable to MS documented in the medical record. The investigators randomly selected two control individuals from the population and matched them to each case by age, sex, race or ethnicity, and dates of sample collection. Eligible controls were on active duty on the date of onset of the matched case.

Dr. Bjornevik and colleagues identified 245 patients with MS. Among this sample, the researchers selected two groups that each included 30 cases and 30 controls. The first group included patients who had provided at least one serum sample before MS onset and one sample within 2 years after MS onset. The second group included cases with at least two presymptomatic serum samples, one of which was collected more than 5 years before MS diagnosis, and the other of which was collected between 2 and 5 years before diagnosis. The investigators handled pairs of serum samples in the same way and assayed them in the same batch. The order of the samples in each pair was arranged at random.
 

Levels were higher in cases than in controls

About 77% of the population was male. Sixty percent of participants were white, 28% were black, and 6.7% were Hispanic. The population’s mean age at first sample collection was approximately 27 years. Mean age at MS onset was approximately 31 years.

For patients who provided samples before and after the clinical onset of MS, serum NfL levels were higher than in matched controls at both points. Most patients who passed from the presymptomatic stage to the symptomatic stage had a significant increase in serum NfL level (i.e., from a median of 25.0 pg/mL to a median of 45.1 pg/mL). Serum NfL levels at the two time points in controls did not differ significantly. For any given patient, an increase in serum NfL level from the presymptomatic measurement to the symptomatic measurement was associated with an increased risk of MS.

In patients with two presymptomatic samples, serum NfL levels were significantly higher in both samples than in the corresponding samples from matched controls. In cases, the earlier sample was collected at a median of 6 years before clinical onset of MS, and the later sample was collected at a median of 1 year before clinical onset. The serum NfL levels increased significantly between the two points for cases (i.e., a median increase of 1.3 pg/mL per year), but there was no significant difference in serum NfL level between the two samples in controls. A within-patient increase in presymptomatic serum NfL level was associated with an increased risk of MS.
 

Population included few women

“Our study differs from previous studies on the prodromal phase of MS because these have used indirect markers of this phase, which included unspecific symptoms or disturbances occurring before the clinical onset, compared with a marker of neurodegeneration,” wrote Dr. Bjornevik and colleagues. Initiation of treatment with disease-modifying therapy is associated with reductions in serum NfL levels, and this association could explain why some patients in the current study had higher NfL levels before MS onset than afterward. Furthermore, serum NfL levels are highly associated with levels of NfL in cerebrospinal fluid. “Thus, our findings of a presymptomatic increase in serum NfL not only suggest the presence of a prodromal phase in MS, but also that this phase is associated with neurodegeneration,” wrote the investigators.

The study’s well-defined population helped to minimize selection bias, and the blinded, randomized method of analyzing the serum samples eliminated artifactual differences in serum NfL concentrations. But the small sample size precluded analyses that could have influenced clinical practice, wrote Dr. Bjornevik and colleagues. For example, the researchers could not evaluate distinct cutoffs in serum NfL level that could mark the beginning of the prodromal phase of MS. Nor could they determine whether presymptomatic serum NfL levels varied with age at clinical onset, sex, or race. The small number of women in the sample was another limitation of the study.

The Swiss National Research Foundation and the National Institute of Neurologic Disorders and Stroke funded the study. Several of the investigators received fees from various drug companies that were unrelated to the study, and one researcher received grants from the National Institutes of Health during the study.

egreb@mdedge.com

SOURCE: Bjornevik K et al. JAMA Neurol. 2020;77(1):58-64.

Serum levels of neurofilament light (NfL) are elevated as long as 6 years before the clinical onset of multiple sclerosis (MS), according to research published in the January issue of JAMA Neurology. These results lend weight to the idea that MS has a prodromal phase, and this phase appears to be associated with neurodegeneration, according to the authors.

Patients often have CNS lesions of various stages of development at the time of their first demyelinating event, and this finding was one basis for neurologists’ hypothesis of a prodromal phase of MS. The finding that one-third of patients with radiologically isolated syndrome develop MS within 5 years also lends credence to this idea. Diagnosing MS early would enable early treatment that could prevent demyelination and the progression of neurodegeneration.
 

Researchers compared presymptomatic and symptomatic samples

With this idea in mind, Kjetil Bjornevik, MD, PhD, a member of the neuroepidemiology research group at Harvard TH Chan School of Public Health in Boston, and colleagues evaluated whether serum levels of NfL, a marker of ongoing neuroaxonal degeneration, were increased in the years before and around the time of clinical onset of MS. For their study population, the investigators chose active-duty U.S. military personnel who have at least one serum sample stored in the U.S. Department of Defense Serum Repository. Samples are collected after routine HIV type 1 antibody testing.

Within this population, Dr. Bjornevik and colleagues identified patients with MS who had at least one presymptomatic serum sample. The date of clinical MS onset was defined as the date of the first neurologic symptoms attributable to MS documented in the medical record. The investigators randomly selected two control individuals from the population and matched them to each case by age, sex, race or ethnicity, and dates of sample collection. Eligible controls were on active duty on the date of onset of the matched case.

Dr. Bjornevik and colleagues identified 245 patients with MS. Among this sample, the researchers selected two groups that each included 30 cases and 30 controls. The first group included patients who had provided at least one serum sample before MS onset and one sample within 2 years after MS onset. The second group included cases with at least two presymptomatic serum samples, one of which was collected more than 5 years before MS diagnosis, and the other of which was collected between 2 and 5 years before diagnosis. The investigators handled pairs of serum samples in the same way and assayed them in the same batch. The order of the samples in each pair was arranged at random.
 

Levels were higher in cases than in controls

About 77% of the population was male. Sixty percent of participants were white, 28% were black, and 6.7% were Hispanic. The population’s mean age at first sample collection was approximately 27 years. Mean age at MS onset was approximately 31 years.

For patients who provided samples before and after the clinical onset of MS, serum NfL levels were higher than in matched controls at both points. Most patients who passed from the presymptomatic stage to the symptomatic stage had a significant increase in serum NfL level (i.e., from a median of 25.0 pg/mL to a median of 45.1 pg/mL). Serum NfL levels at the two time points in controls did not differ significantly. For any given patient, an increase in serum NfL level from the presymptomatic measurement to the symptomatic measurement was associated with an increased risk of MS.

In patients with two presymptomatic samples, serum NfL levels were significantly higher in both samples than in the corresponding samples from matched controls. In cases, the earlier sample was collected at a median of 6 years before clinical onset of MS, and the later sample was collected at a median of 1 year before clinical onset. The serum NfL levels increased significantly between the two points for cases (i.e., a median increase of 1.3 pg/mL per year), but there was no significant difference in serum NfL level between the two samples in controls. A within-patient increase in presymptomatic serum NfL level was associated with an increased risk of MS.
 

Population included few women

“Our study differs from previous studies on the prodromal phase of MS because these have used indirect markers of this phase, which included unspecific symptoms or disturbances occurring before the clinical onset, compared with a marker of neurodegeneration,” wrote Dr. Bjornevik and colleagues. Initiation of treatment with disease-modifying therapy is associated with reductions in serum NfL levels, and this association could explain why some patients in the current study had higher NfL levels before MS onset than afterward. Furthermore, serum NfL levels are highly associated with levels of NfL in cerebrospinal fluid. “Thus, our findings of a presymptomatic increase in serum NfL not only suggest the presence of a prodromal phase in MS, but also that this phase is associated with neurodegeneration,” wrote the investigators.

The study’s well-defined population helped to minimize selection bias, and the blinded, randomized method of analyzing the serum samples eliminated artifactual differences in serum NfL concentrations. But the small sample size precluded analyses that could have influenced clinical practice, wrote Dr. Bjornevik and colleagues. For example, the researchers could not evaluate distinct cutoffs in serum NfL level that could mark the beginning of the prodromal phase of MS. Nor could they determine whether presymptomatic serum NfL levels varied with age at clinical onset, sex, or race. The small number of women in the sample was another limitation of the study.

The Swiss National Research Foundation and the National Institute of Neurologic Disorders and Stroke funded the study. Several of the investigators received fees from various drug companies that were unrelated to the study, and one researcher received grants from the National Institutes of Health during the study.

egreb@mdedge.com

SOURCE: Bjornevik K et al. JAMA Neurol. 2020;77(1):58-64.

People with neurologic disorders have a higher rate of suicide, compared with people without neurologic conditions, according to a population-based study in Denmark.

The absolute risk difference is small, but statistically significant. “These findings do not necessarily warrant changing the management of treatment for individual patients,” wrote Annette Erlangsen, PhD, a researcher at the Danish Research Institute for Suicide Prevention in Hellerup, and colleagues. “As with all patients, physicians should be aware of the potential for depression, demoralization, and suicide.”

In addition, dementia, Alzheimer’s disease, and intellectual disabilities may be associated with lower suicide rates, according to the study, which was published in JAMA.

“Plausible mechanisms” could underlie the association between neurologic disease and suicide, the authors wrote. A neurologic diagnosis “may constitute a distressing life event,” and the diseases may have psychological, physical, and psychiatric effects. Patients may see themselves as a burden or have less financial security. In addition, the diseases may entail “communication difficulties, poor sleep, and pain.” Neurologic diseases may alter brain circuitry and functioning and influence aggression and impulsivity. “People with neurologic disorders may also have easier access to toxic medication,” they added.
 

More than a dozen conditions examined

Prior studies have found associations between neurologic conditions and rates of suicide, but data have been inconclusive or inconsistent for some of the disorders. To examine whether people with neurologic disorders have higher suicide rates, relative to people without these disorders, the researchers conducted a retrospective study. They analyzed data from more than 7.3 million people aged 15 years or older who lived in Denmark between 1980 and 2016. The cohort included more than 1.2 million people with neurologic disorders. The investigators identified neurologic disorders using ICD codes for head injury, stroke, epilepsy, polyneuropathy, diseases of the myoneural junction, Parkinson’s disease, multiple sclerosis, CNS infections, meningitis, encephalitis, amyotrophic lateral sclerosis, Huntington’s disease, dementia, intellectual disability, and other brain disorders. They compared incidence rates using a Poisson regression model and adjusted for time period, sex, age, region, socioeconomic status, comorbidity, self-harm or psychiatric hospitalization prior to a neurologic diagnosis, and whether a person lived alone.

In all, 35,483 people in the cohort died by suicide at an average age of about 52 years; 77.4% were male. About 15% of those who died by suicide had a neurologic disorder. The suicide incidence rate among people with a neurologic disorder was 44.0 per 100,000 person-years, whereas the rate among people without a neurologic disorder was 20.1 per 100,000 person-years.

The adjusted incidence rate ratio for people with a neurologic disorder was 1.8. The rate ratio was highest during the 3 months after diagnosis, at 3.1. Huntington’s disease and amyotrophic lateral sclerosis were associated with “the largest excess adjusted [incidence rate ratios] of suicide mortality,” with a rate ratio of 4.9 for each condition, the researchers reported. The adjusted incidence rate ratio was 1.7 for head injury, 1.3 for stroke, 1.7 for epilepsy, 1.4 for intracerebral hemorrhage, 1.3 for cerebral infarction, 1.3 for subarachnoid hemorrhage, 1.7 for polyneuropathy and peripheral neuropathy, 2.2 for Guillain-Barré syndrome, 1.9 for diseases of myoneural junction and muscle, 1.8 for other brain disorders, 1.7 for Parkinson’s disease, 2.2 for multiple sclerosis, and 1.6 for CNS infection.

Compared with people without a neurologic condition, people with dementia, Alzheimer’s disease, and intellectual disabilities had lower suicide rates, with adjusted incidence rate ratios of 0.8, 0.2, and 0.6, respectively. “However, the adjusted [incidence rate ratio] for people with dementia during the first month after diagnosis was 3.0,” the researchers wrote.

In addition, the suicide rate increased with an increasing cumulative number of hospital contacts for neurologic conditions.

Overall incidence rates declined

“Over the study period, the suicide incidence rate for people with neurological disorders decreased from 78.6 per 100,000 person-years during the 1980-1999 years to 27.3 per 100,000 person-years during the 2000-2016 years,” wrote Dr. Erlangsen and colleagues. “The suicide incidence rate for those without a disorder decreased from 26.3 to 12.7 during the same time spans. ... The decline in the overall suicide rate over time did not affect the relative risk pattern.”

The decline in the general suicide rate in Denmark “has largely been attributed to means restriction, such as efforts to limit availability of firearms and particularly toxic medication,” the authors added.

In those time spans, the adjusted incidence rate ratio for suicide among those with dementia decreased from 2.4 to 1.0, and among those with multiple sclerosis from 2.0 to 1.0. “It is possible that the improvements observed for dementia and multiple sclerosis may be related to improvements in treatment and intensified community-based support,” Dr. Erlangsen and coauthors wrote.

When the researchers used people with rheumatoid arthritis as a reference group, those with a neurologic disorder had a higher suicide rate per 100,000 person-years, 30.2 versus 18.4. The adjusted incidence rate ratio for that comparison was 1.4.

In patients with Huntington’s disease, depression mediated by hyperactivity in the hypothalamic-pituitary-adrenal axis may contribute to the risk of suicide. “Witnessing the course of the disease in one’s parent” also may contribute the risk, the researchers wrote.

The analysis may have missed people with neurologic disorders diagnosed before 1977 if they did not have subsequent contact with a hospital, the investigators noted. In addition, diagnoses given in primary care were not included, suicide deaths may be underrecorded, and “adjusting for preexisting mental disorders could be viewed as overadjusting,” they wrote.

The study was supported by a grant from the Psychiatric Research Foundation in Denmark. The authors reported that they had no disclosures.

jremaly@mdedge.com

SOURCE: Erlangsen A et al. JAMA. 2020 Feb 4. doi: 10.1001/jama.2019.21834.

People with neurologic disorders have a higher rate of suicide, compared with people without neurologic conditions, according to a population-based study in Denmark.

The absolute risk difference is small, but statistically significant. “These findings do not necessarily warrant changing the management of treatment for individual patients,” wrote Annette Erlangsen, PhD, a researcher at the Danish Research Institute for Suicide Prevention in Hellerup, and colleagues. “As with all patients, physicians should be aware of the potential for depression, demoralization, and suicide.”

In addition, dementia, Alzheimer’s disease, and intellectual disabilities may be associated with lower suicide rates, according to the study, which was published in JAMA.

“Plausible mechanisms” could underlie the association between neurologic disease and suicide, the authors wrote. A neurologic diagnosis “may constitute a distressing life event,” and the diseases may have psychological, physical, and psychiatric effects. Patients may see themselves as a burden or have less financial security. In addition, the diseases may entail “communication difficulties, poor sleep, and pain.” Neurologic diseases may alter brain circuitry and functioning and influence aggression and impulsivity. “People with neurologic disorders may also have easier access to toxic medication,” they added.
 

More than a dozen conditions examined

Prior studies have found associations between neurologic conditions and rates of suicide, but data have been inconclusive or inconsistent for some of the disorders. To examine whether people with neurologic disorders have higher suicide rates, relative to people without these disorders, the researchers conducted a retrospective study. They analyzed data from more than 7.3 million people aged 15 years or older who lived in Denmark between 1980 and 2016. The cohort included more than 1.2 million people with neurologic disorders. The investigators identified neurologic disorders using ICD codes for head injury, stroke, epilepsy, polyneuropathy, diseases of the myoneural junction, Parkinson’s disease, multiple sclerosis, CNS infections, meningitis, encephalitis, amyotrophic lateral sclerosis, Huntington’s disease, dementia, intellectual disability, and other brain disorders. They compared incidence rates using a Poisson regression model and adjusted for time period, sex, age, region, socioeconomic status, comorbidity, self-harm or psychiatric hospitalization prior to a neurologic diagnosis, and whether a person lived alone.

In all, 35,483 people in the cohort died by suicide at an average age of about 52 years; 77.4% were male. About 15% of those who died by suicide had a neurologic disorder. The suicide incidence rate among people with a neurologic disorder was 44.0 per 100,000 person-years, whereas the rate among people without a neurologic disorder was 20.1 per 100,000 person-years.

The adjusted incidence rate ratio for people with a neurologic disorder was 1.8. The rate ratio was highest during the 3 months after diagnosis, at 3.1. Huntington’s disease and amyotrophic lateral sclerosis were associated with “the largest excess adjusted [incidence rate ratios] of suicide mortality,” with a rate ratio of 4.9 for each condition, the researchers reported. The adjusted incidence rate ratio was 1.7 for head injury, 1.3 for stroke, 1.7 for epilepsy, 1.4 for intracerebral hemorrhage, 1.3 for cerebral infarction, 1.3 for subarachnoid hemorrhage, 1.7 for polyneuropathy and peripheral neuropathy, 2.2 for Guillain-Barré syndrome, 1.9 for diseases of myoneural junction and muscle, 1.8 for other brain disorders, 1.7 for Parkinson’s disease, 2.2 for multiple sclerosis, and 1.6 for CNS infection.

Compared with people without a neurologic condition, people with dementia, Alzheimer’s disease, and intellectual disabilities had lower suicide rates, with adjusted incidence rate ratios of 0.8, 0.2, and 0.6, respectively. “However, the adjusted [incidence rate ratio] for people with dementia during the first month after diagnosis was 3.0,” the researchers wrote.

In addition, the suicide rate increased with an increasing cumulative number of hospital contacts for neurologic conditions.

Overall incidence rates declined

“Over the study period, the suicide incidence rate for people with neurological disorders decreased from 78.6 per 100,000 person-years during the 1980-1999 years to 27.3 per 100,000 person-years during the 2000-2016 years,” wrote Dr. Erlangsen and colleagues. “The suicide incidence rate for those without a disorder decreased from 26.3 to 12.7 during the same time spans. ... The decline in the overall suicide rate over time did not affect the relative risk pattern.”

The decline in the general suicide rate in Denmark “has largely been attributed to means restriction, such as efforts to limit availability of firearms and particularly toxic medication,” the authors added.

In those time spans, the adjusted incidence rate ratio for suicide among those with dementia decreased from 2.4 to 1.0, and among those with multiple sclerosis from 2.0 to 1.0. “It is possible that the improvements observed for dementia and multiple sclerosis may be related to improvements in treatment and intensified community-based support,” Dr. Erlangsen and coauthors wrote.

When the researchers used people with rheumatoid arthritis as a reference group, those with a neurologic disorder had a higher suicide rate per 100,000 person-years, 30.2 versus 18.4. The adjusted incidence rate ratio for that comparison was 1.4.

In patients with Huntington’s disease, depression mediated by hyperactivity in the hypothalamic-pituitary-adrenal axis may contribute to the risk of suicide. “Witnessing the course of the disease in one’s parent” also may contribute the risk, the researchers wrote.

The analysis may have missed people with neurologic disorders diagnosed before 1977 if they did not have subsequent contact with a hospital, the investigators noted. In addition, diagnoses given in primary care were not included, suicide deaths may be underrecorded, and “adjusting for preexisting mental disorders could be viewed as overadjusting,” they wrote.

The study was supported by a grant from the Psychiatric Research Foundation in Denmark. The authors reported that they had no disclosures.

jremaly@mdedge.com

SOURCE: Erlangsen A et al. JAMA. 2020 Feb 4. doi: 10.1001/jama.2019.21834.

People with neurologic disorders have a higher rate of suicide, compared with people without neurologic conditions, according to a population-based study in Denmark.

The absolute risk difference is small, but statistically significant. “These findings do not necessarily warrant changing the management of treatment for individual patients,” wrote Annette Erlangsen, PhD, a researcher at the Danish Research Institute for Suicide Prevention in Hellerup, and colleagues. “As with all patients, physicians should be aware of the potential for depression, demoralization, and suicide.”

In addition, dementia, Alzheimer’s disease, and intellectual disabilities may be associated with lower suicide rates, according to the study, which was published in JAMA.

“Plausible mechanisms” could underlie the association between neurologic disease and suicide, the authors wrote. A neurologic diagnosis “may constitute a distressing life event,” and the diseases may have psychological, physical, and psychiatric effects. Patients may see themselves as a burden or have less financial security. In addition, the diseases may entail “communication difficulties, poor sleep, and pain.” Neurologic diseases may alter brain circuitry and functioning and influence aggression and impulsivity. “People with neurologic disorders may also have easier access to toxic medication,” they added.
 

More than a dozen conditions examined

Prior studies have found associations between neurologic conditions and rates of suicide, but data have been inconclusive or inconsistent for some of the disorders. To examine whether people with neurologic disorders have higher suicide rates, relative to people without these disorders, the researchers conducted a retrospective study. They analyzed data from more than 7.3 million people aged 15 years or older who lived in Denmark between 1980 and 2016. The cohort included more than 1.2 million people with neurologic disorders. The investigators identified neurologic disorders using ICD codes for head injury, stroke, epilepsy, polyneuropathy, diseases of the myoneural junction, Parkinson’s disease, multiple sclerosis, CNS infections, meningitis, encephalitis, amyotrophic lateral sclerosis, Huntington’s disease, dementia, intellectual disability, and other brain disorders. They compared incidence rates using a Poisson regression model and adjusted for time period, sex, age, region, socioeconomic status, comorbidity, self-harm or psychiatric hospitalization prior to a neurologic diagnosis, and whether a person lived alone.

In all, 35,483 people in the cohort died by suicide at an average age of about 52 years; 77.4% were male. About 15% of those who died by suicide had a neurologic disorder. The suicide incidence rate among people with a neurologic disorder was 44.0 per 100,000 person-years, whereas the rate among people without a neurologic disorder was 20.1 per 100,000 person-years.

The adjusted incidence rate ratio for people with a neurologic disorder was 1.8. The rate ratio was highest during the 3 months after diagnosis, at 3.1. Huntington’s disease and amyotrophic lateral sclerosis were associated with “the largest excess adjusted [incidence rate ratios] of suicide mortality,” with a rate ratio of 4.9 for each condition, the researchers reported. The adjusted incidence rate ratio was 1.7 for head injury, 1.3 for stroke, 1.7 for epilepsy, 1.4 for intracerebral hemorrhage, 1.3 for cerebral infarction, 1.3 for subarachnoid hemorrhage, 1.7 for polyneuropathy and peripheral neuropathy, 2.2 for Guillain-Barré syndrome, 1.9 for diseases of myoneural junction and muscle, 1.8 for other brain disorders, 1.7 for Parkinson’s disease, 2.2 for multiple sclerosis, and 1.6 for CNS infection.

Compared with people without a neurologic condition, people with dementia, Alzheimer’s disease, and intellectual disabilities had lower suicide rates, with adjusted incidence rate ratios of 0.8, 0.2, and 0.6, respectively. “However, the adjusted [incidence rate ratio] for people with dementia during the first month after diagnosis was 3.0,” the researchers wrote.

In addition, the suicide rate increased with an increasing cumulative number of hospital contacts for neurologic conditions.

Overall incidence rates declined

“Over the study period, the suicide incidence rate for people with neurological disorders decreased from 78.6 per 100,000 person-years during the 1980-1999 years to 27.3 per 100,000 person-years during the 2000-2016 years,” wrote Dr. Erlangsen and colleagues. “The suicide incidence rate for those without a disorder decreased from 26.3 to 12.7 during the same time spans. ... The decline in the overall suicide rate over time did not affect the relative risk pattern.”

The decline in the general suicide rate in Denmark “has largely been attributed to means restriction, such as efforts to limit availability of firearms and particularly toxic medication,” the authors added.

In those time spans, the adjusted incidence rate ratio for suicide among those with dementia decreased from 2.4 to 1.0, and among those with multiple sclerosis from 2.0 to 1.0. “It is possible that the improvements observed for dementia and multiple sclerosis may be related to improvements in treatment and intensified community-based support,” Dr. Erlangsen and coauthors wrote.

When the researchers used people with rheumatoid arthritis as a reference group, those with a neurologic disorder had a higher suicide rate per 100,000 person-years, 30.2 versus 18.4. The adjusted incidence rate ratio for that comparison was 1.4.

In patients with Huntington’s disease, depression mediated by hyperactivity in the hypothalamic-pituitary-adrenal axis may contribute to the risk of suicide. “Witnessing the course of the disease in one’s parent” also may contribute the risk, the researchers wrote.

The analysis may have missed people with neurologic disorders diagnosed before 1977 if they did not have subsequent contact with a hospital, the investigators noted. In addition, diagnoses given in primary care were not included, suicide deaths may be underrecorded, and “adjusting for preexisting mental disorders could be viewed as overadjusting,” they wrote.

The study was supported by a grant from the Psychiatric Research Foundation in Denmark. The authors reported that they had no disclosures.

jremaly@mdedge.com

SOURCE: Erlangsen A et al. JAMA. 2020 Feb 4. doi: 10.1001/jama.2019.21834.