Literature Review

All patients with chronic insomnia should receive cognitive behavioral therapy as a primary intervention, and clinicians should use a shared decision-making approach when determining whether patients should start pharmacotherapy, according to a new guideline developed by the American Academy of Sleep Medicine (AASM). The guideline, which includes 14 recommendations, was published in the February 15 issue of the Journal of Clinical Sleep Medicine. It is the first guideline from the AASM to provide comprehensive evidence-based analyses of individual drugs commonly used to treat chronic insomnia disorder.

Chronic insomnia is associated with increased work absenteeism and impairment in functional status. Studies have also identified persistent insomnia as a significant risk factor for the development of psychiatric disorders, especially mood disorder. Pharmacologic treatment of insomnia is the most widely used approach to therapy, after treatment of comorbidities. No evidence-based clinical guideline had been published previously, however. The AASM commissioned a task force of four sleep medicine experts to develop the clinical guideline for treatment of chronic insomnia in adults.

The task force conducted a systematic review to identify randomized controlled trials. In addition, the group used the Grading of Recommendations Assessment, Development, and Evaluation process to assess the evidence. Recommendations were then made based on the quality of evidence, the balance of benefits and harms, and patient values and preferences.

Sleep Onset Insomnia Treatment Recommendations

The guideline recommends eszopiclone for the treatment of sleep onset insomnia, based on trials of 2-mg and 3-mg doses of the drug. Mean reduction of sleep latency was 14 minutes greater with eszopiclone than with placebo. Researchers also observed a moderate-to-large improvement in quality of sleep when they compared eszopiclone with placebo.

The experts also recommend ramelteon, based on trials of 8-mg doses of the drug. Mean reduction of sleep latency was nine minutes greater with ramelteon than with placebo. Ramelteon may not improve quality of sleep, however. Clinicians also are advised to use temazepam, based on trials of 15-mg doses. Temazepam reduced sleep latency by 37 minutes, compared with placebo, and provided a small improvement in quality of sleep.

The quality of evidence for the use of triazolam was high, and the drug reduced sleep latency by nine minutes, compared with placebo. The task force determined that the majority of patients would be more likely to use triazolam, compared with no treatment, but many would not use it. Zaleplon was recommended based on trials of 5-mg and 10-mg doses. It reduced sleep latency by 10 minutes, compared with placebo. Finally, zolpidem reduced sleep latency by five to 12 minutes, compared with placebo, and was associated with a moderate improvement in quality of sleep. The quality of evidence was very low, however.

Sleep Maintenance Insomnia Recommendations

The task force found four studies evaluating a 3-mg dose of doxepin and four studies investigating a 6-mg dose in sleep maintenance insomnia. Mean improvement in total sleep time with the drug was 26–32 min longer, compared with placebo. The mean reduction in wake after sleep onset (WASO) associated with doxepin was 22–23 min greater, compared with placebo.

The recommendation for the use of eszopiclone was based on trials of 2-mg and 3-mg doses of the drug. Mean improvement in total sleep time was 28–57 min longer with eszopiclone, compared with placebo. Mean reduction in WASO was 10–14 min greater with eszopiclone, compared with placebo.

Trials of 15-mg doses of temazepam were the basis for the task force’s recommendation of the drug. Mean improvement in total sleep time with temazepam was 99 min longer, compared with placebo. The drug’s effect on WASO was not reported. Compared with placebo, temazepam may provide a small improvement in quality of sleep.

Suvorexant was evaluated in trials of 10-mg, 15–20-mg, and 20-mg doses. Mean improvement in total sleep time was 10 min longer with suvorexant, compared with placebo. Mean reduction in WASO was 16–28 min greater with suvorexant, compared to placebo.

The guideline also recommends zolpidem, based on trials of 10-mg doses. Zolpidem provided a mean improvement in total sleep time that was 29 min longer, compared with placebo. The mean reduction in WASO was 25 min greater with zolpidem, compared with placebo.

Certain Drugs Are Not Recommended

Several drugs were not recommended for treating sleep onset or sleep maintenance insomnia. The task force suggests that clinicians not use diphenhydramine, because the evidence suggests that it is not effective for improving sleep onset or total sleep time. Similarly, evidence suggests that the effects of tiagabine on objective and subjective measures of sleep latency are clinically insignificant, and the drug’s harms may outweigh its benefits. Sleep outcome variables also did not improve with trazodone to a clinically significant degree. The task force also suggested that clinicians not use melatonin, valerian, or L-tryptophan because of the treatments’ lack of clinically significant effects.

All recommendations were classified as weak, due to the task force’s low degree of certainty in the appropriateness of the patient-care strategy. Further study is required to determine the drugs’ efficacy or lack thereof, said the task force. “Clinicians must continue to exercise sound clinical judgment based not only on these recommendations, but also on clinical experience, prior patient response, patient preferences, and potential adverse effects,” the authors concluded.

—Erica Tricarico

Suggested Reading

Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: An American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349.

All patients with chronic insomnia should receive cognitive behavioral therapy as a primary intervention, and clinicians should use a shared decision-making approach when determining whether patients should start pharmacotherapy, according to a new guideline developed by the American Academy of Sleep Medicine (AASM). The guideline, which includes 14 recommendations, was published in the February 15 issue of the Journal of Clinical Sleep Medicine. It is the first guideline from the AASM to provide comprehensive evidence-based analyses of individual drugs commonly used to treat chronic insomnia disorder.

Chronic insomnia is associated with increased work absenteeism and impairment in functional status. Studies have also identified persistent insomnia as a significant risk factor for the development of psychiatric disorders, especially mood disorder. Pharmacologic treatment of insomnia is the most widely used approach to therapy, after treatment of comorbidities. No evidence-based clinical guideline had been published previously, however. The AASM commissioned a task force of four sleep medicine experts to develop the clinical guideline for treatment of chronic insomnia in adults.

The task force conducted a systematic review to identify randomized controlled trials. In addition, the group used the Grading of Recommendations Assessment, Development, and Evaluation process to assess the evidence. Recommendations were then made based on the quality of evidence, the balance of benefits and harms, and patient values and preferences.

Sleep Onset Insomnia Treatment Recommendations

The guideline recommends eszopiclone for the treatment of sleep onset insomnia, based on trials of 2-mg and 3-mg doses of the drug. Mean reduction of sleep latency was 14 minutes greater with eszopiclone than with placebo. Researchers also observed a moderate-to-large improvement in quality of sleep when they compared eszopiclone with placebo.

The experts also recommend ramelteon, based on trials of 8-mg doses of the drug. Mean reduction of sleep latency was nine minutes greater with ramelteon than with placebo. Ramelteon may not improve quality of sleep, however. Clinicians also are advised to use temazepam, based on trials of 15-mg doses. Temazepam reduced sleep latency by 37 minutes, compared with placebo, and provided a small improvement in quality of sleep.

The quality of evidence for the use of triazolam was high, and the drug reduced sleep latency by nine minutes, compared with placebo. The task force determined that the majority of patients would be more likely to use triazolam, compared with no treatment, but many would not use it. Zaleplon was recommended based on trials of 5-mg and 10-mg doses. It reduced sleep latency by 10 minutes, compared with placebo. Finally, zolpidem reduced sleep latency by five to 12 minutes, compared with placebo, and was associated with a moderate improvement in quality of sleep. The quality of evidence was very low, however.

Sleep Maintenance Insomnia Recommendations

The task force found four studies evaluating a 3-mg dose of doxepin and four studies investigating a 6-mg dose in sleep maintenance insomnia. Mean improvement in total sleep time with the drug was 26–32 min longer, compared with placebo. The mean reduction in wake after sleep onset (WASO) associated with doxepin was 22–23 min greater, compared with placebo.

The recommendation for the use of eszopiclone was based on trials of 2-mg and 3-mg doses of the drug. Mean improvement in total sleep time was 28–57 min longer with eszopiclone, compared with placebo. Mean reduction in WASO was 10–14 min greater with eszopiclone, compared with placebo.

Trials of 15-mg doses of temazepam were the basis for the task force’s recommendation of the drug. Mean improvement in total sleep time with temazepam was 99 min longer, compared with placebo. The drug’s effect on WASO was not reported. Compared with placebo, temazepam may provide a small improvement in quality of sleep.

Suvorexant was evaluated in trials of 10-mg, 15–20-mg, and 20-mg doses. Mean improvement in total sleep time was 10 min longer with suvorexant, compared with placebo. Mean reduction in WASO was 16–28 min greater with suvorexant, compared to placebo.

The guideline also recommends zolpidem, based on trials of 10-mg doses. Zolpidem provided a mean improvement in total sleep time that was 29 min longer, compared with placebo. The mean reduction in WASO was 25 min greater with zolpidem, compared with placebo.

Certain Drugs Are Not Recommended

Several drugs were not recommended for treating sleep onset or sleep maintenance insomnia. The task force suggests that clinicians not use diphenhydramine, because the evidence suggests that it is not effective for improving sleep onset or total sleep time. Similarly, evidence suggests that the effects of tiagabine on objective and subjective measures of sleep latency are clinically insignificant, and the drug’s harms may outweigh its benefits. Sleep outcome variables also did not improve with trazodone to a clinically significant degree. The task force also suggested that clinicians not use melatonin, valerian, or L-tryptophan because of the treatments’ lack of clinically significant effects.

All recommendations were classified as weak, due to the task force’s low degree of certainty in the appropriateness of the patient-care strategy. Further study is required to determine the drugs’ efficacy or lack thereof, said the task force. “Clinicians must continue to exercise sound clinical judgment based not only on these recommendations, but also on clinical experience, prior patient response, patient preferences, and potential adverse effects,” the authors concluded.

—Erica Tricarico

Suggested Reading

Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: An American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349.

All patients with chronic insomnia should receive cognitive behavioral therapy as a primary intervention, and clinicians should use a shared decision-making approach when determining whether patients should start pharmacotherapy, according to a new guideline developed by the American Academy of Sleep Medicine (AASM). The guideline, which includes 14 recommendations, was published in the February 15 issue of the Journal of Clinical Sleep Medicine. It is the first guideline from the AASM to provide comprehensive evidence-based analyses of individual drugs commonly used to treat chronic insomnia disorder.

Chronic insomnia is associated with increased work absenteeism and impairment in functional status. Studies have also identified persistent insomnia as a significant risk factor for the development of psychiatric disorders, especially mood disorder. Pharmacologic treatment of insomnia is the most widely used approach to therapy, after treatment of comorbidities. No evidence-based clinical guideline had been published previously, however. The AASM commissioned a task force of four sleep medicine experts to develop the clinical guideline for treatment of chronic insomnia in adults.

The task force conducted a systematic review to identify randomized controlled trials. In addition, the group used the Grading of Recommendations Assessment, Development, and Evaluation process to assess the evidence. Recommendations were then made based on the quality of evidence, the balance of benefits and harms, and patient values and preferences.

Sleep Onset Insomnia Treatment Recommendations

The guideline recommends eszopiclone for the treatment of sleep onset insomnia, based on trials of 2-mg and 3-mg doses of the drug. Mean reduction of sleep latency was 14 minutes greater with eszopiclone than with placebo. Researchers also observed a moderate-to-large improvement in quality of sleep when they compared eszopiclone with placebo.

The experts also recommend ramelteon, based on trials of 8-mg doses of the drug. Mean reduction of sleep latency was nine minutes greater with ramelteon than with placebo. Ramelteon may not improve quality of sleep, however. Clinicians also are advised to use temazepam, based on trials of 15-mg doses. Temazepam reduced sleep latency by 37 minutes, compared with placebo, and provided a small improvement in quality of sleep.

The quality of evidence for the use of triazolam was high, and the drug reduced sleep latency by nine minutes, compared with placebo. The task force determined that the majority of patients would be more likely to use triazolam, compared with no treatment, but many would not use it. Zaleplon was recommended based on trials of 5-mg and 10-mg doses. It reduced sleep latency by 10 minutes, compared with placebo. Finally, zolpidem reduced sleep latency by five to 12 minutes, compared with placebo, and was associated with a moderate improvement in quality of sleep. The quality of evidence was very low, however.

Sleep Maintenance Insomnia Recommendations

The task force found four studies evaluating a 3-mg dose of doxepin and four studies investigating a 6-mg dose in sleep maintenance insomnia. Mean improvement in total sleep time with the drug was 26–32 min longer, compared with placebo. The mean reduction in wake after sleep onset (WASO) associated with doxepin was 22–23 min greater, compared with placebo.

The recommendation for the use of eszopiclone was based on trials of 2-mg and 3-mg doses of the drug. Mean improvement in total sleep time was 28–57 min longer with eszopiclone, compared with placebo. Mean reduction in WASO was 10–14 min greater with eszopiclone, compared with placebo.

Trials of 15-mg doses of temazepam were the basis for the task force’s recommendation of the drug. Mean improvement in total sleep time with temazepam was 99 min longer, compared with placebo. The drug’s effect on WASO was not reported. Compared with placebo, temazepam may provide a small improvement in quality of sleep.

Suvorexant was evaluated in trials of 10-mg, 15–20-mg, and 20-mg doses. Mean improvement in total sleep time was 10 min longer with suvorexant, compared with placebo. Mean reduction in WASO was 16–28 min greater with suvorexant, compared to placebo.

The guideline also recommends zolpidem, based on trials of 10-mg doses. Zolpidem provided a mean improvement in total sleep time that was 29 min longer, compared with placebo. The mean reduction in WASO was 25 min greater with zolpidem, compared with placebo.

Certain Drugs Are Not Recommended

Several drugs were not recommended for treating sleep onset or sleep maintenance insomnia. The task force suggests that clinicians not use diphenhydramine, because the evidence suggests that it is not effective for improving sleep onset or total sleep time. Similarly, evidence suggests that the effects of tiagabine on objective and subjective measures of sleep latency are clinically insignificant, and the drug’s harms may outweigh its benefits. Sleep outcome variables also did not improve with trazodone to a clinically significant degree. The task force also suggested that clinicians not use melatonin, valerian, or L-tryptophan because of the treatments’ lack of clinically significant effects.

All recommendations were classified as weak, due to the task force’s low degree of certainty in the appropriateness of the patient-care strategy. Further study is required to determine the drugs’ efficacy or lack thereof, said the task force. “Clinicians must continue to exercise sound clinical judgment based not only on these recommendations, but also on clinical experience, prior patient response, patient preferences, and potential adverse effects,” the authors concluded.

—Erica Tricarico

Suggested Reading

Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: An American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349.

Bilateral deep brain stimulation of the anterior nucleus of the thalamus can help control seizures, but there are reports that suggest it also causes memory problems and depression. When Tröster et al analyzed data from a randomized trial (SANTE), they did find subjective evidence of both adverse events but were unable to confirm the presence of these problems with objective neurobehavioral measures. Nonetheless, they recommend that patients undergoing deep brain stimulation be monitored and undergo neuropsychological assessment for depression and memory problems.

Tröster AI, Meador KJ, Irwin CP, Fisher RS. Memory and mood outcomes after anterior thalamic stimulation for refractory partial epilepsy. Seizure. 2017;45:133-141.

Bilateral deep brain stimulation of the anterior nucleus of the thalamus can help control seizures, but there are reports that suggest it also causes memory problems and depression. When Tröster et al analyzed data from a randomized trial (SANTE), they did find subjective evidence of both adverse events but were unable to confirm the presence of these problems with objective neurobehavioral measures. Nonetheless, they recommend that patients undergoing deep brain stimulation be monitored and undergo neuropsychological assessment for depression and memory problems.

Tröster AI, Meador KJ, Irwin CP, Fisher RS. Memory and mood outcomes after anterior thalamic stimulation for refractory partial epilepsy. Seizure. 2017;45:133-141.

Bilateral deep brain stimulation of the anterior nucleus of the thalamus can help control seizures, but there are reports that suggest it also causes memory problems and depression. When Tröster et al analyzed data from a randomized trial (SANTE), they did find subjective evidence of both adverse events but were unable to confirm the presence of these problems with objective neurobehavioral measures. Nonetheless, they recommend that patients undergoing deep brain stimulation be monitored and undergo neuropsychological assessment for depression and memory problems.

Tröster AI, Meador KJ, Irwin CP, Fisher RS. Memory and mood outcomes after anterior thalamic stimulation for refractory partial epilepsy. Seizure. 2017;45:133-141.

Patients vary widely in their response to cortical electric stimulation (CES). A retrospective analysis of 92 patients with medically intractable epilepsy who underwent CES was unable to detect any clinical or demographic factors that would explain the varied response to the procedure. Corley et al also found striking variability and a wide range of motor, sensory, and speech response thresholds between patients and within the different regions of the brain in the same patient.

Corley JA, Nazari P, Rossi VJ, et al. Cortical stimulation parameters for functional mapping. Seizure. 2017;45:36-71.

Patients vary widely in their response to cortical electric stimulation (CES). A retrospective analysis of 92 patients with medically intractable epilepsy who underwent CES was unable to detect any clinical or demographic factors that would explain the varied response to the procedure. Corley et al also found striking variability and a wide range of motor, sensory, and speech response thresholds between patients and within the different regions of the brain in the same patient.

Corley JA, Nazari P, Rossi VJ, et al. Cortical stimulation parameters for functional mapping. Seizure. 2017;45:36-71.

Patients vary widely in their response to cortical electric stimulation (CES). A retrospective analysis of 92 patients with medically intractable epilepsy who underwent CES was unable to detect any clinical or demographic factors that would explain the varied response to the procedure. Corley et al also found striking variability and a wide range of motor, sensory, and speech response thresholds between patients and within the different regions of the brain in the same patient.

Corley JA, Nazari P, Rossi VJ, et al. Cortical stimulation parameters for functional mapping. Seizure. 2017;45:36-71.

Dementia, poor mental status during electroencephalogram (EEG), chronic focal abnormalities on neuroimaging, cardiac arrest, and chronic obstructive pulmonary disease (COPD) were independently associated with increased in-hospital mortality in patients with generalized periodic discharges (GPDs), according to an analysis of 113 patients at 3 hospitals. To determine the prognostic significance of GPDs observed during EEGs, Jadeja et al reviewed EEG tracings of the patients, of whom there were 60 inpatient deaths (53.1%).

Jadeja N, Zarnegar R, Legatt AD. Clinical outcomes in patients with generalized periodic discharges. Seizure. 2017; 45:114-118.

Dementia, poor mental status during electroencephalogram (EEG), chronic focal abnormalities on neuroimaging, cardiac arrest, and chronic obstructive pulmonary disease (COPD) were independently associated with increased in-hospital mortality in patients with generalized periodic discharges (GPDs), according to an analysis of 113 patients at 3 hospitals. To determine the prognostic significance of GPDs observed during EEGs, Jadeja et al reviewed EEG tracings of the patients, of whom there were 60 inpatient deaths (53.1%).

Jadeja N, Zarnegar R, Legatt AD. Clinical outcomes in patients with generalized periodic discharges. Seizure. 2017; 45:114-118.

Dementia, poor mental status during electroencephalogram (EEG), chronic focal abnormalities on neuroimaging, cardiac arrest, and chronic obstructive pulmonary disease (COPD) were independently associated with increased in-hospital mortality in patients with generalized periodic discharges (GPDs), according to an analysis of 113 patients at 3 hospitals. To determine the prognostic significance of GPDs observed during EEGs, Jadeja et al reviewed EEG tracings of the patients, of whom there were 60 inpatient deaths (53.1%).

Jadeja N, Zarnegar R, Legatt AD. Clinical outcomes in patients with generalized periodic discharges. Seizure. 2017; 45:114-118.

In patients presenting with a first clinical demyelinating event, early treatment with subcutaneous interferon beta-1a three times per week over five years prolonged the time to clinically definite multiple sclerosis (MS), compared with delayed treatment, according to research published online ahead of print December 30, 2016 in the Journal of Neurology, Neurosurgery and Psychiatry. Compared with delayed treatment, early treatment also prolonged the time to McDonald MS conversion.

Giancarlo Comi, MD, Professor of Neurology at the Scientific Institute H.S. Raffaele in Milan, and colleagues conducted REFLEXION, a preplanned extension of the REFLEX study, to compare the effect of more frequent and early dosing with that of delayed treatment. Eligible patients were between ages 18 and 50, had an Expanded Disability Status Scale (EDSS) score of 5.0 or lower, and a single clinical event suggestive of MS within 60 days of enrollment. In REFLEX, patients had been randomized to interferon beta-1a (44 μg) thrice weekly or once weekly, or placebo. Treatment lasted for 24 months or until a patient developed clinically definite MS.

In REFLEXION, patients first randomized to interferon beta-1a who had not converted to clinically definite MS continued their original dosing regimen. Patients originally receiving placebo who had not converted to clinically definite MS were switched to interferon beta-1a (44 μg thrice weekly). These patients became the delayed-treatment group. Patients who converted to clinically definite MS during REFLEX or REFLEXION received open-label interferon beta-1a 44 μg thrice weekly from then on.

EDSS scores and clinically definite MS assessments were recorded at extension baseline (ie, month 24) and every six months thereafter. The primary end point was time to conversion to clinically definite MS from first randomization to month 36. Time to clinically definite MS to month 60 was a secondary end point.

The extension study included 127 participants originally randomized to interferon beta-1a thrice weekly, 142 participants originally randomized to interferon beta-1a once weekly, and 133 patients originally randomized to placebo. At month 36, the proportion of patients who had converted to clinically definite MS was lower among patients receiving interferon thrice weekly or weekly, compared with the delayed-treatment group (25.1%, 25.7%, and 38.6%, respectively). The risk of conversion to clinically definite MS was significantly reduced for patients receiving early treatment, compared with delayed treatment. The researchers found no significant difference between the early-treatment groups.

The analysis for month 60 also found that both early-treatment groups had longer times to clinically definite MS, compared with delayed treatment. The proportion of patients who converted to clinically definite MS increased at month 60, but was still lower among participants receiving thrice-weekly or weekly interferon than among patients on delayed treatment (32.2%, 36.0%, and 40.4%, respectively). Cumulative probability of conversion was lower with thrice-weekly and weekly early treatment than with delayed treatment (39.2%, 40.7%, and 44.6%, respectively).

—Erik Greb

Suggested Reading

Comi G, De Stefano N, Freedman MS, et al. Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. J Neurol Neurosurg Psychiatry. 2016 Dec 30 [Epub ahead of print].

In patients presenting with a first clinical demyelinating event, early treatment with subcutaneous interferon beta-1a three times per week over five years prolonged the time to clinically definite multiple sclerosis (MS), compared with delayed treatment, according to research published online ahead of print December 30, 2016 in the Journal of Neurology, Neurosurgery and Psychiatry. Compared with delayed treatment, early treatment also prolonged the time to McDonald MS conversion.

Giancarlo Comi, MD, Professor of Neurology at the Scientific Institute H.S. Raffaele in Milan, and colleagues conducted REFLEXION, a preplanned extension of the REFLEX study, to compare the effect of more frequent and early dosing with that of delayed treatment. Eligible patients were between ages 18 and 50, had an Expanded Disability Status Scale (EDSS) score of 5.0 or lower, and a single clinical event suggestive of MS within 60 days of enrollment. In REFLEX, patients had been randomized to interferon beta-1a (44 μg) thrice weekly or once weekly, or placebo. Treatment lasted for 24 months or until a patient developed clinically definite MS.

In REFLEXION, patients first randomized to interferon beta-1a who had not converted to clinically definite MS continued their original dosing regimen. Patients originally receiving placebo who had not converted to clinically definite MS were switched to interferon beta-1a (44 μg thrice weekly). These patients became the delayed-treatment group. Patients who converted to clinically definite MS during REFLEX or REFLEXION received open-label interferon beta-1a 44 μg thrice weekly from then on.

EDSS scores and clinically definite MS assessments were recorded at extension baseline (ie, month 24) and every six months thereafter. The primary end point was time to conversion to clinically definite MS from first randomization to month 36. Time to clinically definite MS to month 60 was a secondary end point.

The extension study included 127 participants originally randomized to interferon beta-1a thrice weekly, 142 participants originally randomized to interferon beta-1a once weekly, and 133 patients originally randomized to placebo. At month 36, the proportion of patients who had converted to clinically definite MS was lower among patients receiving interferon thrice weekly or weekly, compared with the delayed-treatment group (25.1%, 25.7%, and 38.6%, respectively). The risk of conversion to clinically definite MS was significantly reduced for patients receiving early treatment, compared with delayed treatment. The researchers found no significant difference between the early-treatment groups.

The analysis for month 60 also found that both early-treatment groups had longer times to clinically definite MS, compared with delayed treatment. The proportion of patients who converted to clinically definite MS increased at month 60, but was still lower among participants receiving thrice-weekly or weekly interferon than among patients on delayed treatment (32.2%, 36.0%, and 40.4%, respectively). Cumulative probability of conversion was lower with thrice-weekly and weekly early treatment than with delayed treatment (39.2%, 40.7%, and 44.6%, respectively).

—Erik Greb

Suggested Reading

Comi G, De Stefano N, Freedman MS, et al. Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. J Neurol Neurosurg Psychiatry. 2016 Dec 30 [Epub ahead of print].

In patients presenting with a first clinical demyelinating event, early treatment with subcutaneous interferon beta-1a three times per week over five years prolonged the time to clinically definite multiple sclerosis (MS), compared with delayed treatment, according to research published online ahead of print December 30, 2016 in the Journal of Neurology, Neurosurgery and Psychiatry. Compared with delayed treatment, early treatment also prolonged the time to McDonald MS conversion.

Giancarlo Comi, MD, Professor of Neurology at the Scientific Institute H.S. Raffaele in Milan, and colleagues conducted REFLEXION, a preplanned extension of the REFLEX study, to compare the effect of more frequent and early dosing with that of delayed treatment. Eligible patients were between ages 18 and 50, had an Expanded Disability Status Scale (EDSS) score of 5.0 or lower, and a single clinical event suggestive of MS within 60 days of enrollment. In REFLEX, patients had been randomized to interferon beta-1a (44 μg) thrice weekly or once weekly, or placebo. Treatment lasted for 24 months or until a patient developed clinically definite MS.

In REFLEXION, patients first randomized to interferon beta-1a who had not converted to clinically definite MS continued their original dosing regimen. Patients originally receiving placebo who had not converted to clinically definite MS were switched to interferon beta-1a (44 μg thrice weekly). These patients became the delayed-treatment group. Patients who converted to clinically definite MS during REFLEX or REFLEXION received open-label interferon beta-1a 44 μg thrice weekly from then on.

EDSS scores and clinically definite MS assessments were recorded at extension baseline (ie, month 24) and every six months thereafter. The primary end point was time to conversion to clinically definite MS from first randomization to month 36. Time to clinically definite MS to month 60 was a secondary end point.

The extension study included 127 participants originally randomized to interferon beta-1a thrice weekly, 142 participants originally randomized to interferon beta-1a once weekly, and 133 patients originally randomized to placebo. At month 36, the proportion of patients who had converted to clinically definite MS was lower among patients receiving interferon thrice weekly or weekly, compared with the delayed-treatment group (25.1%, 25.7%, and 38.6%, respectively). The risk of conversion to clinically definite MS was significantly reduced for patients receiving early treatment, compared with delayed treatment. The researchers found no significant difference between the early-treatment groups.

The analysis for month 60 also found that both early-treatment groups had longer times to clinically definite MS, compared with delayed treatment. The proportion of patients who converted to clinically definite MS increased at month 60, but was still lower among participants receiving thrice-weekly or weekly interferon than among patients on delayed treatment (32.2%, 36.0%, and 40.4%, respectively). Cumulative probability of conversion was lower with thrice-weekly and weekly early treatment than with delayed treatment (39.2%, 40.7%, and 44.6%, respectively).

—Erik Greb

Suggested Reading

Comi G, De Stefano N, Freedman MS, et al. Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. J Neurol Neurosurg Psychiatry. 2016 Dec 30 [Epub ahead of print].

Children with refractory status epilepticus do not receive more timely treatment if they have a prior diagnosis of epilepsy, according to an investigation published January 24 in Neurology. A history of status epilepticus, however, is associated with more timely administration of abortive medication.

Most episodes of pediatric status epilepticus occur in children with no history of seizures. Investigators had not examined whether having a history of seizures or status epilepticus leads to more timely treatment, including escalation of therapy when indicated, and better outcomes.

Iván Sánchez Fernández, MD, Clinical Fellow in Neurology at Boston Children’s Hospital, and colleagues conducted a prospective observational study to compare the management and outcomes of refractory status epilepticus in children with and without a prior diagnosis of epilepsy and with and without a history of status epilepticus. Eligible patients were between ages one month and 21 years and had convulsive seizures at onset that continued after administration of at least two antiepileptic drugs (AEDs).

The investigators enrolled 189 participants (53% male) with a median age of 4.2 years. Eighty-nine (47%) patients had a prior diagnosis of epilepsy. Thirty-four (18%) patients had a history of status epilepticus.

The time to first benzodiazepine was similar in participants with and without a diagnosis of epilepsy (15 minutes vs 16.5 minutes). Patients with a diagnosis of epilepsy received their first nonbenzodiazepine AED later (93 minutes vs 50.5 minutes) and were less likely to receive at least one continuous infusion (39.3% vs 57%). The time to the first continuous infusion, however, was similar in patients with and without a diagnosis of epilepsy (258.5 vs 149 minutes).

Patients with a diagnosis of epilepsy were less likely to be intubated (66.3% vs 83%), had a longer duration of status epilepticus (174 minutes vs 120 minutes), and had a shorter ICU stay (3.9 days vs 5 days). At hospital discharge, patients with a diagnosis of epilepsy were more likely to return to baseline (75% vs 65%) and had lower mortality (0% vs 7%).

Time to the first benzodiazepine was shorter for patients with a history of status epilepticus, compared with patients without (8 minutes vs 20 minutes). The time to first nonbenzodiazepine AED was similar in patients with and without a history of status epilepticus (76.5 minutes vs 65 minutes). Patients with and without a history of status epilepticus were as likely to receive continuous infusions (52.9% vs 47.7%), had a similar time to the first continuous infusion (182 vs 180 minutes), and were as likely to be intubated (82.4% vs 73.5%). Patients with a history of status epilepticus had a longer duration of status epilepticus (150 minutes vs 124.5 minutes) and a shorter ICU stay (5 vs 4.3 days).

At hospital discharge, return to baseline function was similar between patients with and without a history of status epilepticus (76.5% vs 68.4%). The difference between groups in mortality rate was not statistically significant (0% vs 4.5%). The more timely administration of the first benzodiazepine in patients with a history of status epilepticus mainly resulted from cases with onset outside a hospital, while management of status epilepticus with in-hospital onset was similar in patients with and without a history of status epilepticus.

—Erik Greb

Suggested Reading

Sánchez Fernández I, Jackson MC, Abend NS, et al. Refractory status epilepticus in children with and without prior epilepsy or status epilepticus. Neurology. 2017;88(4):386-394.

Children with refractory status epilepticus do not receive more timely treatment if they have a prior diagnosis of epilepsy, according to an investigation published January 24 in Neurology. A history of status epilepticus, however, is associated with more timely administration of abortive medication.

Most episodes of pediatric status epilepticus occur in children with no history of seizures. Investigators had not examined whether having a history of seizures or status epilepticus leads to more timely treatment, including escalation of therapy when indicated, and better outcomes.

Iván Sánchez Fernández, MD, Clinical Fellow in Neurology at Boston Children’s Hospital, and colleagues conducted a prospective observational study to compare the management and outcomes of refractory status epilepticus in children with and without a prior diagnosis of epilepsy and with and without a history of status epilepticus. Eligible patients were between ages one month and 21 years and had convulsive seizures at onset that continued after administration of at least two antiepileptic drugs (AEDs).

The investigators enrolled 189 participants (53% male) with a median age of 4.2 years. Eighty-nine (47%) patients had a prior diagnosis of epilepsy. Thirty-four (18%) patients had a history of status epilepticus.

The time to first benzodiazepine was similar in participants with and without a diagnosis of epilepsy (15 minutes vs 16.5 minutes). Patients with a diagnosis of epilepsy received their first nonbenzodiazepine AED later (93 minutes vs 50.5 minutes) and were less likely to receive at least one continuous infusion (39.3% vs 57%). The time to the first continuous infusion, however, was similar in patients with and without a diagnosis of epilepsy (258.5 vs 149 minutes).

Patients with a diagnosis of epilepsy were less likely to be intubated (66.3% vs 83%), had a longer duration of status epilepticus (174 minutes vs 120 minutes), and had a shorter ICU stay (3.9 days vs 5 days). At hospital discharge, patients with a diagnosis of epilepsy were more likely to return to baseline (75% vs 65%) and had lower mortality (0% vs 7%).

Time to the first benzodiazepine was shorter for patients with a history of status epilepticus, compared with patients without (8 minutes vs 20 minutes). The time to first nonbenzodiazepine AED was similar in patients with and without a history of status epilepticus (76.5 minutes vs 65 minutes). Patients with and without a history of status epilepticus were as likely to receive continuous infusions (52.9% vs 47.7%), had a similar time to the first continuous infusion (182 vs 180 minutes), and were as likely to be intubated (82.4% vs 73.5%). Patients with a history of status epilepticus had a longer duration of status epilepticus (150 minutes vs 124.5 minutes) and a shorter ICU stay (5 vs 4.3 days).

At hospital discharge, return to baseline function was similar between patients with and without a history of status epilepticus (76.5% vs 68.4%). The difference between groups in mortality rate was not statistically significant (0% vs 4.5%). The more timely administration of the first benzodiazepine in patients with a history of status epilepticus mainly resulted from cases with onset outside a hospital, while management of status epilepticus with in-hospital onset was similar in patients with and without a history of status epilepticus.

—Erik Greb

Suggested Reading

Sánchez Fernández I, Jackson MC, Abend NS, et al. Refractory status epilepticus in children with and without prior epilepsy or status epilepticus. Neurology. 2017;88(4):386-394.

Children with refractory status epilepticus do not receive more timely treatment if they have a prior diagnosis of epilepsy, according to an investigation published January 24 in Neurology. A history of status epilepticus, however, is associated with more timely administration of abortive medication.

Most episodes of pediatric status epilepticus occur in children with no history of seizures. Investigators had not examined whether having a history of seizures or status epilepticus leads to more timely treatment, including escalation of therapy when indicated, and better outcomes.

Iván Sánchez Fernández, MD, Clinical Fellow in Neurology at Boston Children’s Hospital, and colleagues conducted a prospective observational study to compare the management and outcomes of refractory status epilepticus in children with and without a prior diagnosis of epilepsy and with and without a history of status epilepticus. Eligible patients were between ages one month and 21 years and had convulsive seizures at onset that continued after administration of at least two antiepileptic drugs (AEDs).

The investigators enrolled 189 participants (53% male) with a median age of 4.2 years. Eighty-nine (47%) patients had a prior diagnosis of epilepsy. Thirty-four (18%) patients had a history of status epilepticus.

The time to first benzodiazepine was similar in participants with and without a diagnosis of epilepsy (15 minutes vs 16.5 minutes). Patients with a diagnosis of epilepsy received their first nonbenzodiazepine AED later (93 minutes vs 50.5 minutes) and were less likely to receive at least one continuous infusion (39.3% vs 57%). The time to the first continuous infusion, however, was similar in patients with and without a diagnosis of epilepsy (258.5 vs 149 minutes).

Patients with a diagnosis of epilepsy were less likely to be intubated (66.3% vs 83%), had a longer duration of status epilepticus (174 minutes vs 120 minutes), and had a shorter ICU stay (3.9 days vs 5 days). At hospital discharge, patients with a diagnosis of epilepsy were more likely to return to baseline (75% vs 65%) and had lower mortality (0% vs 7%).

Time to the first benzodiazepine was shorter for patients with a history of status epilepticus, compared with patients without (8 minutes vs 20 minutes). The time to first nonbenzodiazepine AED was similar in patients with and without a history of status epilepticus (76.5 minutes vs 65 minutes). Patients with and without a history of status epilepticus were as likely to receive continuous infusions (52.9% vs 47.7%), had a similar time to the first continuous infusion (182 vs 180 minutes), and were as likely to be intubated (82.4% vs 73.5%). Patients with a history of status epilepticus had a longer duration of status epilepticus (150 minutes vs 124.5 minutes) and a shorter ICU stay (5 vs 4.3 days).

At hospital discharge, return to baseline function was similar between patients with and without a history of status epilepticus (76.5% vs 68.4%). The difference between groups in mortality rate was not statistically significant (0% vs 4.5%). The more timely administration of the first benzodiazepine in patients with a history of status epilepticus mainly resulted from cases with onset outside a hospital, while management of status epilepticus with in-hospital onset was similar in patients with and without a history of status epilepticus.

—Erik Greb

Suggested Reading

Sánchez Fernández I, Jackson MC, Abend NS, et al. Refractory status epilepticus in children with and without prior epilepsy or status epilepticus. Neurology. 2017;88(4):386-394.

The online PREDICT-PD algorithm effectively identifies people at increased risk of Parkinson’s disease, according to research published online ahead of print January 16 in Movement Disorders. The risk scores that the algorithm assigns are significantly associated with intermediate markers of Parkinson’s disease. Higher PREDICT-PD risk score at baseline also is associated with an increased rate of incident Parkinson’s disease.

Previous research with the goal of identifying patients at risk of Parkinson’s disease mainly has focused on people with a family history of the disease, asymptomatic carriers of genes associated with the disease, or people with imaging abnormalities associated with the disease (eg, hyperechogenicity on transcranial sonography). The rarity, the representativeness, and the feasibility of identifying these factors have limited these studies, however.

Internet-Based Testing

To overcome these limitations, Anette-Eleonore Schrag, PhD, Professor of Clinical Neurosciences at University College London, and colleagues developed an online, evidence-based algorithm to identify risk indicators of Parkinson’s disease in the UK population. The investigators used a study website to recruit participants between ages 60 and 80 who did not have Parkinson’s disease, any other movement disorder, or stroke. Participants were prompted to return to the website yearly and complete tests.

Among the tests was a survey that included demographic questions and validated questionnaires about early nonmotor features of and risk factors for Parkinson’s disease (eg, the Hospital Anxiety Depression Scale and the REM sleep behavior disorder Screening Questionnaire [RBDSQ]). Participants also took the Bradykinesia Akinesia Incoordination (BRAIN) test, an online keyboard-tapping task. At baseline and at year three, participants took the University of Pennsylvania Smell Identification Test (UPSIT). The annual survey included a question about whether the participants had received any new diagnoses, including Parkinson’s disease or movement disorder. At year three, participants also gave saliva samples that were genotyped for mutations in exons 8 to 11 of glucocerebrosidase (GBA) and exon 41 in the LRRK2 gene.

The investigators used participants’ early features and risk factors to calculate their risk scores and rank participants according to their risk. Dr. Schrag and colleagues also tested support for enrichment of the population at risk of Parkinson’s disease by examining associations between risk scores and the following intermediate markers of Parkinson’s disease: reduced sense of smell, presence of subjective RBD, and slowing of finger tapping speed.

Risk Scores Were Associated With Incident Disease

The researchers recruited 1,323 eligible volunteers. At baseline, their mean age was 66, and approximately 61% of the population was female. In all, 1,040 of the participants completed follow-up testing at year 1, 939 completed year 2 follow-up, and 846 completed year 3 follow-up. A total of 223 participants completed the baseline assessment only.

Baseline risk scores were associated with significantly higher rates of all intermediate markers of Parkinson’s disease during each year of follow-up. The group of patients at higher risk (ie, those above the 15th percentile) had significantly worse UPSIT score, RBDSQ score, and finger tapping in all years, compared with patients at lower risk (ie, those below the 85th percentile).

Risk scores in the entire sample were strongly associated with intermediate markers of Parkinson’s disease each year. Higher- and lower-risk groups differed significantly in median UPSIT score, RBDSQ score, and mean finger tapping speed in all years of follow-up.

At year 1, three patients had been newly diagnosed with Parkinson’s disease. An additional participant received the diagnosis in year 2, and three other participants received the diagnosis in year 3. All of the participants with newly diagnosed Parkinson’s disease at year 1 were in the higher risk group, and two had also been in the higher risk group at baseline. The participant diagnosed at year 2 was in the higher risk group at baseline, year 1, and year 2. All of the three participants diagnosed by year 3 were in the middle risk group at baseline. “There was substantial heterogeneity in the occurrence of intermediate markers in these individuals,” said the researchers.

The incidence of independently diagnosed Parkinson’s disease in participants who had been in the higher risk group during three years of follow-up was 1.6% per year and 0.2% across the whole population. Exploratory Cox regression analysis using incident Parkinson’s disease over three years as the outcome indicated an association with baseline risk estimate. In participants for whom GBA and LRRK2 status was known, the association between baseline risk and incident Parkinson’s disease was weaker. But the addition of GBA and LRRK2 variants in the algorithm improved the strength of association between baseline risk and incident Parkinson’s disease. Among the intermediate markers of disease, baseline finger tapping was associated with incident Parkinson’s disease at three years.

Results Could Reflect Selection Bias

“Although only a small number of individuals have been independently diagnosed with Parkinson’s disease during follow-up so far, the overall incidence of 0.2% is consistent with the expected incidence rate in the age group of 60 to 80 from the general population (one to three per 1,000 per year) and supports the representativeness of our sample,” said Dr. Schrag.

The recruitment of participants may have introduced selection bias into the study, she acknowledged. “However, we did not use family history as an entry criterion, and the proportion with a positive family history was lower than in other landmark studies.” The fact that 17% of participants only completed the baseline assessment also may have introduced selection bias, “although there were no differences between those with or without follow-up, meaning that bias as a result of loss to follow-up was less likely.

“This Internet-based approach may be useful for population screening because it can easily be scaled upward,” added Dr. Schrag. “It will allow larger numbers of Parkinson’s disease cases that represent the spectrum of the disease to be identified, rather than what would be possible from cohorts of carriers of specific risk factors.”

—Erik Greb

Suggested Readings

Noyce AJ, R’Bibo L, Peress L, et al. PREDICT-PD: An online approach to prospectively identify risk indicators of Parkinson’s disease. Mov Disord. 2017 Jan 16 [Epub ahead of print].

The online PREDICT-PD algorithm effectively identifies people at increased risk of Parkinson’s disease, according to research published online ahead of print January 16 in Movement Disorders. The risk scores that the algorithm assigns are significantly associated with intermediate markers of Parkinson’s disease. Higher PREDICT-PD risk score at baseline also is associated with an increased rate of incident Parkinson’s disease.

Previous research with the goal of identifying patients at risk of Parkinson’s disease mainly has focused on people with a family history of the disease, asymptomatic carriers of genes associated with the disease, or people with imaging abnormalities associated with the disease (eg, hyperechogenicity on transcranial sonography). The rarity, the representativeness, and the feasibility of identifying these factors have limited these studies, however.

Internet-Based Testing

To overcome these limitations, Anette-Eleonore Schrag, PhD, Professor of Clinical Neurosciences at University College London, and colleagues developed an online, evidence-based algorithm to identify risk indicators of Parkinson’s disease in the UK population. The investigators used a study website to recruit participants between ages 60 and 80 who did not have Parkinson’s disease, any other movement disorder, or stroke. Participants were prompted to return to the website yearly and complete tests.

Among the tests was a survey that included demographic questions and validated questionnaires about early nonmotor features of and risk factors for Parkinson’s disease (eg, the Hospital Anxiety Depression Scale and the REM sleep behavior disorder Screening Questionnaire [RBDSQ]). Participants also took the Bradykinesia Akinesia Incoordination (BRAIN) test, an online keyboard-tapping task. At baseline and at year three, participants took the University of Pennsylvania Smell Identification Test (UPSIT). The annual survey included a question about whether the participants had received any new diagnoses, including Parkinson’s disease or movement disorder. At year three, participants also gave saliva samples that were genotyped for mutations in exons 8 to 11 of glucocerebrosidase (GBA) and exon 41 in the LRRK2 gene.

The investigators used participants’ early features and risk factors to calculate their risk scores and rank participants according to their risk. Dr. Schrag and colleagues also tested support for enrichment of the population at risk of Parkinson’s disease by examining associations between risk scores and the following intermediate markers of Parkinson’s disease: reduced sense of smell, presence of subjective RBD, and slowing of finger tapping speed.

Risk Scores Were Associated With Incident Disease

The researchers recruited 1,323 eligible volunteers. At baseline, their mean age was 66, and approximately 61% of the population was female. In all, 1,040 of the participants completed follow-up testing at year 1, 939 completed year 2 follow-up, and 846 completed year 3 follow-up. A total of 223 participants completed the baseline assessment only.

Baseline risk scores were associated with significantly higher rates of all intermediate markers of Parkinson’s disease during each year of follow-up. The group of patients at higher risk (ie, those above the 15th percentile) had significantly worse UPSIT score, RBDSQ score, and finger tapping in all years, compared with patients at lower risk (ie, those below the 85th percentile).

Risk scores in the entire sample were strongly associated with intermediate markers of Parkinson’s disease each year. Higher- and lower-risk groups differed significantly in median UPSIT score, RBDSQ score, and mean finger tapping speed in all years of follow-up.

At year 1, three patients had been newly diagnosed with Parkinson’s disease. An additional participant received the diagnosis in year 2, and three other participants received the diagnosis in year 3. All of the participants with newly diagnosed Parkinson’s disease at year 1 were in the higher risk group, and two had also been in the higher risk group at baseline. The participant diagnosed at year 2 was in the higher risk group at baseline, year 1, and year 2. All of the three participants diagnosed by year 3 were in the middle risk group at baseline. “There was substantial heterogeneity in the occurrence of intermediate markers in these individuals,” said the researchers.

The incidence of independently diagnosed Parkinson’s disease in participants who had been in the higher risk group during three years of follow-up was 1.6% per year and 0.2% across the whole population. Exploratory Cox regression analysis using incident Parkinson’s disease over three years as the outcome indicated an association with baseline risk estimate. In participants for whom GBA and LRRK2 status was known, the association between baseline risk and incident Parkinson’s disease was weaker. But the addition of GBA and LRRK2 variants in the algorithm improved the strength of association between baseline risk and incident Parkinson’s disease. Among the intermediate markers of disease, baseline finger tapping was associated with incident Parkinson’s disease at three years.

Results Could Reflect Selection Bias

“Although only a small number of individuals have been independently diagnosed with Parkinson’s disease during follow-up so far, the overall incidence of 0.2% is consistent with the expected incidence rate in the age group of 60 to 80 from the general population (one to three per 1,000 per year) and supports the representativeness of our sample,” said Dr. Schrag.

The recruitment of participants may have introduced selection bias into the study, she acknowledged. “However, we did not use family history as an entry criterion, and the proportion with a positive family history was lower than in other landmark studies.” The fact that 17% of participants only completed the baseline assessment also may have introduced selection bias, “although there were no differences between those with or without follow-up, meaning that bias as a result of loss to follow-up was less likely.

“This Internet-based approach may be useful for population screening because it can easily be scaled upward,” added Dr. Schrag. “It will allow larger numbers of Parkinson’s disease cases that represent the spectrum of the disease to be identified, rather than what would be possible from cohorts of carriers of specific risk factors.”

—Erik Greb

Suggested Readings

Noyce AJ, R’Bibo L, Peress L, et al. PREDICT-PD: An online approach to prospectively identify risk indicators of Parkinson’s disease. Mov Disord. 2017 Jan 16 [Epub ahead of print].

The online PREDICT-PD algorithm effectively identifies people at increased risk of Parkinson’s disease, according to research published online ahead of print January 16 in Movement Disorders. The risk scores that the algorithm assigns are significantly associated with intermediate markers of Parkinson’s disease. Higher PREDICT-PD risk score at baseline also is associated with an increased rate of incident Parkinson’s disease.

Previous research with the goal of identifying patients at risk of Parkinson’s disease mainly has focused on people with a family history of the disease, asymptomatic carriers of genes associated with the disease, or people with imaging abnormalities associated with the disease (eg, hyperechogenicity on transcranial sonography). The rarity, the representativeness, and the feasibility of identifying these factors have limited these studies, however.

Internet-Based Testing

To overcome these limitations, Anette-Eleonore Schrag, PhD, Professor of Clinical Neurosciences at University College London, and colleagues developed an online, evidence-based algorithm to identify risk indicators of Parkinson’s disease in the UK population. The investigators used a study website to recruit participants between ages 60 and 80 who did not have Parkinson’s disease, any other movement disorder, or stroke. Participants were prompted to return to the website yearly and complete tests.

Among the tests was a survey that included demographic questions and validated questionnaires about early nonmotor features of and risk factors for Parkinson’s disease (eg, the Hospital Anxiety Depression Scale and the REM sleep behavior disorder Screening Questionnaire [RBDSQ]). Participants also took the Bradykinesia Akinesia Incoordination (BRAIN) test, an online keyboard-tapping task. At baseline and at year three, participants took the University of Pennsylvania Smell Identification Test (UPSIT). The annual survey included a question about whether the participants had received any new diagnoses, including Parkinson’s disease or movement disorder. At year three, participants also gave saliva samples that were genotyped for mutations in exons 8 to 11 of glucocerebrosidase (GBA) and exon 41 in the LRRK2 gene.

The investigators used participants’ early features and risk factors to calculate their risk scores and rank participants according to their risk. Dr. Schrag and colleagues also tested support for enrichment of the population at risk of Parkinson’s disease by examining associations between risk scores and the following intermediate markers of Parkinson’s disease: reduced sense of smell, presence of subjective RBD, and slowing of finger tapping speed.

Risk Scores Were Associated With Incident Disease

The researchers recruited 1,323 eligible volunteers. At baseline, their mean age was 66, and approximately 61% of the population was female. In all, 1,040 of the participants completed follow-up testing at year 1, 939 completed year 2 follow-up, and 846 completed year 3 follow-up. A total of 223 participants completed the baseline assessment only.

Baseline risk scores were associated with significantly higher rates of all intermediate markers of Parkinson’s disease during each year of follow-up. The group of patients at higher risk (ie, those above the 15th percentile) had significantly worse UPSIT score, RBDSQ score, and finger tapping in all years, compared with patients at lower risk (ie, those below the 85th percentile).

Risk scores in the entire sample were strongly associated with intermediate markers of Parkinson’s disease each year. Higher- and lower-risk groups differed significantly in median UPSIT score, RBDSQ score, and mean finger tapping speed in all years of follow-up.

At year 1, three patients had been newly diagnosed with Parkinson’s disease. An additional participant received the diagnosis in year 2, and three other participants received the diagnosis in year 3. All of the participants with newly diagnosed Parkinson’s disease at year 1 were in the higher risk group, and two had also been in the higher risk group at baseline. The participant diagnosed at year 2 was in the higher risk group at baseline, year 1, and year 2. All of the three participants diagnosed by year 3 were in the middle risk group at baseline. “There was substantial heterogeneity in the occurrence of intermediate markers in these individuals,” said the researchers.

The incidence of independently diagnosed Parkinson’s disease in participants who had been in the higher risk group during three years of follow-up was 1.6% per year and 0.2% across the whole population. Exploratory Cox regression analysis using incident Parkinson’s disease over three years as the outcome indicated an association with baseline risk estimate. In participants for whom GBA and LRRK2 status was known, the association between baseline risk and incident Parkinson’s disease was weaker. But the addition of GBA and LRRK2 variants in the algorithm improved the strength of association between baseline risk and incident Parkinson’s disease. Among the intermediate markers of disease, baseline finger tapping was associated with incident Parkinson’s disease at three years.

Results Could Reflect Selection Bias

“Although only a small number of individuals have been independently diagnosed with Parkinson’s disease during follow-up so far, the overall incidence of 0.2% is consistent with the expected incidence rate in the age group of 60 to 80 from the general population (one to three per 1,000 per year) and supports the representativeness of our sample,” said Dr. Schrag.

The recruitment of participants may have introduced selection bias into the study, she acknowledged. “However, we did not use family history as an entry criterion, and the proportion with a positive family history was lower than in other landmark studies.” The fact that 17% of participants only completed the baseline assessment also may have introduced selection bias, “although there were no differences between those with or without follow-up, meaning that bias as a result of loss to follow-up was less likely.

“This Internet-based approach may be useful for population screening because it can easily be scaled upward,” added Dr. Schrag. “It will allow larger numbers of Parkinson’s disease cases that represent the spectrum of the disease to be identified, rather than what would be possible from cohorts of carriers of specific risk factors.”

—Erik Greb

Suggested Readings

Noyce AJ, R’Bibo L, Peress L, et al. PREDICT-PD: An online approach to prospectively identify risk indicators of Parkinson’s disease. Mov Disord. 2017 Jan 16 [Epub ahead of print].

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

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

A Population-Based Cohort

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

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

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

Diagnosing Parkinson’s Disease Dementia

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

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

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

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

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

—Erica Tricarico

Suggested Reading

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

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

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

A Population-Based Cohort

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

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

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

Diagnosing Parkinson’s Disease Dementia

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

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

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

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

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

—Erica Tricarico

Suggested Reading

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

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

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

A Population-Based Cohort

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

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

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

Diagnosing Parkinson’s Disease Dementia

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

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

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

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

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

—Erica Tricarico

Suggested Reading

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

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

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

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

—Erica Tricarico

Suggested Reading

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

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

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

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

—Erica Tricarico

Suggested Reading

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

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

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

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

—Erica Tricarico

Suggested Reading

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

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

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

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

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

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

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

—M. Alexander Otto

Suggested Reading

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

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

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

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

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

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

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

—M. Alexander Otto

Suggested Reading

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

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

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

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

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

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

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

—M. Alexander Otto

Suggested Reading

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