Literature Monitor

Magnetoencephalography (MEG) and network-based analyses can help characterize absence epilepsy in children according to a study that looked at 16 patients between ages 6 and 12 years who had absence epilepsy.

• Researchers found functional/anatomical hubs in a network that contained bilateral precuneus, left thalamus, three anterior cerebellar subunits of lobule IV-V, vermis, and lobule III.
• Their analysis suggests that these hubs, which are highly connected brain areas, exist in focal cortical, subcortical, and cerebellar areas during absence seizures.
• The existence of hubs in thalami, precuneus and cingulate cortex suggest bilaterally distributed networks of cortical and subcortical regions that may be responsible for seizures.
• Hubs in the anterior cerebellum may be related to terminating motor automatism seen in absence seizures.

Youssofzadeh, V, Agler W, Tenney JF, Kadis DS. Whole-brain MEG connectivity-based analyses reveals critical hubs in childhood absence epilepsy. Epilepsy Res. 2018;145:102-109.

Magnetoencephalography (MEG) and network-based analyses can help characterize absence epilepsy in children according to a study that looked at 16 patients between ages 6 and 12 years who had absence epilepsy.

• Researchers found functional/anatomical hubs in a network that contained bilateral precuneus, left thalamus, three anterior cerebellar subunits of lobule IV-V, vermis, and lobule III.
• Their analysis suggests that these hubs, which are highly connected brain areas, exist in focal cortical, subcortical, and cerebellar areas during absence seizures.
• The existence of hubs in thalami, precuneus and cingulate cortex suggest bilaterally distributed networks of cortical and subcortical regions that may be responsible for seizures.
• Hubs in the anterior cerebellum may be related to terminating motor automatism seen in absence seizures.

Youssofzadeh, V, Agler W, Tenney JF, Kadis DS. Whole-brain MEG connectivity-based analyses reveals critical hubs in childhood absence epilepsy. Epilepsy Res. 2018;145:102-109.

Magnetoencephalography (MEG) and network-based analyses can help characterize absence epilepsy in children according to a study that looked at 16 patients between ages 6 and 12 years who had absence epilepsy.

• Researchers found functional/anatomical hubs in a network that contained bilateral precuneus, left thalamus, three anterior cerebellar subunits of lobule IV-V, vermis, and lobule III.
• Their analysis suggests that these hubs, which are highly connected brain areas, exist in focal cortical, subcortical, and cerebellar areas during absence seizures.
• The existence of hubs in thalami, precuneus and cingulate cortex suggest bilaterally distributed networks of cortical and subcortical regions that may be responsible for seizures.
• Hubs in the anterior cerebellum may be related to terminating motor automatism seen in absence seizures.

Youssofzadeh, V, Agler W, Tenney JF, Kadis DS. Whole-brain MEG connectivity-based analyses reveals critical hubs in childhood absence epilepsy. Epilepsy Res. 2018;145:102-109.

The Food and Drug Administration has approved a deep brain stimulation system that has been shown to reduce seizures in a select group of patients with epilepsy.

• Medtronics DBS System for Epilepsy has been cleared as adjunct treatment for patients with partial onset seizures with or without secondary generalization.
• The system is only indicated for patients who have not responded to 3 or more antiepileptic drugs and who have experienced an average of 6 or more seizures each month for the last 3 months.
• The FDA approval also stipulates that the patients’ seizures be no more than 30 days apart.
• The DBS System includes a pulse generator that is implanted in a patient’s chest and 2 lead wires implanted in the brain.

Voelker R. Electrical stimulation for epilepsy. JAMA; 2018;319(21):2164.

The Food and Drug Administration has approved a deep brain stimulation system that has been shown to reduce seizures in a select group of patients with epilepsy.

• Medtronics DBS System for Epilepsy has been cleared as adjunct treatment for patients with partial onset seizures with or without secondary generalization.
• The system is only indicated for patients who have not responded to 3 or more antiepileptic drugs and who have experienced an average of 6 or more seizures each month for the last 3 months.
• The FDA approval also stipulates that the patients’ seizures be no more than 30 days apart.
• The DBS System includes a pulse generator that is implanted in a patient’s chest and 2 lead wires implanted in the brain.

Voelker R. Electrical stimulation for epilepsy. JAMA; 2018;319(21):2164.

The Food and Drug Administration has approved a deep brain stimulation system that has been shown to reduce seizures in a select group of patients with epilepsy.

• Medtronics DBS System for Epilepsy has been cleared as adjunct treatment for patients with partial onset seizures with or without secondary generalization.
• The system is only indicated for patients who have not responded to 3 or more antiepileptic drugs and who have experienced an average of 6 or more seizures each month for the last 3 months.
• The FDA approval also stipulates that the patients’ seizures be no more than 30 days apart.
• The DBS System includes a pulse generator that is implanted in a patient’s chest and 2 lead wires implanted in the brain.

Voelker R. Electrical stimulation for epilepsy. JAMA; 2018;319(21):2164.

Clinicians need to pay more attention to the psychological impact of epilepsy and its treatment according to a report from the International League Against Epilepsy Psychology Task Force.

• The task force identified the best interventions for depression, neurocognitive problems, and medication adherence.
• Several psychological strategies are worth consideration according to the task force, including cognitive behavioral therapy and mindfulness-based treatment.
• These interventions have the potential to improve health-related quality of life among adults and children.
• The recommendations outlined by the League are based primarily on evidence discussed in a recent Cochrane review of randomized clinical trials that evaluated psychological treatment of patients with epilepsy.

Michaelis R, Tang V, Goldstein LH, et al. Psychological treatments for adults and children with epilepsy: Evidence-based recommendations by the International League Against Epilepsy Psychology Task Force. Epilepsia. 2018;59(7):1282-1302.

Clinicians need to pay more attention to the psychological impact of epilepsy and its treatment according to a report from the International League Against Epilepsy Psychology Task Force.

• The task force identified the best interventions for depression, neurocognitive problems, and medication adherence.
• Several psychological strategies are worth consideration according to the task force, including cognitive behavioral therapy and mindfulness-based treatment.
• These interventions have the potential to improve health-related quality of life among adults and children.
• The recommendations outlined by the League are based primarily on evidence discussed in a recent Cochrane review of randomized clinical trials that evaluated psychological treatment of patients with epilepsy.

Michaelis R, Tang V, Goldstein LH, et al. Psychological treatments for adults and children with epilepsy: Evidence-based recommendations by the International League Against Epilepsy Psychology Task Force. Epilepsia. 2018;59(7):1282-1302.

Clinicians need to pay more attention to the psychological impact of epilepsy and its treatment according to a report from the International League Against Epilepsy Psychology Task Force.

• The task force identified the best interventions for depression, neurocognitive problems, and medication adherence.
• Several psychological strategies are worth consideration according to the task force, including cognitive behavioral therapy and mindfulness-based treatment.
• These interventions have the potential to improve health-related quality of life among adults and children.
• The recommendations outlined by the League are based primarily on evidence discussed in a recent Cochrane review of randomized clinical trials that evaluated psychological treatment of patients with epilepsy.

Michaelis R, Tang V, Goldstein LH, et al. Psychological treatments for adults and children with epilepsy: Evidence-based recommendations by the International League Against Epilepsy Psychology Task Force. Epilepsia. 2018;59(7):1282-1302.

Switching patients from brand name antiepileptic drugs to generics is generally safe and cost effective according to an analysis published in Epilepsia.

• Researchers looked at data on bioequivalence, health care utilization, and clinical studies on the safety of antiepileptic agents, including a comparison of area under the plasma concentration-time curve (AUC) and peak plasma concentration.
• For most of the drugs that were evaluated, there were negligible differences in AUC and peak plasma concentration between generic drugs and brand name equivalents.
• There were significant increases in health care usage when patients were switched from brand name to generic versions.
• Clinical studies were unable to detect differences in seizure frequency or tolerability.

Holtkamp M, Theodore WH. Generic antiepileptic drugs—safe or harmful in patients with epilepsy? Epilepsia. 2018;59(7):1273-1281.

Switching patients from brand name antiepileptic drugs to generics is generally safe and cost effective according to an analysis published in Epilepsia.

• Researchers looked at data on bioequivalence, health care utilization, and clinical studies on the safety of antiepileptic agents, including a comparison of area under the plasma concentration-time curve (AUC) and peak plasma concentration.
• For most of the drugs that were evaluated, there were negligible differences in AUC and peak plasma concentration between generic drugs and brand name equivalents.
• There were significant increases in health care usage when patients were switched from brand name to generic versions.
• Clinical studies were unable to detect differences in seizure frequency or tolerability.

Holtkamp M, Theodore WH. Generic antiepileptic drugs—safe or harmful in patients with epilepsy? Epilepsia. 2018;59(7):1273-1281.

Switching patients from brand name antiepileptic drugs to generics is generally safe and cost effective according to an analysis published in Epilepsia.

• Researchers looked at data on bioequivalence, health care utilization, and clinical studies on the safety of antiepileptic agents, including a comparison of area under the plasma concentration-time curve (AUC) and peak plasma concentration.
• For most of the drugs that were evaluated, there were negligible differences in AUC and peak plasma concentration between generic drugs and brand name equivalents.
• There were significant increases in health care usage when patients were switched from brand name to generic versions.
• Clinical studies were unable to detect differences in seizure frequency or tolerability.

Holtkamp M, Theodore WH. Generic antiepileptic drugs—safe or harmful in patients with epilepsy? Epilepsia. 2018;59(7):1273-1281.

Family caregivers of patients with intractable epilepsy are subject to significant stigma because of societal views about the disorder, according to cross-sectional analysis recently published in Epilepsy and Behavior.

• Self-administered surveys were taken by caregivers of adults and children with a confirmed diagnosis of intractable epilepsy.
• Affiliate stigma was defined as perceiving and internalizing negative societal views of the disorder and having a psychological response to those views.
• Caregivers’ psychological burdens were measured using the 30-item Carer’s Assessment of Difficulties Index and the stigma was evaluated with a separate 6-item scale that measured their perceptions of stigma.
• The 136 respondents were mostly white, female, and married.
• Investigators found the link between the stigma of epilepsy and the burden caregivers experienced was stronger among family members caring for adult patients.

Hansena B, Szaflarski M, Bebin EB, Szaflarski JP. Affiliate stigma and caregiver burden in intractable epilepsy. Epilepsy Behav. 2018;85:1-6.

Family caregivers of patients with intractable epilepsy are subject to significant stigma because of societal views about the disorder, according to cross-sectional analysis recently published in Epilepsy and Behavior.

• Self-administered surveys were taken by caregivers of adults and children with a confirmed diagnosis of intractable epilepsy.
• Affiliate stigma was defined as perceiving and internalizing negative societal views of the disorder and having a psychological response to those views.
• Caregivers’ psychological burdens were measured using the 30-item Carer’s Assessment of Difficulties Index and the stigma was evaluated with a separate 6-item scale that measured their perceptions of stigma.
• The 136 respondents were mostly white, female, and married.
• Investigators found the link between the stigma of epilepsy and the burden caregivers experienced was stronger among family members caring for adult patients.

Hansena B, Szaflarski M, Bebin EB, Szaflarski JP. Affiliate stigma and caregiver burden in intractable epilepsy. Epilepsy Behav. 2018;85:1-6.

Family caregivers of patients with intractable epilepsy are subject to significant stigma because of societal views about the disorder, according to cross-sectional analysis recently published in Epilepsy and Behavior.

• Self-administered surveys were taken by caregivers of adults and children with a confirmed diagnosis of intractable epilepsy.
• Affiliate stigma was defined as perceiving and internalizing negative societal views of the disorder and having a psychological response to those views.
• Caregivers’ psychological burdens were measured using the 30-item Carer’s Assessment of Difficulties Index and the stigma was evaluated with a separate 6-item scale that measured their perceptions of stigma.
• The 136 respondents were mostly white, female, and married.
• Investigators found the link between the stigma of epilepsy and the burden caregivers experienced was stronger among family members caring for adult patients.

Hansena B, Szaflarski M, Bebin EB, Szaflarski JP. Affiliate stigma and caregiver burden in intractable epilepsy. Epilepsy Behav. 2018;85:1-6.

About 50% of patients with epilepsy remained untreated for 6 months after their initial diagnosis according to a retrospective analysis of more than 58,000 cases.

• At 6 months after diagnosis, 46.8% were receiving treatment with antiepilepsy medication; at 12 months, that statistic had only climbed to 52.2%.
• Among the 29,226 patients who were receiving medication, nearly three quarters received monotherapy and 1.6% polytherapy as first treatment for 90 days or longer.
• The likelihood of patients remaining on antiepilepsy medication after a year was 61% for those on a single agent and 36.5% for those on more than one drug.

Faught E, Helmers S, Thurman D, et al. Patient characteristics and treatment patterns in patients with newly diagnosed epilepsy: A US database analysis. Epilepsy Behav. 2018;85:37-44.

About 50% of patients with epilepsy remained untreated for 6 months after their initial diagnosis according to a retrospective analysis of more than 58,000 cases.

• At 6 months after diagnosis, 46.8% were receiving treatment with antiepilepsy medication; at 12 months, that statistic had only climbed to 52.2%.
• Among the 29,226 patients who were receiving medication, nearly three quarters received monotherapy and 1.6% polytherapy as first treatment for 90 days or longer.
• The likelihood of patients remaining on antiepilepsy medication after a year was 61% for those on a single agent and 36.5% for those on more than one drug.

Faught E, Helmers S, Thurman D, et al. Patient characteristics and treatment patterns in patients with newly diagnosed epilepsy: A US database analysis. Epilepsy Behav. 2018;85:37-44.

About 50% of patients with epilepsy remained untreated for 6 months after their initial diagnosis according to a retrospective analysis of more than 58,000 cases.

• At 6 months after diagnosis, 46.8% were receiving treatment with antiepilepsy medication; at 12 months, that statistic had only climbed to 52.2%.
• Among the 29,226 patients who were receiving medication, nearly three quarters received monotherapy and 1.6% polytherapy as first treatment for 90 days or longer.
• The likelihood of patients remaining on antiepilepsy medication after a year was 61% for those on a single agent and 36.5% for those on more than one drug.

Faught E, Helmers S, Thurman D, et al. Patient characteristics and treatment patterns in patients with newly diagnosed epilepsy: A US database analysis. Epilepsy Behav. 2018;85:37-44.

Nearly half of patients with epilepsy have symptoms of high anxiety according to a study of adults treated in tertiary care centers.

• The study, which included 540 patients, evaluated the presence of anxiety with the Symptoms Checklist 90-R anxiety subscale. It also evaluated patients for depression with separate scales.
• 250 patients (46.1%) reported high anxiety.
• Focal epilepsy and epilepsy of unknown type, as well as depression scores, were independently linked to high anxiety.
• In patients with focal epilepsy, mesial temporal sclerosis was independently associated with high anxiety.
• Other factors linked to high anxiety included lower education level, being non-white, having Spanish as a native language, prior head trauma, and polydrug therapy for epilepsy.
• The researchers suggest that screening for anxiety in an epilepsy clinic can help spot patients in need of treatment.

Munger Clary HM, Snively BM, Hamberger MJ. Anxiety is common and independently associated with clinical features of epilepsy. Epilepsy Behav. 2018;85:64-71.

Nearly half of patients with epilepsy have symptoms of high anxiety according to a study of adults treated in tertiary care centers.

• The study, which included 540 patients, evaluated the presence of anxiety with the Symptoms Checklist 90-R anxiety subscale. It also evaluated patients for depression with separate scales.
• 250 patients (46.1%) reported high anxiety.
• Focal epilepsy and epilepsy of unknown type, as well as depression scores, were independently linked to high anxiety.
• In patients with focal epilepsy, mesial temporal sclerosis was independently associated with high anxiety.
• Other factors linked to high anxiety included lower education level, being non-white, having Spanish as a native language, prior head trauma, and polydrug therapy for epilepsy.
• The researchers suggest that screening for anxiety in an epilepsy clinic can help spot patients in need of treatment.

Munger Clary HM, Snively BM, Hamberger MJ. Anxiety is common and independently associated with clinical features of epilepsy. Epilepsy Behav. 2018;85:64-71.

Nearly half of patients with epilepsy have symptoms of high anxiety according to a study of adults treated in tertiary care centers.

• The study, which included 540 patients, evaluated the presence of anxiety with the Symptoms Checklist 90-R anxiety subscale. It also evaluated patients for depression with separate scales.
• 250 patients (46.1%) reported high anxiety.
• Focal epilepsy and epilepsy of unknown type, as well as depression scores, were independently linked to high anxiety.
• In patients with focal epilepsy, mesial temporal sclerosis was independently associated with high anxiety.
• Other factors linked to high anxiety included lower education level, being non-white, having Spanish as a native language, prior head trauma, and polydrug therapy for epilepsy.
• The researchers suggest that screening for anxiety in an epilepsy clinic can help spot patients in need of treatment.

Munger Clary HM, Snively BM, Hamberger MJ. Anxiety is common and independently associated with clinical features of epilepsy. Epilepsy Behav. 2018;85:64-71.

A ketogenic diet appears to be effective for children with refractory status epilepticus (RSE) suggests a small trial that included 14 patients.

• A study conducted by the Status Epilepticus Research Group from January 2011 to December 2016 found that 71% of patients with refractory status epilepticus who received a ketogenic diet experienced seizure resolution, verified by EEG findings, within 7 days of starting the regimen.
• 79% of the children with RSE were weaned off enteral infusions of the diet within 14 days.
• Possible adverse effects from the ketogenic diet occurred in 3 of 14 patients, including gastrointestinal paresis and elevated triglyceride levels.
• The regimen produced ketosis within a median of 2 days after it was initiated.
• By 3 months, 4 patients were still seizure free and 3 had fewer seizures.

pediatric Status Epilepticus Research Group (pSERG). Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus. Epilepsy Res. 2018;144:1-6.

A ketogenic diet appears to be effective for children with refractory status epilepticus (RSE) suggests a small trial that included 14 patients.

• A study conducted by the Status Epilepticus Research Group from January 2011 to December 2016 found that 71% of patients with refractory status epilepticus who received a ketogenic diet experienced seizure resolution, verified by EEG findings, within 7 days of starting the regimen.
• 79% of the children with RSE were weaned off enteral infusions of the diet within 14 days.
• Possible adverse effects from the ketogenic diet occurred in 3 of 14 patients, including gastrointestinal paresis and elevated triglyceride levels.
• The regimen produced ketosis within a median of 2 days after it was initiated.
• By 3 months, 4 patients were still seizure free and 3 had fewer seizures.

pediatric Status Epilepticus Research Group (pSERG). Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus. Epilepsy Res. 2018;144:1-6.

A ketogenic diet appears to be effective for children with refractory status epilepticus (RSE) suggests a small trial that included 14 patients.

• A study conducted by the Status Epilepticus Research Group from January 2011 to December 2016 found that 71% of patients with refractory status epilepticus who received a ketogenic diet experienced seizure resolution, verified by EEG findings, within 7 days of starting the regimen.
• 79% of the children with RSE were weaned off enteral infusions of the diet within 14 days.
• Possible adverse effects from the ketogenic diet occurred in 3 of 14 patients, including gastrointestinal paresis and elevated triglyceride levels.
• The regimen produced ketosis within a median of 2 days after it was initiated.
• By 3 months, 4 patients were still seizure free and 3 had fewer seizures.

pediatric Status Epilepticus Research Group (pSERG). Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus. Epilepsy Res. 2018;144:1-6.

The epilepsy associated with focal cortical dysplasia remains a major challenge, but early recognition of the disorder will allow clinicians to consider the possibility of resective surgery, which has been shown to eliminate seizures in some patients.

• A recent review of the medical literature found that most children with focal cortical dysplasia have intractable focal epilepsy.
• The epilepsy observed in patients with focal cortical dysplasia is related to activation of the mTOR pathway and altered receptor neurotransmission.
• The literature review discusses the epidemiology, natural history, and mechanisms that precipitate seizures in children with focal cortical dysplasia.
• Between 25% and 29% of children in a surgical series had focal cortical dysplasia.

Challenges in managing epilepsy associated with focal cortical dysplasia in children. Epilepsy Res. 2018;145:1-17.

The epilepsy associated with focal cortical dysplasia remains a major challenge, but early recognition of the disorder will allow clinicians to consider the possibility of resective surgery, which has been shown to eliminate seizures in some patients.

• A recent review of the medical literature found that most children with focal cortical dysplasia have intractable focal epilepsy.
• The epilepsy observed in patients with focal cortical dysplasia is related to activation of the mTOR pathway and altered receptor neurotransmission.
• The literature review discusses the epidemiology, natural history, and mechanisms that precipitate seizures in children with focal cortical dysplasia.
• Between 25% and 29% of children in a surgical series had focal cortical dysplasia.

Challenges in managing epilepsy associated with focal cortical dysplasia in children. Epilepsy Res. 2018;145:1-17.

The epilepsy associated with focal cortical dysplasia remains a major challenge, but early recognition of the disorder will allow clinicians to consider the possibility of resective surgery, which has been shown to eliminate seizures in some patients.

• A recent review of the medical literature found that most children with focal cortical dysplasia have intractable focal epilepsy.
• The epilepsy observed in patients with focal cortical dysplasia is related to activation of the mTOR pathway and altered receptor neurotransmission.
• The literature review discusses the epidemiology, natural history, and mechanisms that precipitate seizures in children with focal cortical dysplasia.
• Between 25% and 29% of children in a surgical series had focal cortical dysplasia.

Challenges in managing epilepsy associated with focal cortical dysplasia in children. Epilepsy Res. 2018;145:1-17.

Drug therapy for pregnant women with epilepsy has changed markedly in recent years according to analysis of data from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

• MONEAD, an NIH-funded, observational, multicenter study that looked at pregnancy outcomes in mothers and their children, included women ages 14-45 years and up to 20 weeks pregnant.
• Among 351 pregnant women with epilepsy enrolled in the study, 73.8% (259) were on monotherapy and 21.9% (77) on polytherapy; 4% were not taking an antiepileptic drug.
• Lamotrigine was the most popular drug in women on monotherapy, followed by levetiracetam, carbamazepine, zonisamide, oxcarbazepine, and topiramate.
• The most common polypharmacy regimen included  lamotrigine and levetiracetam.

The researchers point out that these percentages only reflect drug usage in US tertiary epilepsy centers and may not indicate usage in community practice.

MONEAD Investigator Group. Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy. Epilepsy Behav. 2018;84:10-14.

Drug therapy for pregnant women with epilepsy has changed markedly in recent years according to analysis of data from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

• MONEAD, an NIH-funded, observational, multicenter study that looked at pregnancy outcomes in mothers and their children, included women ages 14-45 years and up to 20 weeks pregnant.
• Among 351 pregnant women with epilepsy enrolled in the study, 73.8% (259) were on monotherapy and 21.9% (77) on polytherapy; 4% were not taking an antiepileptic drug.
• Lamotrigine was the most popular drug in women on monotherapy, followed by levetiracetam, carbamazepine, zonisamide, oxcarbazepine, and topiramate.
• The most common polypharmacy regimen included  lamotrigine and levetiracetam.

The researchers point out that these percentages only reflect drug usage in US tertiary epilepsy centers and may not indicate usage in community practice.

MONEAD Investigator Group. Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy. Epilepsy Behav. 2018;84:10-14.

Drug therapy for pregnant women with epilepsy has changed markedly in recent years according to analysis of data from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

• MONEAD, an NIH-funded, observational, multicenter study that looked at pregnancy outcomes in mothers and their children, included women ages 14-45 years and up to 20 weeks pregnant.
• Among 351 pregnant women with epilepsy enrolled in the study, 73.8% (259) were on monotherapy and 21.9% (77) on polytherapy; 4% were not taking an antiepileptic drug.
• Lamotrigine was the most popular drug in women on monotherapy, followed by levetiracetam, carbamazepine, zonisamide, oxcarbazepine, and topiramate.
• The most common polypharmacy regimen included  lamotrigine and levetiracetam.

The researchers point out that these percentages only reflect drug usage in US tertiary epilepsy centers and may not indicate usage in community practice.

MONEAD Investigator Group. Changes in antiepileptic drug-prescribing patterns in pregnant women with epilepsy. Epilepsy Behav. 2018;84:10-14.