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Liberalized low–glycemic-index diet effective for seizure reduction
BANGKOK – in a randomized, double-blind, 24-week, noninferiority study.
The low–glycemic-index diet (LGID) was introduced as a kinder, gentler, variant of the classic ketogenic diet for seizure frequency reduction. The ketogenic diet’s efficacy for this purpose is well established, but compliance is a problem and discontinuation rates are high. Yet even though the LGID was designed to be less onerous than the ketogenic diet, many children and parents also find the 7-days-a-week LGID to be excessively burdensome. This was the impetus for pitting the daily LGID against an intermittent version – 5 days on, 2 days off – in a randomized trial, Prateek K. Panda, MD, explained at the International Epilepsy Congress.
The hypothesis of this noninferiority trial was that adherence to the liberalized LGID would be similar to or better than that with the daily LGID regimen, with resultant similar reductions in seizure frequency. And further, that patients on the intermittent LGID would feel better because it would help improve depleted glycogen stores important for daily activity and that the liberalized diet would also be rated more favorably by caregivers, Dr. Panda said at the congress sponsored by the International League Against Epilepsy.
The 24-week, single-center trial included 122 children ages 1-15 years with drug-resistant epilepsy. At baseline they averaged 99 seizures per week by parental diary despite being on a median of four antiepileptic drugs. A total of 88% of participants had some form of structural epilepsy; the rest had a probable or confirmed genetic cause for their seizure disorder, according to Dr. Panda of the All-India Institute of Medical Sciences in New Delhi.
The standard daily LGID was comprised of 10% carbohydrate, 30% protein, and 60% fat, with only low–glycemic-index foods permitted. The cohort randomized to the liberalized diet ate that way on weekdays; however, on Saturdays and Sundays their diet was 20% carbohydrate, 30% protein, and 50% fat, with both medium- and low–glycemic-index foods allowed.
The primary outcome was the mean reduction in seizures per week by caregiver records at 24 weeks. The reduction from baseline was 54% in the strict LGID group and not significantly different at 49% in the intermittent LGID patients. Overall, 54% of patients in the strict LGID arm experienced a greater than 50% reduction in weekly seizure frequency, as did 50% on the liberalized diet, a nonsignificant difference.
There were five study dropouts in the strict LGID group and three in the liberalized LGID cohort. The two groups showed similar improvements over baseline in measures of social function, behavior, and cognition. Parents of children in the liberalized LGID group rated that diet as significantly less difficult to administer than those randomized to the strict LGID therapy.
Mean hemoglobin A1c improved in the strict LGID patients from 5.7% at baseline to 5.1% at both 12 and 24 weeks. The intermittent LGID group went from 5.6% to 5.0% and then to 5.2%. There was no correlation between HbA1c and reduction in seizure frequency. In contrast, serum beta-hydroxybutyrate levels showed a moderate correlation with seizure frequency, a novel finding which if confirmed might render beta-hydroxybutyrate useful as a biomarker, according to Dr. Panda.
Adverse events – mostly dyslipidemia and GI complaints such as vomiting or constipation – occurred in 25% of the strict LGID group and 13% with the intermittent LGID. All adverse events were mild.
Dr. Panda reported having no financial conflicts regarding the study, sponsored by the All-India Institute of Medical Sciences.
SOURCE: Panda PK et al. IEC 2019, Abstract P056.
BANGKOK – in a randomized, double-blind, 24-week, noninferiority study.
The low–glycemic-index diet (LGID) was introduced as a kinder, gentler, variant of the classic ketogenic diet for seizure frequency reduction. The ketogenic diet’s efficacy for this purpose is well established, but compliance is a problem and discontinuation rates are high. Yet even though the LGID was designed to be less onerous than the ketogenic diet, many children and parents also find the 7-days-a-week LGID to be excessively burdensome. This was the impetus for pitting the daily LGID against an intermittent version – 5 days on, 2 days off – in a randomized trial, Prateek K. Panda, MD, explained at the International Epilepsy Congress.
The hypothesis of this noninferiority trial was that adherence to the liberalized LGID would be similar to or better than that with the daily LGID regimen, with resultant similar reductions in seizure frequency. And further, that patients on the intermittent LGID would feel better because it would help improve depleted glycogen stores important for daily activity and that the liberalized diet would also be rated more favorably by caregivers, Dr. Panda said at the congress sponsored by the International League Against Epilepsy.
The 24-week, single-center trial included 122 children ages 1-15 years with drug-resistant epilepsy. At baseline they averaged 99 seizures per week by parental diary despite being on a median of four antiepileptic drugs. A total of 88% of participants had some form of structural epilepsy; the rest had a probable or confirmed genetic cause for their seizure disorder, according to Dr. Panda of the All-India Institute of Medical Sciences in New Delhi.
The standard daily LGID was comprised of 10% carbohydrate, 30% protein, and 60% fat, with only low–glycemic-index foods permitted. The cohort randomized to the liberalized diet ate that way on weekdays; however, on Saturdays and Sundays their diet was 20% carbohydrate, 30% protein, and 50% fat, with both medium- and low–glycemic-index foods allowed.
The primary outcome was the mean reduction in seizures per week by caregiver records at 24 weeks. The reduction from baseline was 54% in the strict LGID group and not significantly different at 49% in the intermittent LGID patients. Overall, 54% of patients in the strict LGID arm experienced a greater than 50% reduction in weekly seizure frequency, as did 50% on the liberalized diet, a nonsignificant difference.
There were five study dropouts in the strict LGID group and three in the liberalized LGID cohort. The two groups showed similar improvements over baseline in measures of social function, behavior, and cognition. Parents of children in the liberalized LGID group rated that diet as significantly less difficult to administer than those randomized to the strict LGID therapy.
Mean hemoglobin A1c improved in the strict LGID patients from 5.7% at baseline to 5.1% at both 12 and 24 weeks. The intermittent LGID group went from 5.6% to 5.0% and then to 5.2%. There was no correlation between HbA1c and reduction in seizure frequency. In contrast, serum beta-hydroxybutyrate levels showed a moderate correlation with seizure frequency, a novel finding which if confirmed might render beta-hydroxybutyrate useful as a biomarker, according to Dr. Panda.
Adverse events – mostly dyslipidemia and GI complaints such as vomiting or constipation – occurred in 25% of the strict LGID group and 13% with the intermittent LGID. All adverse events were mild.
Dr. Panda reported having no financial conflicts regarding the study, sponsored by the All-India Institute of Medical Sciences.
SOURCE: Panda PK et al. IEC 2019, Abstract P056.
BANGKOK – in a randomized, double-blind, 24-week, noninferiority study.
The low–glycemic-index diet (LGID) was introduced as a kinder, gentler, variant of the classic ketogenic diet for seizure frequency reduction. The ketogenic diet’s efficacy for this purpose is well established, but compliance is a problem and discontinuation rates are high. Yet even though the LGID was designed to be less onerous than the ketogenic diet, many children and parents also find the 7-days-a-week LGID to be excessively burdensome. This was the impetus for pitting the daily LGID against an intermittent version – 5 days on, 2 days off – in a randomized trial, Prateek K. Panda, MD, explained at the International Epilepsy Congress.
The hypothesis of this noninferiority trial was that adherence to the liberalized LGID would be similar to or better than that with the daily LGID regimen, with resultant similar reductions in seizure frequency. And further, that patients on the intermittent LGID would feel better because it would help improve depleted glycogen stores important for daily activity and that the liberalized diet would also be rated more favorably by caregivers, Dr. Panda said at the congress sponsored by the International League Against Epilepsy.
The 24-week, single-center trial included 122 children ages 1-15 years with drug-resistant epilepsy. At baseline they averaged 99 seizures per week by parental diary despite being on a median of four antiepileptic drugs. A total of 88% of participants had some form of structural epilepsy; the rest had a probable or confirmed genetic cause for their seizure disorder, according to Dr. Panda of the All-India Institute of Medical Sciences in New Delhi.
The standard daily LGID was comprised of 10% carbohydrate, 30% protein, and 60% fat, with only low–glycemic-index foods permitted. The cohort randomized to the liberalized diet ate that way on weekdays; however, on Saturdays and Sundays their diet was 20% carbohydrate, 30% protein, and 50% fat, with both medium- and low–glycemic-index foods allowed.
The primary outcome was the mean reduction in seizures per week by caregiver records at 24 weeks. The reduction from baseline was 54% in the strict LGID group and not significantly different at 49% in the intermittent LGID patients. Overall, 54% of patients in the strict LGID arm experienced a greater than 50% reduction in weekly seizure frequency, as did 50% on the liberalized diet, a nonsignificant difference.
There were five study dropouts in the strict LGID group and three in the liberalized LGID cohort. The two groups showed similar improvements over baseline in measures of social function, behavior, and cognition. Parents of children in the liberalized LGID group rated that diet as significantly less difficult to administer than those randomized to the strict LGID therapy.
Mean hemoglobin A1c improved in the strict LGID patients from 5.7% at baseline to 5.1% at both 12 and 24 weeks. The intermittent LGID group went from 5.6% to 5.0% and then to 5.2%. There was no correlation between HbA1c and reduction in seizure frequency. In contrast, serum beta-hydroxybutyrate levels showed a moderate correlation with seizure frequency, a novel finding which if confirmed might render beta-hydroxybutyrate useful as a biomarker, according to Dr. Panda.
Adverse events – mostly dyslipidemia and GI complaints such as vomiting or constipation – occurred in 25% of the strict LGID group and 13% with the intermittent LGID. All adverse events were mild.
Dr. Panda reported having no financial conflicts regarding the study, sponsored by the All-India Institute of Medical Sciences.
SOURCE: Panda PK et al. IEC 2019, Abstract P056.
REPORTING FROM IEC 2019
Statins crush early seizure risk poststroke
BANGKOK – Statin therapy, even when initiated only upon hospitalization for acute ischemic stroke, was associated with a striking reduction in the risk of early poststroke symptomatic seizure in a large observational study.
Using propensity-score matching to control for potential confounders, use of a statin during acute stroke management was associated with a “robust” 77% reduction in the risk of developing a symptomatic seizure within 7 days after hospital admission, Soichiro Matsubara, MD, reported at the International Epilepsy Congress.
This is an important finding because early symptomatic seizure (ESS) occurs in 2%-7% of patients following an acute ischemic stroke. Moreover, an Italian meta-analysis concluded that ESS was associated with a 4.4-fold increased risk of developing poststroke epilepsy (Epilepsia. 2016 Aug;57[8]:1205-14), noted Dr. Matsubara, a neurologist at the National Cerebral and Cardiovascular Center in Suita, Japan, as well as at Kumamoto (Japan) University.
He presented a study of 2,969 consecutive acute ischemic stroke patients with no history of epilepsy who were admitted to the Japanese comprehensive stroke center, of whom 2.2% experienced ESS. At physician discretion, 19% of the ESS cohort were on a statin during their acute stroke management, as were 55% of the no-ESS group. Four-fifths of patients on a statin initiated the drug only upon hospital admission.
Strokes tended to be more severe in the ESS group, with a median initial National Institutes of Health Stroke Scale score of 12.5, compared with 4 in the seizure-free patients. A cortical stroke lesion was evident upon imaging in 89% of the ESS group and 55% of no-ESS patients. Among ESS patients, 46% had a cardiometabolic stroke, compared with 34% of the no-ESS cohort. Mean C-reactive protein levels and white blood cell counts were significantly higher in the ESS cohort as well. Their median hospital length of stay was 25.5 days, versus 18 days in the no-ESS group, Dr. Matsubara said at the congress sponsored by the International League Against Epilepsy.
Of the 76 ESSs that occurred in 66 patients, 37% were focal awareness seizures, 35% were focal to bilateral tonic-clonic seizures, and 28% were focal impaired awareness seizures.
In a multivariate analysis adjusted for age, sex, body mass index, stroke subtype, and other potential confounders, statin therapy during acute management of stroke was independently associated with a 56% reduction in the relative risk of ESS. In contrast, a cortical stroke lesion was associated with a 2.83-fold increased risk.
Since this wasn’t a randomized trial of statin therapy, Dr. Matsubara and his coinvestigators felt the need to go further in analyzing the data. After extensive propensity score matching for atrial fibrillation, current smoking, systolic blood pressure, the presence or absence of a cortical stroke lesion, large vessel stenosis, and other possible confounders, they were left with two closely comparable groups: 886 statin-treated stroke patients and an equal number who were not on statin therapy during their acute stroke management. The key finding: The risk of ESS was reduced by a whopping 77% in the patients on statin therapy.
The neurologist observed that these new findings in acute ischemic stroke patients are consistent with an earlier study in a U.S. Veterans Affairs population, which demonstrated that statin therapy was associated with a significantly lower risk of new-onset geriatric epilepsy (J Am Geriatr Soc. 2009 Feb;57[2]:237-42).
As to the possible mechanism by which statins may protect against ESS, Dr. Matsubara noted that acute ischemic stroke causes toxic neuronal excitation because of blood-brain barrier disruption, ion channel dysfunction, altered gene expression, and increased release of neurotransmitters. In animal models, statins provide a neuroprotective effect by reducing glutamate levels, activating endothelial nitric oxide synthase, and inhibiting production of interleukin-6, tumor necrosis factor-alpha, and other inflammatory cytokines.
Asked about the intensity of the statin therapy, Dr. Matsubara replied that the target was typically an LDL cholesterol below 100 mg/dL.
He reported having no financial conflicts regarding the study, conducted free of commercial support.
SOURCE: Matsubara S et al. IEC 219, Abstract P002.
BANGKOK – Statin therapy, even when initiated only upon hospitalization for acute ischemic stroke, was associated with a striking reduction in the risk of early poststroke symptomatic seizure in a large observational study.
Using propensity-score matching to control for potential confounders, use of a statin during acute stroke management was associated with a “robust” 77% reduction in the risk of developing a symptomatic seizure within 7 days after hospital admission, Soichiro Matsubara, MD, reported at the International Epilepsy Congress.
This is an important finding because early symptomatic seizure (ESS) occurs in 2%-7% of patients following an acute ischemic stroke. Moreover, an Italian meta-analysis concluded that ESS was associated with a 4.4-fold increased risk of developing poststroke epilepsy (Epilepsia. 2016 Aug;57[8]:1205-14), noted Dr. Matsubara, a neurologist at the National Cerebral and Cardiovascular Center in Suita, Japan, as well as at Kumamoto (Japan) University.
He presented a study of 2,969 consecutive acute ischemic stroke patients with no history of epilepsy who were admitted to the Japanese comprehensive stroke center, of whom 2.2% experienced ESS. At physician discretion, 19% of the ESS cohort were on a statin during their acute stroke management, as were 55% of the no-ESS group. Four-fifths of patients on a statin initiated the drug only upon hospital admission.
Strokes tended to be more severe in the ESS group, with a median initial National Institutes of Health Stroke Scale score of 12.5, compared with 4 in the seizure-free patients. A cortical stroke lesion was evident upon imaging in 89% of the ESS group and 55% of no-ESS patients. Among ESS patients, 46% had a cardiometabolic stroke, compared with 34% of the no-ESS cohort. Mean C-reactive protein levels and white blood cell counts were significantly higher in the ESS cohort as well. Their median hospital length of stay was 25.5 days, versus 18 days in the no-ESS group, Dr. Matsubara said at the congress sponsored by the International League Against Epilepsy.
Of the 76 ESSs that occurred in 66 patients, 37% were focal awareness seizures, 35% were focal to bilateral tonic-clonic seizures, and 28% were focal impaired awareness seizures.
In a multivariate analysis adjusted for age, sex, body mass index, stroke subtype, and other potential confounders, statin therapy during acute management of stroke was independently associated with a 56% reduction in the relative risk of ESS. In contrast, a cortical stroke lesion was associated with a 2.83-fold increased risk.
Since this wasn’t a randomized trial of statin therapy, Dr. Matsubara and his coinvestigators felt the need to go further in analyzing the data. After extensive propensity score matching for atrial fibrillation, current smoking, systolic blood pressure, the presence or absence of a cortical stroke lesion, large vessel stenosis, and other possible confounders, they were left with two closely comparable groups: 886 statin-treated stroke patients and an equal number who were not on statin therapy during their acute stroke management. The key finding: The risk of ESS was reduced by a whopping 77% in the patients on statin therapy.
The neurologist observed that these new findings in acute ischemic stroke patients are consistent with an earlier study in a U.S. Veterans Affairs population, which demonstrated that statin therapy was associated with a significantly lower risk of new-onset geriatric epilepsy (J Am Geriatr Soc. 2009 Feb;57[2]:237-42).
As to the possible mechanism by which statins may protect against ESS, Dr. Matsubara noted that acute ischemic stroke causes toxic neuronal excitation because of blood-brain barrier disruption, ion channel dysfunction, altered gene expression, and increased release of neurotransmitters. In animal models, statins provide a neuroprotective effect by reducing glutamate levels, activating endothelial nitric oxide synthase, and inhibiting production of interleukin-6, tumor necrosis factor-alpha, and other inflammatory cytokines.
Asked about the intensity of the statin therapy, Dr. Matsubara replied that the target was typically an LDL cholesterol below 100 mg/dL.
He reported having no financial conflicts regarding the study, conducted free of commercial support.
SOURCE: Matsubara S et al. IEC 219, Abstract P002.
BANGKOK – Statin therapy, even when initiated only upon hospitalization for acute ischemic stroke, was associated with a striking reduction in the risk of early poststroke symptomatic seizure in a large observational study.
Using propensity-score matching to control for potential confounders, use of a statin during acute stroke management was associated with a “robust” 77% reduction in the risk of developing a symptomatic seizure within 7 days after hospital admission, Soichiro Matsubara, MD, reported at the International Epilepsy Congress.
This is an important finding because early symptomatic seizure (ESS) occurs in 2%-7% of patients following an acute ischemic stroke. Moreover, an Italian meta-analysis concluded that ESS was associated with a 4.4-fold increased risk of developing poststroke epilepsy (Epilepsia. 2016 Aug;57[8]:1205-14), noted Dr. Matsubara, a neurologist at the National Cerebral and Cardiovascular Center in Suita, Japan, as well as at Kumamoto (Japan) University.
He presented a study of 2,969 consecutive acute ischemic stroke patients with no history of epilepsy who were admitted to the Japanese comprehensive stroke center, of whom 2.2% experienced ESS. At physician discretion, 19% of the ESS cohort were on a statin during their acute stroke management, as were 55% of the no-ESS group. Four-fifths of patients on a statin initiated the drug only upon hospital admission.
Strokes tended to be more severe in the ESS group, with a median initial National Institutes of Health Stroke Scale score of 12.5, compared with 4 in the seizure-free patients. A cortical stroke lesion was evident upon imaging in 89% of the ESS group and 55% of no-ESS patients. Among ESS patients, 46% had a cardiometabolic stroke, compared with 34% of the no-ESS cohort. Mean C-reactive protein levels and white blood cell counts were significantly higher in the ESS cohort as well. Their median hospital length of stay was 25.5 days, versus 18 days in the no-ESS group, Dr. Matsubara said at the congress sponsored by the International League Against Epilepsy.
Of the 76 ESSs that occurred in 66 patients, 37% were focal awareness seizures, 35% were focal to bilateral tonic-clonic seizures, and 28% were focal impaired awareness seizures.
In a multivariate analysis adjusted for age, sex, body mass index, stroke subtype, and other potential confounders, statin therapy during acute management of stroke was independently associated with a 56% reduction in the relative risk of ESS. In contrast, a cortical stroke lesion was associated with a 2.83-fold increased risk.
Since this wasn’t a randomized trial of statin therapy, Dr. Matsubara and his coinvestigators felt the need to go further in analyzing the data. After extensive propensity score matching for atrial fibrillation, current smoking, systolic blood pressure, the presence or absence of a cortical stroke lesion, large vessel stenosis, and other possible confounders, they were left with two closely comparable groups: 886 statin-treated stroke patients and an equal number who were not on statin therapy during their acute stroke management. The key finding: The risk of ESS was reduced by a whopping 77% in the patients on statin therapy.
The neurologist observed that these new findings in acute ischemic stroke patients are consistent with an earlier study in a U.S. Veterans Affairs population, which demonstrated that statin therapy was associated with a significantly lower risk of new-onset geriatric epilepsy (J Am Geriatr Soc. 2009 Feb;57[2]:237-42).
As to the possible mechanism by which statins may protect against ESS, Dr. Matsubara noted that acute ischemic stroke causes toxic neuronal excitation because of blood-brain barrier disruption, ion channel dysfunction, altered gene expression, and increased release of neurotransmitters. In animal models, statins provide a neuroprotective effect by reducing glutamate levels, activating endothelial nitric oxide synthase, and inhibiting production of interleukin-6, tumor necrosis factor-alpha, and other inflammatory cytokines.
Asked about the intensity of the statin therapy, Dr. Matsubara replied that the target was typically an LDL cholesterol below 100 mg/dL.
He reported having no financial conflicts regarding the study, conducted free of commercial support.
SOURCE: Matsubara S et al. IEC 219, Abstract P002.
REPORTING FROM IEC 2019
Noninvasive EEG may speed diagnosis of West syndrome
BANGKOK – , Hiroki Nariai, MD, reported at the International Epilepsy Congress.
Among the most promising of these potential EEG biomarkers for development of epilepsy are ictal or interictal high-frequency oscillations (HFOs) at 80 Hz or more, along with cross-frequency coupling of HFOs and delta wave activity, according to Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
West syndrome, the most common epileptic encephalopathy during the first 2 years of life, has diverse etiologies. For example, in 250 infants with West syndrome enrolled in the United Kingdom National Infantile Spasms Consortium, a cause was identified in 64%. The etiology was genetic in 14% of subjects, a structural-congenital anomaly in 11%, tuberous sclerosis – a genetic-structural abnormality – in 10%, stroke in 22%, a metabolic defect in 5%, and infection in 2% (Epilepsia. 2015 Apr;56[4]:617-25).
West syndrome is rare, with an estimated prevalence of roughly 1 per 6,000 live births, but the associated mortality is high: 31% on average. And West syndrome often brings severe neurodevelopmental morbidity, with normal or near-normal intelligence present in only 25% of survivors.
An intensive search is on for an objective, reliable diagnostic biomarker – be it electroencephalographic, biochemical, or perhaps a neuroimaging finding – because the clinical diagnosis of West syndrome is highly subjective. It relies upon the triad of epileptic spasms, developmental regression or psychomotor delay, and hypsarrhythmia, which is a chaotic, disorganized, patternless form of brain electrical activity. And while that description makes hypsarrhythmia sound as if it should be easily recognizable, in fact that’s often not the case: Interrater reliability was poor in a study of six pediatric EEG experts at four centers who viewed 5-minute-long EEG samples obtained from 22 patients with infantile spasms (Epilepsia. 2015 Jan;56[1]:77-81), Dr. Nariai noted at the congress, sponsored by the International League Against Epilepsy.
“The clinical trial is maybe not so useful,” he observed.
The hunt for a reliable biomarker is further fueled by evidence that early diagnosis and treatment of West syndrome and other etiologies of infantile spasms makes a real difference. Indeed, investigators found in the United Kingdom Infantile Spasms Study that increasing lag time from onset of spasms to initiation of treatment was associated in stepwise fashion with significantly lower IQ at 4 years of age. While infants who started treatment within 7 days of onset of the seizure disorder had a mean IQ of 76.2 at age 4 years, those with an 8- to 14-day lag time between symptom onset and treatment averaged an additional 3.9-point decrement in IQ. A 15- to 30-day delay was associated with a 7.8-point reduction in IQ, compared with the reference group, while the decrease in IQ averaged 11.7 points in infants with a 1- to 2-month lag time and 15.6 points in those with a lag time of more than 2 months (Epilepsia. 2011 Jul;52[7]:1359-64).
At the start of the decade, Dr. Nariai and other investigators demonstrated that pathologic HFOs recorded during invasive EEG monitoring in conjunction with epilepsy surgery served as a reliable biomarker of epilepsy. While this was an important observation, a biomarker obtained through invasive monitoring during brain surgery clearly has very limited clinical applicability. But more recently, Dr. Nariai and his coinvestigators in the Tuberous Sclerosis Complex Autism Center of Excellence Network reported that noninvasive detection of interictal HFO fast ripples in the 250-500 Hz range via scalp EEG showed promise as a biomarker of epilepsy. Sensitivity of this far more practical approach to the detection of fast ripples was excellent, whether analyzed visually or by automatic detector (Clin Neurophysiol. 2018 Jul;129[7]:1458-66).
Moreover, in a recent, not-yet published study that Dr. Nariai and coworkers conducted in 24 infants with active epileptic spasms and 6 controls, noninvasive objective measurement of HFO rate using scalp EEG had an 83% sensitivity and 100% specificity for active epileptic spasms, while the modulation index of HFO and delta coupling in the 3-4 Hz range showed 74% sensitivity and 86% specificity.
If future studies validate the utility of detection of HFOs above a defined threshold or another noninvasively obtained EEG biomarker for diagnosis of epilepsy, the same strategy would presumably also be applicable for monitoring response to antiepileptic therapies, thereby eliminating the traditional trial-and-error approach to treatment. This would be a particularly important application in patients with West syndrome, where it’s believed that the electrical activity itself is contributing to the progressive – and often rapid – loss of cognitive function and behavioral disturbances. Thus, unlike in most other forms of epilepsy, the treatment goal isn’t merely to suppress the seizures, but also to achieve disease modification by eliminating the underlying subclinical EEG abnormalities, he explained.
A reliable biomarker would also be a boon in selecting the best participants for clinical trials of new antiseizure therapies.
Dr. Nariai reported having no financial conflicts regarding his presentation. His work is funded by research foundations and the National Institutes of Health.
BANGKOK – , Hiroki Nariai, MD, reported at the International Epilepsy Congress.
Among the most promising of these potential EEG biomarkers for development of epilepsy are ictal or interictal high-frequency oscillations (HFOs) at 80 Hz or more, along with cross-frequency coupling of HFOs and delta wave activity, according to Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
West syndrome, the most common epileptic encephalopathy during the first 2 years of life, has diverse etiologies. For example, in 250 infants with West syndrome enrolled in the United Kingdom National Infantile Spasms Consortium, a cause was identified in 64%. The etiology was genetic in 14% of subjects, a structural-congenital anomaly in 11%, tuberous sclerosis – a genetic-structural abnormality – in 10%, stroke in 22%, a metabolic defect in 5%, and infection in 2% (Epilepsia. 2015 Apr;56[4]:617-25).
West syndrome is rare, with an estimated prevalence of roughly 1 per 6,000 live births, but the associated mortality is high: 31% on average. And West syndrome often brings severe neurodevelopmental morbidity, with normal or near-normal intelligence present in only 25% of survivors.
An intensive search is on for an objective, reliable diagnostic biomarker – be it electroencephalographic, biochemical, or perhaps a neuroimaging finding – because the clinical diagnosis of West syndrome is highly subjective. It relies upon the triad of epileptic spasms, developmental regression or psychomotor delay, and hypsarrhythmia, which is a chaotic, disorganized, patternless form of brain electrical activity. And while that description makes hypsarrhythmia sound as if it should be easily recognizable, in fact that’s often not the case: Interrater reliability was poor in a study of six pediatric EEG experts at four centers who viewed 5-minute-long EEG samples obtained from 22 patients with infantile spasms (Epilepsia. 2015 Jan;56[1]:77-81), Dr. Nariai noted at the congress, sponsored by the International League Against Epilepsy.
“The clinical trial is maybe not so useful,” he observed.
The hunt for a reliable biomarker is further fueled by evidence that early diagnosis and treatment of West syndrome and other etiologies of infantile spasms makes a real difference. Indeed, investigators found in the United Kingdom Infantile Spasms Study that increasing lag time from onset of spasms to initiation of treatment was associated in stepwise fashion with significantly lower IQ at 4 years of age. While infants who started treatment within 7 days of onset of the seizure disorder had a mean IQ of 76.2 at age 4 years, those with an 8- to 14-day lag time between symptom onset and treatment averaged an additional 3.9-point decrement in IQ. A 15- to 30-day delay was associated with a 7.8-point reduction in IQ, compared with the reference group, while the decrease in IQ averaged 11.7 points in infants with a 1- to 2-month lag time and 15.6 points in those with a lag time of more than 2 months (Epilepsia. 2011 Jul;52[7]:1359-64).
At the start of the decade, Dr. Nariai and other investigators demonstrated that pathologic HFOs recorded during invasive EEG monitoring in conjunction with epilepsy surgery served as a reliable biomarker of epilepsy. While this was an important observation, a biomarker obtained through invasive monitoring during brain surgery clearly has very limited clinical applicability. But more recently, Dr. Nariai and his coinvestigators in the Tuberous Sclerosis Complex Autism Center of Excellence Network reported that noninvasive detection of interictal HFO fast ripples in the 250-500 Hz range via scalp EEG showed promise as a biomarker of epilepsy. Sensitivity of this far more practical approach to the detection of fast ripples was excellent, whether analyzed visually or by automatic detector (Clin Neurophysiol. 2018 Jul;129[7]:1458-66).
Moreover, in a recent, not-yet published study that Dr. Nariai and coworkers conducted in 24 infants with active epileptic spasms and 6 controls, noninvasive objective measurement of HFO rate using scalp EEG had an 83% sensitivity and 100% specificity for active epileptic spasms, while the modulation index of HFO and delta coupling in the 3-4 Hz range showed 74% sensitivity and 86% specificity.
If future studies validate the utility of detection of HFOs above a defined threshold or another noninvasively obtained EEG biomarker for diagnosis of epilepsy, the same strategy would presumably also be applicable for monitoring response to antiepileptic therapies, thereby eliminating the traditional trial-and-error approach to treatment. This would be a particularly important application in patients with West syndrome, where it’s believed that the electrical activity itself is contributing to the progressive – and often rapid – loss of cognitive function and behavioral disturbances. Thus, unlike in most other forms of epilepsy, the treatment goal isn’t merely to suppress the seizures, but also to achieve disease modification by eliminating the underlying subclinical EEG abnormalities, he explained.
A reliable biomarker would also be a boon in selecting the best participants for clinical trials of new antiseizure therapies.
Dr. Nariai reported having no financial conflicts regarding his presentation. His work is funded by research foundations and the National Institutes of Health.
BANGKOK – , Hiroki Nariai, MD, reported at the International Epilepsy Congress.
Among the most promising of these potential EEG biomarkers for development of epilepsy are ictal or interictal high-frequency oscillations (HFOs) at 80 Hz or more, along with cross-frequency coupling of HFOs and delta wave activity, according to Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
West syndrome, the most common epileptic encephalopathy during the first 2 years of life, has diverse etiologies. For example, in 250 infants with West syndrome enrolled in the United Kingdom National Infantile Spasms Consortium, a cause was identified in 64%. The etiology was genetic in 14% of subjects, a structural-congenital anomaly in 11%, tuberous sclerosis – a genetic-structural abnormality – in 10%, stroke in 22%, a metabolic defect in 5%, and infection in 2% (Epilepsia. 2015 Apr;56[4]:617-25).
West syndrome is rare, with an estimated prevalence of roughly 1 per 6,000 live births, but the associated mortality is high: 31% on average. And West syndrome often brings severe neurodevelopmental morbidity, with normal or near-normal intelligence present in only 25% of survivors.
An intensive search is on for an objective, reliable diagnostic biomarker – be it electroencephalographic, biochemical, or perhaps a neuroimaging finding – because the clinical diagnosis of West syndrome is highly subjective. It relies upon the triad of epileptic spasms, developmental regression or psychomotor delay, and hypsarrhythmia, which is a chaotic, disorganized, patternless form of brain electrical activity. And while that description makes hypsarrhythmia sound as if it should be easily recognizable, in fact that’s often not the case: Interrater reliability was poor in a study of six pediatric EEG experts at four centers who viewed 5-minute-long EEG samples obtained from 22 patients with infantile spasms (Epilepsia. 2015 Jan;56[1]:77-81), Dr. Nariai noted at the congress, sponsored by the International League Against Epilepsy.
“The clinical trial is maybe not so useful,” he observed.
The hunt for a reliable biomarker is further fueled by evidence that early diagnosis and treatment of West syndrome and other etiologies of infantile spasms makes a real difference. Indeed, investigators found in the United Kingdom Infantile Spasms Study that increasing lag time from onset of spasms to initiation of treatment was associated in stepwise fashion with significantly lower IQ at 4 years of age. While infants who started treatment within 7 days of onset of the seizure disorder had a mean IQ of 76.2 at age 4 years, those with an 8- to 14-day lag time between symptom onset and treatment averaged an additional 3.9-point decrement in IQ. A 15- to 30-day delay was associated with a 7.8-point reduction in IQ, compared with the reference group, while the decrease in IQ averaged 11.7 points in infants with a 1- to 2-month lag time and 15.6 points in those with a lag time of more than 2 months (Epilepsia. 2011 Jul;52[7]:1359-64).
At the start of the decade, Dr. Nariai and other investigators demonstrated that pathologic HFOs recorded during invasive EEG monitoring in conjunction with epilepsy surgery served as a reliable biomarker of epilepsy. While this was an important observation, a biomarker obtained through invasive monitoring during brain surgery clearly has very limited clinical applicability. But more recently, Dr. Nariai and his coinvestigators in the Tuberous Sclerosis Complex Autism Center of Excellence Network reported that noninvasive detection of interictal HFO fast ripples in the 250-500 Hz range via scalp EEG showed promise as a biomarker of epilepsy. Sensitivity of this far more practical approach to the detection of fast ripples was excellent, whether analyzed visually or by automatic detector (Clin Neurophysiol. 2018 Jul;129[7]:1458-66).
Moreover, in a recent, not-yet published study that Dr. Nariai and coworkers conducted in 24 infants with active epileptic spasms and 6 controls, noninvasive objective measurement of HFO rate using scalp EEG had an 83% sensitivity and 100% specificity for active epileptic spasms, while the modulation index of HFO and delta coupling in the 3-4 Hz range showed 74% sensitivity and 86% specificity.
If future studies validate the utility of detection of HFOs above a defined threshold or another noninvasively obtained EEG biomarker for diagnosis of epilepsy, the same strategy would presumably also be applicable for monitoring response to antiepileptic therapies, thereby eliminating the traditional trial-and-error approach to treatment. This would be a particularly important application in patients with West syndrome, where it’s believed that the electrical activity itself is contributing to the progressive – and often rapid – loss of cognitive function and behavioral disturbances. Thus, unlike in most other forms of epilepsy, the treatment goal isn’t merely to suppress the seizures, but also to achieve disease modification by eliminating the underlying subclinical EEG abnormalities, he explained.
A reliable biomarker would also be a boon in selecting the best participants for clinical trials of new antiseizure therapies.
Dr. Nariai reported having no financial conflicts regarding his presentation. His work is funded by research foundations and the National Institutes of Health.
REPORTING FROM IEC 2019
Cutaneous reaction to AEDs? Think autoimmune epilepsy
BANGKOK – Cutaneous reactions to antiepileptic drugs in patients with chronic epilepsy suggest increased likelihood of an autoimmune element to their seizure disorder, Fernando Cendes, MD, PhD, reported at the International Epilepsy Congress.
“My recommendation based on our findings is that if you have a patient who has a history of skin reactions to AEDs [antiepileptic drugs], or who has psychosis, or who has a very strange response to antiepileptic medication – meaning that at some points they are refractory and at other points they are very well controlled – I think those patients are probably at risk for having an autoantibody,” he said at the congress sponsored by the International League Against Epilepsy.
Screening for autoantibodies in such patients is appropriate. However, there’s a caveat: “The thing is, we don’t have evidence that treating these autoantibodies with immunotherapy will have any benefit on seizure control in these patients. We don’t have that data yet, but we are looking into it,” according to Dr. Cendes, professor of neurology at the State University of Campinas (Brazil).
He presented a study of 221 consecutive adults with severe chronic refractory epilepsy as evidenced by a mean disease duration of nearly 29 years, with an average of 5.93 seizures per month. A total of 77% had a structural etiology for their epilepsy, in most cases hippocampal sclerosis. In 19% of patients, the etiology was unknown. Overall, 95% of subjects had focal epilepsy, and the remainder had generalized epilepsy. All underwent serum testing for a variety of antibodies against neuronal surface antigens that have been implicated in encephalitis, seizures, and/or psychosis. Those who tested positive then underwent confirmatory testing of their cerebrospinal fluid.
The impetus for this study, the neurologist explained, is that although it’s now well established that seizures are a common clinical expression of acute- and subacute-phase autoimmune encephalitis marked by neuronal autoantibodies, little is known about the relationship between chronic epilepsy and such antibodies.
Only five Brazilian patients with chronic epilepsy, or 2.2%, tested positive for autoantibodies, all of whom had mesial temporal lobe epilepsy with hippocampal sclerosis. This suggests a possible autoimmune etiology for hippocampal sclerosis. Three of the five patients had anti-N-methyl-D-aspartate receptor antibodies (anti-NMDA) and two had antiglutamic acid decarboxylate antibodies (anti-GAD). No one was positive for anti–leucine-rich glioma-inactivated 1 antibodies (anti-LGI1), anti–contactin-associated proteinlike 2 (anti-caspr2), anti-glutamate receptor antibodies (anti-AMPAr), or anti–gamma-aminobutyric acid receptor antibodies (anti-GABAr).
The autoantibody-negative and the much smaller autoantibody-positive groups didn’t differ significantly in terms of demographics, seizure frequency, disease duration, drug resistance, cognitive impairment, comorbid autoimmune conditions, or history of status epilepticus. Indeed, only two between-group differences were found: fluctuation in seizure control was an issue in 10.6% of autoantibody-negative and 40% of autoantibody-positive patients, and cutaneous adverse reactions to antiepileptic drugs were noted in 10.6% of antibody-negative and 60% of antibody-positive patients. Psychiatric comorbidities were present in 49.5% of autoantibody-negative patients as compared with 80% – that is, four of five – who were autoantibody-positive, a trend that didn’t achieve statistical significance.
Asked if he thinks the autoantibodies found in a small subset of patients with chronic epilepsy were a cause or an effect of repeated seizures for so long, Dr. Cendes replied, “That’s a very interesting question, and I don’t have an answer, actually. But if seizures trigger development of these antibodies – and remember, this population we’re talking about had many, many seizures over the years – I would expect antibodies to be more frequent than the figure we found.”
He reported having no financial conflicts regarding his study.
SOURCE: Watanabe N et al. IEC 2019, Abstract P004.
BANGKOK – Cutaneous reactions to antiepileptic drugs in patients with chronic epilepsy suggest increased likelihood of an autoimmune element to their seizure disorder, Fernando Cendes, MD, PhD, reported at the International Epilepsy Congress.
“My recommendation based on our findings is that if you have a patient who has a history of skin reactions to AEDs [antiepileptic drugs], or who has psychosis, or who has a very strange response to antiepileptic medication – meaning that at some points they are refractory and at other points they are very well controlled – I think those patients are probably at risk for having an autoantibody,” he said at the congress sponsored by the International League Against Epilepsy.
Screening for autoantibodies in such patients is appropriate. However, there’s a caveat: “The thing is, we don’t have evidence that treating these autoantibodies with immunotherapy will have any benefit on seizure control in these patients. We don’t have that data yet, but we are looking into it,” according to Dr. Cendes, professor of neurology at the State University of Campinas (Brazil).
He presented a study of 221 consecutive adults with severe chronic refractory epilepsy as evidenced by a mean disease duration of nearly 29 years, with an average of 5.93 seizures per month. A total of 77% had a structural etiology for their epilepsy, in most cases hippocampal sclerosis. In 19% of patients, the etiology was unknown. Overall, 95% of subjects had focal epilepsy, and the remainder had generalized epilepsy. All underwent serum testing for a variety of antibodies against neuronal surface antigens that have been implicated in encephalitis, seizures, and/or psychosis. Those who tested positive then underwent confirmatory testing of their cerebrospinal fluid.
The impetus for this study, the neurologist explained, is that although it’s now well established that seizures are a common clinical expression of acute- and subacute-phase autoimmune encephalitis marked by neuronal autoantibodies, little is known about the relationship between chronic epilepsy and such antibodies.
Only five Brazilian patients with chronic epilepsy, or 2.2%, tested positive for autoantibodies, all of whom had mesial temporal lobe epilepsy with hippocampal sclerosis. This suggests a possible autoimmune etiology for hippocampal sclerosis. Three of the five patients had anti-N-methyl-D-aspartate receptor antibodies (anti-NMDA) and two had antiglutamic acid decarboxylate antibodies (anti-GAD). No one was positive for anti–leucine-rich glioma-inactivated 1 antibodies (anti-LGI1), anti–contactin-associated proteinlike 2 (anti-caspr2), anti-glutamate receptor antibodies (anti-AMPAr), or anti–gamma-aminobutyric acid receptor antibodies (anti-GABAr).
The autoantibody-negative and the much smaller autoantibody-positive groups didn’t differ significantly in terms of demographics, seizure frequency, disease duration, drug resistance, cognitive impairment, comorbid autoimmune conditions, or history of status epilepticus. Indeed, only two between-group differences were found: fluctuation in seizure control was an issue in 10.6% of autoantibody-negative and 40% of autoantibody-positive patients, and cutaneous adverse reactions to antiepileptic drugs were noted in 10.6% of antibody-negative and 60% of antibody-positive patients. Psychiatric comorbidities were present in 49.5% of autoantibody-negative patients as compared with 80% – that is, four of five – who were autoantibody-positive, a trend that didn’t achieve statistical significance.
Asked if he thinks the autoantibodies found in a small subset of patients with chronic epilepsy were a cause or an effect of repeated seizures for so long, Dr. Cendes replied, “That’s a very interesting question, and I don’t have an answer, actually. But if seizures trigger development of these antibodies – and remember, this population we’re talking about had many, many seizures over the years – I would expect antibodies to be more frequent than the figure we found.”
He reported having no financial conflicts regarding his study.
SOURCE: Watanabe N et al. IEC 2019, Abstract P004.
BANGKOK – Cutaneous reactions to antiepileptic drugs in patients with chronic epilepsy suggest increased likelihood of an autoimmune element to their seizure disorder, Fernando Cendes, MD, PhD, reported at the International Epilepsy Congress.
“My recommendation based on our findings is that if you have a patient who has a history of skin reactions to AEDs [antiepileptic drugs], or who has psychosis, or who has a very strange response to antiepileptic medication – meaning that at some points they are refractory and at other points they are very well controlled – I think those patients are probably at risk for having an autoantibody,” he said at the congress sponsored by the International League Against Epilepsy.
Screening for autoantibodies in such patients is appropriate. However, there’s a caveat: “The thing is, we don’t have evidence that treating these autoantibodies with immunotherapy will have any benefit on seizure control in these patients. We don’t have that data yet, but we are looking into it,” according to Dr. Cendes, professor of neurology at the State University of Campinas (Brazil).
He presented a study of 221 consecutive adults with severe chronic refractory epilepsy as evidenced by a mean disease duration of nearly 29 years, with an average of 5.93 seizures per month. A total of 77% had a structural etiology for their epilepsy, in most cases hippocampal sclerosis. In 19% of patients, the etiology was unknown. Overall, 95% of subjects had focal epilepsy, and the remainder had generalized epilepsy. All underwent serum testing for a variety of antibodies against neuronal surface antigens that have been implicated in encephalitis, seizures, and/or psychosis. Those who tested positive then underwent confirmatory testing of their cerebrospinal fluid.
The impetus for this study, the neurologist explained, is that although it’s now well established that seizures are a common clinical expression of acute- and subacute-phase autoimmune encephalitis marked by neuronal autoantibodies, little is known about the relationship between chronic epilepsy and such antibodies.
Only five Brazilian patients with chronic epilepsy, or 2.2%, tested positive for autoantibodies, all of whom had mesial temporal lobe epilepsy with hippocampal sclerosis. This suggests a possible autoimmune etiology for hippocampal sclerosis. Three of the five patients had anti-N-methyl-D-aspartate receptor antibodies (anti-NMDA) and two had antiglutamic acid decarboxylate antibodies (anti-GAD). No one was positive for anti–leucine-rich glioma-inactivated 1 antibodies (anti-LGI1), anti–contactin-associated proteinlike 2 (anti-caspr2), anti-glutamate receptor antibodies (anti-AMPAr), or anti–gamma-aminobutyric acid receptor antibodies (anti-GABAr).
The autoantibody-negative and the much smaller autoantibody-positive groups didn’t differ significantly in terms of demographics, seizure frequency, disease duration, drug resistance, cognitive impairment, comorbid autoimmune conditions, or history of status epilepticus. Indeed, only two between-group differences were found: fluctuation in seizure control was an issue in 10.6% of autoantibody-negative and 40% of autoantibody-positive patients, and cutaneous adverse reactions to antiepileptic drugs were noted in 10.6% of antibody-negative and 60% of antibody-positive patients. Psychiatric comorbidities were present in 49.5% of autoantibody-negative patients as compared with 80% – that is, four of five – who were autoantibody-positive, a trend that didn’t achieve statistical significance.
Asked if he thinks the autoantibodies found in a small subset of patients with chronic epilepsy were a cause or an effect of repeated seizures for so long, Dr. Cendes replied, “That’s a very interesting question, and I don’t have an answer, actually. But if seizures trigger development of these antibodies – and remember, this population we’re talking about had many, many seizures over the years – I would expect antibodies to be more frequent than the figure we found.”
He reported having no financial conflicts regarding his study.
SOURCE: Watanabe N et al. IEC 2019, Abstract P004.
REPORTING FROM IEC 2019
Alzheimer’s disease raises risk for recurrent seizures
LOS ANGELES – Seizures are not uncommon among patients with Alzheimer’s disease – particularly as patients live longer with the disease – and are often associated with worse cognitive and functional performance, according to research findings presented at the Alzheimer’s Association International Conference.
Jonathan Vöglein, MD, of the German Center for Neurodegenerative Diseases and Ludwig-Maximilian University in Munich presented results from a cohort of 9,127 patients with Alzheimer’s disease (AD), of whom 287 had experienced a seizure, and more than 10,000 non-AD control subjects recruited at clinics during 2005-2016.
Dr. Vöglein and colleagues found that seizure risk increased with duration of disease, from 1.5% of patients at 4.8 years with the disease to 5.4% at 11 years, with likelihood of a seizure increasing steadily over time.
Moreover, 70% of AD patients who experienced a seizure had a second one within 7.5 months. People who had seizures fared worse on cognitive and functional tests: a mean 16.6 on the Mini Mental State Examination, compared with 19.6 for patients without seizures. On a severity rating scale, the Clinical Dementia Rating Sum of Boxes, patients with seizures also fared worse, with scores of 9.3, compared with 6.8 for patients without seizures (P less than .0001 for all, with results adjusted for age and disease duration).
“The data of our study show that there’s an association of seizures with worse cognitive and functional performance,” Dr. Vöglein said in an interview.
“It’s important for clinicians to know that Alzheimer’s patients are at an increased risk for seizures,” Dr. Vöglein said. “In my clinical care experience, seizures are rarely the main complaint of patients with Alzheimer’s disease.” Detailed interviews with the patient and a proxy are important, he added, because patients with Alzheimer’s disease may not always remember events that could be a seizure.
Dr. Vöglein noted that, to his knowledge, there are no reliable data showing that treating seizures with antiepileptic drugs slows cognitive decline. “The results of our study suggest that an antiepileptic treatment after a first seizure in patients with Alzheimer’s dementia may be considered,” he said.
Also at the conference, researcher Ruby Castilla-Puentes, MD, DrPH, of Janssen Pharmaceuticals in Hopewell, N.J., along with Miguel Habeych, MD, MPH, of the University of Cincinnati presented findings on dementia and seizure risk from a large U.S. national managed care database of nearly 3 million people aged 60 years and older, of whom 56% were women.
The researchers analyzed this cohort during 2005-2014 and identified 80,000 people (2.8% of the cohort) as having any dementia diagnosis. The overall incidence of new-onset seizures in patients with dementia was 12.3% per year. In general, all subtypes of seizures and epileptic disorders (partial, generalized, or undifferentiated) occurred more frequently in patients with dementia, compared against patients without dementia (P less than .0001).
People with dementia had more than six times greater risk for experiencing recurring epileptic seizures than did people without dementia (95% confidence interval, 4.4-9.5). They were at six times higher risk for partial seizures (95% CI, 5.5-6.6); fivefold higher risk for generalized (95% CI, 4.9-5.5) and undifferentiated epilepsy (95% CI, 4.8-5.2); and 4.75 times higher risk for generalized seizures (95% CI, 4.5-5.0) and partial epilepsy (95% CI, 4.4-5.1).
“Although there are limitations with the use of administrative claims databases to calculate incidence rates, this analysis suggests that patients of 60 years of age or older have higher risks of new-onset seizures associated with a dementia diagnosis,” Dr. Castilla-Puentes commented.
The findings, she said, reinforce the need for clinicians to monitor for seizures to ensure that patients with dementia receive appropriate treatment.
Dr. Vöglein disclosed no financial conflicts of interest. Dr. Castilla-Puentes disclosed being an employee of Janssen, which funded her study.
LOS ANGELES – Seizures are not uncommon among patients with Alzheimer’s disease – particularly as patients live longer with the disease – and are often associated with worse cognitive and functional performance, according to research findings presented at the Alzheimer’s Association International Conference.
Jonathan Vöglein, MD, of the German Center for Neurodegenerative Diseases and Ludwig-Maximilian University in Munich presented results from a cohort of 9,127 patients with Alzheimer’s disease (AD), of whom 287 had experienced a seizure, and more than 10,000 non-AD control subjects recruited at clinics during 2005-2016.
Dr. Vöglein and colleagues found that seizure risk increased with duration of disease, from 1.5% of patients at 4.8 years with the disease to 5.4% at 11 years, with likelihood of a seizure increasing steadily over time.
Moreover, 70% of AD patients who experienced a seizure had a second one within 7.5 months. People who had seizures fared worse on cognitive and functional tests: a mean 16.6 on the Mini Mental State Examination, compared with 19.6 for patients without seizures. On a severity rating scale, the Clinical Dementia Rating Sum of Boxes, patients with seizures also fared worse, with scores of 9.3, compared with 6.8 for patients without seizures (P less than .0001 for all, with results adjusted for age and disease duration).
“The data of our study show that there’s an association of seizures with worse cognitive and functional performance,” Dr. Vöglein said in an interview.
“It’s important for clinicians to know that Alzheimer’s patients are at an increased risk for seizures,” Dr. Vöglein said. “In my clinical care experience, seizures are rarely the main complaint of patients with Alzheimer’s disease.” Detailed interviews with the patient and a proxy are important, he added, because patients with Alzheimer’s disease may not always remember events that could be a seizure.
Dr. Vöglein noted that, to his knowledge, there are no reliable data showing that treating seizures with antiepileptic drugs slows cognitive decline. “The results of our study suggest that an antiepileptic treatment after a first seizure in patients with Alzheimer’s dementia may be considered,” he said.
Also at the conference, researcher Ruby Castilla-Puentes, MD, DrPH, of Janssen Pharmaceuticals in Hopewell, N.J., along with Miguel Habeych, MD, MPH, of the University of Cincinnati presented findings on dementia and seizure risk from a large U.S. national managed care database of nearly 3 million people aged 60 years and older, of whom 56% were women.
The researchers analyzed this cohort during 2005-2014 and identified 80,000 people (2.8% of the cohort) as having any dementia diagnosis. The overall incidence of new-onset seizures in patients with dementia was 12.3% per year. In general, all subtypes of seizures and epileptic disorders (partial, generalized, or undifferentiated) occurred more frequently in patients with dementia, compared against patients without dementia (P less than .0001).
People with dementia had more than six times greater risk for experiencing recurring epileptic seizures than did people without dementia (95% confidence interval, 4.4-9.5). They were at six times higher risk for partial seizures (95% CI, 5.5-6.6); fivefold higher risk for generalized (95% CI, 4.9-5.5) and undifferentiated epilepsy (95% CI, 4.8-5.2); and 4.75 times higher risk for generalized seizures (95% CI, 4.5-5.0) and partial epilepsy (95% CI, 4.4-5.1).
“Although there are limitations with the use of administrative claims databases to calculate incidence rates, this analysis suggests that patients of 60 years of age or older have higher risks of new-onset seizures associated with a dementia diagnosis,” Dr. Castilla-Puentes commented.
The findings, she said, reinforce the need for clinicians to monitor for seizures to ensure that patients with dementia receive appropriate treatment.
Dr. Vöglein disclosed no financial conflicts of interest. Dr. Castilla-Puentes disclosed being an employee of Janssen, which funded her study.
LOS ANGELES – Seizures are not uncommon among patients with Alzheimer’s disease – particularly as patients live longer with the disease – and are often associated with worse cognitive and functional performance, according to research findings presented at the Alzheimer’s Association International Conference.
Jonathan Vöglein, MD, of the German Center for Neurodegenerative Diseases and Ludwig-Maximilian University in Munich presented results from a cohort of 9,127 patients with Alzheimer’s disease (AD), of whom 287 had experienced a seizure, and more than 10,000 non-AD control subjects recruited at clinics during 2005-2016.
Dr. Vöglein and colleagues found that seizure risk increased with duration of disease, from 1.5% of patients at 4.8 years with the disease to 5.4% at 11 years, with likelihood of a seizure increasing steadily over time.
Moreover, 70% of AD patients who experienced a seizure had a second one within 7.5 months. People who had seizures fared worse on cognitive and functional tests: a mean 16.6 on the Mini Mental State Examination, compared with 19.6 for patients without seizures. On a severity rating scale, the Clinical Dementia Rating Sum of Boxes, patients with seizures also fared worse, with scores of 9.3, compared with 6.8 for patients without seizures (P less than .0001 for all, with results adjusted for age and disease duration).
“The data of our study show that there’s an association of seizures with worse cognitive and functional performance,” Dr. Vöglein said in an interview.
“It’s important for clinicians to know that Alzheimer’s patients are at an increased risk for seizures,” Dr. Vöglein said. “In my clinical care experience, seizures are rarely the main complaint of patients with Alzheimer’s disease.” Detailed interviews with the patient and a proxy are important, he added, because patients with Alzheimer’s disease may not always remember events that could be a seizure.
Dr. Vöglein noted that, to his knowledge, there are no reliable data showing that treating seizures with antiepileptic drugs slows cognitive decline. “The results of our study suggest that an antiepileptic treatment after a first seizure in patients with Alzheimer’s dementia may be considered,” he said.
Also at the conference, researcher Ruby Castilla-Puentes, MD, DrPH, of Janssen Pharmaceuticals in Hopewell, N.J., along with Miguel Habeych, MD, MPH, of the University of Cincinnati presented findings on dementia and seizure risk from a large U.S. national managed care database of nearly 3 million people aged 60 years and older, of whom 56% were women.
The researchers analyzed this cohort during 2005-2014 and identified 80,000 people (2.8% of the cohort) as having any dementia diagnosis. The overall incidence of new-onset seizures in patients with dementia was 12.3% per year. In general, all subtypes of seizures and epileptic disorders (partial, generalized, or undifferentiated) occurred more frequently in patients with dementia, compared against patients without dementia (P less than .0001).
People with dementia had more than six times greater risk for experiencing recurring epileptic seizures than did people without dementia (95% confidence interval, 4.4-9.5). They were at six times higher risk for partial seizures (95% CI, 5.5-6.6); fivefold higher risk for generalized (95% CI, 4.9-5.5) and undifferentiated epilepsy (95% CI, 4.8-5.2); and 4.75 times higher risk for generalized seizures (95% CI, 4.5-5.0) and partial epilepsy (95% CI, 4.4-5.1).
“Although there are limitations with the use of administrative claims databases to calculate incidence rates, this analysis suggests that patients of 60 years of age or older have higher risks of new-onset seizures associated with a dementia diagnosis,” Dr. Castilla-Puentes commented.
The findings, she said, reinforce the need for clinicians to monitor for seizures to ensure that patients with dementia receive appropriate treatment.
Dr. Vöglein disclosed no financial conflicts of interest. Dr. Castilla-Puentes disclosed being an employee of Janssen, which funded her study.
REPORTING FROM AAIC 2019
Patients with focal epilepsy have progressive cortical thinning
, according to research published online July 1 in JAMA Neurology. Methods for preventing this thinning are unknown. “Our findings appear to highlight the need for longitudinal studies to develop disease-modifying treatments for epilepsy,” said Marian Galovic, MD, a doctoral student at University College London, and colleagues.
To date, neurologists have not found a definitive answer to the question of whether epilepsy is a static or progressive disease. Few longitudinal studies have examined patients with structural neuroimaging to determine whether the brain changes over time. The studies that have taken this approach have had small populations or have lacked control populations.
Comparing brain changes in patients and controls
Dr. Galovic and colleagues analyzed data for consecutive patients with focal epilepsy who underwent follow-up at the National Hospital for Neurology and Neurosurgery in London. The data were collected from Aug. 3, 2004, to Jan. 26, 2016. The researchers chose individuals who had at least 2 high-resolution T1-weighted MRI scans performed on the same scanner more than 6 months apart. They excluded patients with brain lesions other than hippocampal sclerosis, those with inadequate MRI scan quality, and those for whom clinical data were missing. To match these patients with controls, Dr. Galovic and colleagues chose three longitudinal data sets with data for healthy volunteers between ages 20 and 70 years. Each control participant had two high-resolution T1-weighted scans taken more than 6 months apart. The investigators matched patients and controls on age and sex. The automated and validated Computational Anatomy Toolbox (CAT12) estimated cortical thickness.
Dr. Galovic’s group included 190 patients with focal epilepsy, who had had 396 MRI scans, and 141 healthy controls, who had had 282 MRI scans, in their analysis. Age, sex, and image quality did not differ significantly between the two groups. Mean age was 36 years for patients and 35 years for controls. The proportion of women was 52.1% among patients and 53.9% among controls.
The rate of atrophy was doubled in patients
Approximately 77% of people with epilepsy had progressive cortical thinning that was distinct from that associated with normal aging. The mean overall annual rate of global cortical thinning was higher among patients with epilepsy (0.024) than among controls (0.011). The mean annual rate of cortical thinning increased among people with epilepsy who were older than 55 years. This rate was 0.021 in patients aged 18 to less than 35 years, compared with 0.023 in patients aged 35 to less than 55 years. Seizure frequency, number of antiepileptic drugs (AEDs) taken, and history of secondarily generalized seizures did not differ between age groups.
Compared with healthy controls, patients with focal epilepsy had widespread areas of greater progressive atrophy. Bilaterally affected areas included the lateral and posterior temporal lobes, posterior cingulate gyri, occipital lobes, pericentral gyri, and opercula. The distribution of progressive thinning in all patients with epilepsy was similar to regions connected to both hippocampi. Healthy controls had no areas of greater cortical thinning, compared with patients with epilepsy.
Progressive thinning in the left postcentral gyrus was greater in patients with left temporal lobe epilepsy (TLE) than in those with right TLE. Cortical thinning was more progressive in patients with right frontal lobe epilepsy (FLE) than in those with left FLE, particularly in right parietotemporal and right frontal areas.
Dr. Galovic and colleagues found no association between the rate of cortical thinning and seizure frequency, history of secondarily generalized seizures, or number of AEDs taken between MRIs. They found no difference in the rate of atrophy between patients with epilepsy with ongoing seizures and those without. The annual mean rate of cortical thinning was higher in people with a short duration of epilepsy (i.e., less than 5 years), compared with patients with a longer duration of epilepsy (i.e., 5 years or more).
A surrogate marker for neurodegeneration?
“The most likely cause of cortical thinning is neuronal loss, suggesting that these measurements are a surrogate marker for neurodegeneration,” said Dr. Galovic and colleagues. The finding that progressive morphologic changes were most pronounced in the first 5 years after epilepsy onset “supports the need for early diagnosis, rapid treatment, and reduction of delays of surgical referral in people with epilepsy,” they added.
One limitation of the current study is the fact that data from patients and controls were acquired using different MRI scanners. In addition, the patients included in the study had been referred to the center because their cases were more complicated, thus introducing the possibility of referral bias. The findings thus cannot be generalized readily to the overall population, said Dr. Galovic and colleagues.
Future studies should examine whether particular AEDs have differential influences on the progressive morphologic changes observed in epilepsy, said the investigators. “Future research should also address whether progressive changes in cortical morphologic characteristics correlate with deficits on serial cognitive testing or spreading of the irritative zone on EEG recordings,” they concluded.
The study and the authors received support from the Medical Research Council, the Wellcome Trust, and the University College London Hospital.
SOURCE: Galovic M et al. JAMA Neurol. 2019 Jul 1. doi: 10.1001/jamaneurol.2019.1708.
, according to research published online July 1 in JAMA Neurology. Methods for preventing this thinning are unknown. “Our findings appear to highlight the need for longitudinal studies to develop disease-modifying treatments for epilepsy,” said Marian Galovic, MD, a doctoral student at University College London, and colleagues.
To date, neurologists have not found a definitive answer to the question of whether epilepsy is a static or progressive disease. Few longitudinal studies have examined patients with structural neuroimaging to determine whether the brain changes over time. The studies that have taken this approach have had small populations or have lacked control populations.
Comparing brain changes in patients and controls
Dr. Galovic and colleagues analyzed data for consecutive patients with focal epilepsy who underwent follow-up at the National Hospital for Neurology and Neurosurgery in London. The data were collected from Aug. 3, 2004, to Jan. 26, 2016. The researchers chose individuals who had at least 2 high-resolution T1-weighted MRI scans performed on the same scanner more than 6 months apart. They excluded patients with brain lesions other than hippocampal sclerosis, those with inadequate MRI scan quality, and those for whom clinical data were missing. To match these patients with controls, Dr. Galovic and colleagues chose three longitudinal data sets with data for healthy volunteers between ages 20 and 70 years. Each control participant had two high-resolution T1-weighted scans taken more than 6 months apart. The investigators matched patients and controls on age and sex. The automated and validated Computational Anatomy Toolbox (CAT12) estimated cortical thickness.
Dr. Galovic’s group included 190 patients with focal epilepsy, who had had 396 MRI scans, and 141 healthy controls, who had had 282 MRI scans, in their analysis. Age, sex, and image quality did not differ significantly between the two groups. Mean age was 36 years for patients and 35 years for controls. The proportion of women was 52.1% among patients and 53.9% among controls.
The rate of atrophy was doubled in patients
Approximately 77% of people with epilepsy had progressive cortical thinning that was distinct from that associated with normal aging. The mean overall annual rate of global cortical thinning was higher among patients with epilepsy (0.024) than among controls (0.011). The mean annual rate of cortical thinning increased among people with epilepsy who were older than 55 years. This rate was 0.021 in patients aged 18 to less than 35 years, compared with 0.023 in patients aged 35 to less than 55 years. Seizure frequency, number of antiepileptic drugs (AEDs) taken, and history of secondarily generalized seizures did not differ between age groups.
Compared with healthy controls, patients with focal epilepsy had widespread areas of greater progressive atrophy. Bilaterally affected areas included the lateral and posterior temporal lobes, posterior cingulate gyri, occipital lobes, pericentral gyri, and opercula. The distribution of progressive thinning in all patients with epilepsy was similar to regions connected to both hippocampi. Healthy controls had no areas of greater cortical thinning, compared with patients with epilepsy.
Progressive thinning in the left postcentral gyrus was greater in patients with left temporal lobe epilepsy (TLE) than in those with right TLE. Cortical thinning was more progressive in patients with right frontal lobe epilepsy (FLE) than in those with left FLE, particularly in right parietotemporal and right frontal areas.
Dr. Galovic and colleagues found no association between the rate of cortical thinning and seizure frequency, history of secondarily generalized seizures, or number of AEDs taken between MRIs. They found no difference in the rate of atrophy between patients with epilepsy with ongoing seizures and those without. The annual mean rate of cortical thinning was higher in people with a short duration of epilepsy (i.e., less than 5 years), compared with patients with a longer duration of epilepsy (i.e., 5 years or more).
A surrogate marker for neurodegeneration?
“The most likely cause of cortical thinning is neuronal loss, suggesting that these measurements are a surrogate marker for neurodegeneration,” said Dr. Galovic and colleagues. The finding that progressive morphologic changes were most pronounced in the first 5 years after epilepsy onset “supports the need for early diagnosis, rapid treatment, and reduction of delays of surgical referral in people with epilepsy,” they added.
One limitation of the current study is the fact that data from patients and controls were acquired using different MRI scanners. In addition, the patients included in the study had been referred to the center because their cases were more complicated, thus introducing the possibility of referral bias. The findings thus cannot be generalized readily to the overall population, said Dr. Galovic and colleagues.
Future studies should examine whether particular AEDs have differential influences on the progressive morphologic changes observed in epilepsy, said the investigators. “Future research should also address whether progressive changes in cortical morphologic characteristics correlate with deficits on serial cognitive testing or spreading of the irritative zone on EEG recordings,” they concluded.
The study and the authors received support from the Medical Research Council, the Wellcome Trust, and the University College London Hospital.
SOURCE: Galovic M et al. JAMA Neurol. 2019 Jul 1. doi: 10.1001/jamaneurol.2019.1708.
, according to research published online July 1 in JAMA Neurology. Methods for preventing this thinning are unknown. “Our findings appear to highlight the need for longitudinal studies to develop disease-modifying treatments for epilepsy,” said Marian Galovic, MD, a doctoral student at University College London, and colleagues.
To date, neurologists have not found a definitive answer to the question of whether epilepsy is a static or progressive disease. Few longitudinal studies have examined patients with structural neuroimaging to determine whether the brain changes over time. The studies that have taken this approach have had small populations or have lacked control populations.
Comparing brain changes in patients and controls
Dr. Galovic and colleagues analyzed data for consecutive patients with focal epilepsy who underwent follow-up at the National Hospital for Neurology and Neurosurgery in London. The data were collected from Aug. 3, 2004, to Jan. 26, 2016. The researchers chose individuals who had at least 2 high-resolution T1-weighted MRI scans performed on the same scanner more than 6 months apart. They excluded patients with brain lesions other than hippocampal sclerosis, those with inadequate MRI scan quality, and those for whom clinical data were missing. To match these patients with controls, Dr. Galovic and colleagues chose three longitudinal data sets with data for healthy volunteers between ages 20 and 70 years. Each control participant had two high-resolution T1-weighted scans taken more than 6 months apart. The investigators matched patients and controls on age and sex. The automated and validated Computational Anatomy Toolbox (CAT12) estimated cortical thickness.
Dr. Galovic’s group included 190 patients with focal epilepsy, who had had 396 MRI scans, and 141 healthy controls, who had had 282 MRI scans, in their analysis. Age, sex, and image quality did not differ significantly between the two groups. Mean age was 36 years for patients and 35 years for controls. The proportion of women was 52.1% among patients and 53.9% among controls.
The rate of atrophy was doubled in patients
Approximately 77% of people with epilepsy had progressive cortical thinning that was distinct from that associated with normal aging. The mean overall annual rate of global cortical thinning was higher among patients with epilepsy (0.024) than among controls (0.011). The mean annual rate of cortical thinning increased among people with epilepsy who were older than 55 years. This rate was 0.021 in patients aged 18 to less than 35 years, compared with 0.023 in patients aged 35 to less than 55 years. Seizure frequency, number of antiepileptic drugs (AEDs) taken, and history of secondarily generalized seizures did not differ between age groups.
Compared with healthy controls, patients with focal epilepsy had widespread areas of greater progressive atrophy. Bilaterally affected areas included the lateral and posterior temporal lobes, posterior cingulate gyri, occipital lobes, pericentral gyri, and opercula. The distribution of progressive thinning in all patients with epilepsy was similar to regions connected to both hippocampi. Healthy controls had no areas of greater cortical thinning, compared with patients with epilepsy.
Progressive thinning in the left postcentral gyrus was greater in patients with left temporal lobe epilepsy (TLE) than in those with right TLE. Cortical thinning was more progressive in patients with right frontal lobe epilepsy (FLE) than in those with left FLE, particularly in right parietotemporal and right frontal areas.
Dr. Galovic and colleagues found no association between the rate of cortical thinning and seizure frequency, history of secondarily generalized seizures, or number of AEDs taken between MRIs. They found no difference in the rate of atrophy between patients with epilepsy with ongoing seizures and those without. The annual mean rate of cortical thinning was higher in people with a short duration of epilepsy (i.e., less than 5 years), compared with patients with a longer duration of epilepsy (i.e., 5 years or more).
A surrogate marker for neurodegeneration?
“The most likely cause of cortical thinning is neuronal loss, suggesting that these measurements are a surrogate marker for neurodegeneration,” said Dr. Galovic and colleagues. The finding that progressive morphologic changes were most pronounced in the first 5 years after epilepsy onset “supports the need for early diagnosis, rapid treatment, and reduction of delays of surgical referral in people with epilepsy,” they added.
One limitation of the current study is the fact that data from patients and controls were acquired using different MRI scanners. In addition, the patients included in the study had been referred to the center because their cases were more complicated, thus introducing the possibility of referral bias. The findings thus cannot be generalized readily to the overall population, said Dr. Galovic and colleagues.
Future studies should examine whether particular AEDs have differential influences on the progressive morphologic changes observed in epilepsy, said the investigators. “Future research should also address whether progressive changes in cortical morphologic characteristics correlate with deficits on serial cognitive testing or spreading of the irritative zone on EEG recordings,” they concluded.
The study and the authors received support from the Medical Research Council, the Wellcome Trust, and the University College London Hospital.
SOURCE: Galovic M et al. JAMA Neurol. 2019 Jul 1. doi: 10.1001/jamaneurol.2019.1708.
FROM JAMA NEUROLOGY
Anticholinergic drugs linked to dementia in older populations
Exposures to various types of anticholinergic medications were associated with a significantly increased risk of dementia in people aged 55 years or older in a large pharmacoepidemiologic study.
“This study was designed to assess the association between cumulative anticholinergic drug use and risk of dementia in a large, representative British population,” wrote Carol A. C. Coupland, PhD, of the division of primary care at the University of Nottingham (England), and colleagues. The findings were published in JAMA Internal Medicine.
The researchers conducted a large nested case-control study that included 58,769 patients with dementia and 225,574 matched controls from the QResearch database in England. Each study participant was matched to five controls based on various characteristics, including sex, age, and calendar time, among others.
Prescription data related to 56 different drugs with strong anticholinergic properties, including antipsychotics, bladder antimuscarinics, antiepileptics, antiparkinson agents, and antidepressants were used to measure drug exposure. The study data were analyzed from 2016 to 2018.
“The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls,” Dr. Coupland and colleagues wrote.
After analysis, the researchers found that exposure to antipsychotics (adjusted odds ratio, 1.70), bladder antimuscarinics (aOR, 1.65), antiepileptics (aOR, 1.39), antiparkinson agents (aOR, 1.52), and anticholinergic antidepressants (aOR, 1.29) was associated with an increased risk of dementia after adjustment for confounding factors.
“Associations were stronger in [dementia] cases diagnosed before the age of 80 years,” the researchers noted.
However, antihistamine, antivertigo/antiemetic, skeletal muscle relaxant, gastrointestinal antispasmodic, antiarrhythmic, and antimuscarinic bronchodilator anticholinergic agents were not associated with any increased risk of dementia.
One key limitation of the study was the absence of medication compliance assessment, which could result in exposure misclassification. Dr. Coupland and colleagues acknowledged this could underestimate some associations with medication exposure.
The stronger risk of dementia found among people who had dementia before age 80 “indicates that anticholinergic drugs should be prescribed with caution in middle-aged and older people,” they concluded.
One question that remains from the current study is whether anticholinergic drugs are a definite modifiable risk factor for Alzheimer’s disease and related dementias, Noll L. Campbell, PharmD, of Purdue University, West Lafayette, Ind., and colleagues wrote in an editorial accompanying the study by Dr. Coupland and associates (JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0676).
While a pharmacologic basis for this association has been proposed, causation has yet to be established by means of prospective randomized studies. The current supposition is that deprescribing anticholinergic medications has the potential to positively effect cholinergic neurotransmission in certain regions of the brain, which could lead to improved cognitive functioning, and lower the likelihood of developing Alzheimer’s disease and related dementias, they wrote in the editorial.
However, the discontinuation of some anticholinergic agents may pose other risks, such as worsening pain or depressive symptoms, in addition to increasing the utilization of acute care facilities. As a result, high-quality, well-designed, randomized trials are needed to better understand the long-term effects of deprescribing anticholinergic medications. These trials would help inform clinicians, patients, and policymakers about the risks and benefits of deprescribing interventions, Dr. Campbell and coauthors said.
The study was supported by the National Institute for Health Research and the University of Nottingham. The authors reported financial affiliations with ClinRisk Ltd. The authors of the editorial reported receiving support from the National Institute on Aging and the Agency for Healthcare Research and Quality. Dr. Campbell reported receiving personal fees from Astellas Pharma US.
SOURCE: Coupland C et al. JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0677
Exposures to various types of anticholinergic medications were associated with a significantly increased risk of dementia in people aged 55 years or older in a large pharmacoepidemiologic study.
“This study was designed to assess the association between cumulative anticholinergic drug use and risk of dementia in a large, representative British population,” wrote Carol A. C. Coupland, PhD, of the division of primary care at the University of Nottingham (England), and colleagues. The findings were published in JAMA Internal Medicine.
The researchers conducted a large nested case-control study that included 58,769 patients with dementia and 225,574 matched controls from the QResearch database in England. Each study participant was matched to five controls based on various characteristics, including sex, age, and calendar time, among others.
Prescription data related to 56 different drugs with strong anticholinergic properties, including antipsychotics, bladder antimuscarinics, antiepileptics, antiparkinson agents, and antidepressants were used to measure drug exposure. The study data were analyzed from 2016 to 2018.
“The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls,” Dr. Coupland and colleagues wrote.
After analysis, the researchers found that exposure to antipsychotics (adjusted odds ratio, 1.70), bladder antimuscarinics (aOR, 1.65), antiepileptics (aOR, 1.39), antiparkinson agents (aOR, 1.52), and anticholinergic antidepressants (aOR, 1.29) was associated with an increased risk of dementia after adjustment for confounding factors.
“Associations were stronger in [dementia] cases diagnosed before the age of 80 years,” the researchers noted.
However, antihistamine, antivertigo/antiemetic, skeletal muscle relaxant, gastrointestinal antispasmodic, antiarrhythmic, and antimuscarinic bronchodilator anticholinergic agents were not associated with any increased risk of dementia.
One key limitation of the study was the absence of medication compliance assessment, which could result in exposure misclassification. Dr. Coupland and colleagues acknowledged this could underestimate some associations with medication exposure.
The stronger risk of dementia found among people who had dementia before age 80 “indicates that anticholinergic drugs should be prescribed with caution in middle-aged and older people,” they concluded.
One question that remains from the current study is whether anticholinergic drugs are a definite modifiable risk factor for Alzheimer’s disease and related dementias, Noll L. Campbell, PharmD, of Purdue University, West Lafayette, Ind., and colleagues wrote in an editorial accompanying the study by Dr. Coupland and associates (JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0676).
While a pharmacologic basis for this association has been proposed, causation has yet to be established by means of prospective randomized studies. The current supposition is that deprescribing anticholinergic medications has the potential to positively effect cholinergic neurotransmission in certain regions of the brain, which could lead to improved cognitive functioning, and lower the likelihood of developing Alzheimer’s disease and related dementias, they wrote in the editorial.
However, the discontinuation of some anticholinergic agents may pose other risks, such as worsening pain or depressive symptoms, in addition to increasing the utilization of acute care facilities. As a result, high-quality, well-designed, randomized trials are needed to better understand the long-term effects of deprescribing anticholinergic medications. These trials would help inform clinicians, patients, and policymakers about the risks and benefits of deprescribing interventions, Dr. Campbell and coauthors said.
The study was supported by the National Institute for Health Research and the University of Nottingham. The authors reported financial affiliations with ClinRisk Ltd. The authors of the editorial reported receiving support from the National Institute on Aging and the Agency for Healthcare Research and Quality. Dr. Campbell reported receiving personal fees from Astellas Pharma US.
SOURCE: Coupland C et al. JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0677
Exposures to various types of anticholinergic medications were associated with a significantly increased risk of dementia in people aged 55 years or older in a large pharmacoepidemiologic study.
“This study was designed to assess the association between cumulative anticholinergic drug use and risk of dementia in a large, representative British population,” wrote Carol A. C. Coupland, PhD, of the division of primary care at the University of Nottingham (England), and colleagues. The findings were published in JAMA Internal Medicine.
The researchers conducted a large nested case-control study that included 58,769 patients with dementia and 225,574 matched controls from the QResearch database in England. Each study participant was matched to five controls based on various characteristics, including sex, age, and calendar time, among others.
Prescription data related to 56 different drugs with strong anticholinergic properties, including antipsychotics, bladder antimuscarinics, antiepileptics, antiparkinson agents, and antidepressants were used to measure drug exposure. The study data were analyzed from 2016 to 2018.
“The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls,” Dr. Coupland and colleagues wrote.
After analysis, the researchers found that exposure to antipsychotics (adjusted odds ratio, 1.70), bladder antimuscarinics (aOR, 1.65), antiepileptics (aOR, 1.39), antiparkinson agents (aOR, 1.52), and anticholinergic antidepressants (aOR, 1.29) was associated with an increased risk of dementia after adjustment for confounding factors.
“Associations were stronger in [dementia] cases diagnosed before the age of 80 years,” the researchers noted.
However, antihistamine, antivertigo/antiemetic, skeletal muscle relaxant, gastrointestinal antispasmodic, antiarrhythmic, and antimuscarinic bronchodilator anticholinergic agents were not associated with any increased risk of dementia.
One key limitation of the study was the absence of medication compliance assessment, which could result in exposure misclassification. Dr. Coupland and colleagues acknowledged this could underestimate some associations with medication exposure.
The stronger risk of dementia found among people who had dementia before age 80 “indicates that anticholinergic drugs should be prescribed with caution in middle-aged and older people,” they concluded.
One question that remains from the current study is whether anticholinergic drugs are a definite modifiable risk factor for Alzheimer’s disease and related dementias, Noll L. Campbell, PharmD, of Purdue University, West Lafayette, Ind., and colleagues wrote in an editorial accompanying the study by Dr. Coupland and associates (JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0676).
While a pharmacologic basis for this association has been proposed, causation has yet to be established by means of prospective randomized studies. The current supposition is that deprescribing anticholinergic medications has the potential to positively effect cholinergic neurotransmission in certain regions of the brain, which could lead to improved cognitive functioning, and lower the likelihood of developing Alzheimer’s disease and related dementias, they wrote in the editorial.
However, the discontinuation of some anticholinergic agents may pose other risks, such as worsening pain or depressive symptoms, in addition to increasing the utilization of acute care facilities. As a result, high-quality, well-designed, randomized trials are needed to better understand the long-term effects of deprescribing anticholinergic medications. These trials would help inform clinicians, patients, and policymakers about the risks and benefits of deprescribing interventions, Dr. Campbell and coauthors said.
The study was supported by the National Institute for Health Research and the University of Nottingham. The authors reported financial affiliations with ClinRisk Ltd. The authors of the editorial reported receiving support from the National Institute on Aging and the Agency for Healthcare Research and Quality. Dr. Campbell reported receiving personal fees from Astellas Pharma US.
SOURCE: Coupland C et al. JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0677
FROM JAMA INTERNAL MEDICINE
Lack of CBD oil regulations hearkens back to patent medicines
My vet sells cannabidiol (CBD) oil for dogs and cats.
So does the vape store down the street, the pharmacy around the corner ... and pretty much every place these days.
I probably have more patients ask me about CBD than any other drug, usually because a friend/cousin/in-law/child/parent/spouse/neighbor/coworker “said I should ask you about this.” That’s the power of the Internet: The most marginally proven treatments are portrayed as definitive cures, while some of the most effective treatments (like vaccines) are treated like a lethal-injection drug.
Nothing is, or ever will be, a miracle cure. There will always be nonresponders and those who have adverse effects. In that respect, what goes for one treatment goes for all of them.
But that doesn’t stop these things from being pushed in the most unreliable ways. On Yelp, Groupon, Facebook, and countless other nonmedical sites that aren’t required to back up their claims with hard evidence.
Anything I prescribe, and all over-the-counter medications, are subject to far more scrutiny. They have known risks and benefits. They’ve been through trials, and most have years of data to review when questions arise.
Granted, CBD oil has been approved, as Epidiolex, for different forms of epilepsy. That kind of regulation is a step forward, but the majority of people selling CBD oil are doing so with unregulated OTC forms.
These may work, but the lack of regulation means every one of these places can make their own formulations, purities, and strengths. In some respects it’s a throwback to the era of patent medicines, where each pharmacy was free to whip up their own concoctions, label them as treatments for whatever they wished, and advertise and sell them.
The Food and Drug Administration, however, continues to take an ostrich approach. At their level these OTC agents are illegal and cannot be sold or marketed. At the same time, though, the restrictions overall are not being enforced. This gives the impression that there is nothing wrong with selling them.
Let’s look at morphine, an effective pain reliever and controlled substance. It’s tightly regulated, as it should be. But what if those regulations were ignored? What if, in addition to it being available by prescription, it were sold OTC in perhaps weaker but unregulated strengths and forms, with a variety of unscientific claims made for its benefits?
I don’t see anyone getting away with doing that.
Like I said earlier, I have nothing against CBD oil. But I do think it should have to go through the same approval process as any other medication, with specific strengths, dosing, benefits, and side effects determined, and enforceable regulations around its manufacturing, sale, and use.
Anything less is snake oil.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
My vet sells cannabidiol (CBD) oil for dogs and cats.
So does the vape store down the street, the pharmacy around the corner ... and pretty much every place these days.
I probably have more patients ask me about CBD than any other drug, usually because a friend/cousin/in-law/child/parent/spouse/neighbor/coworker “said I should ask you about this.” That’s the power of the Internet: The most marginally proven treatments are portrayed as definitive cures, while some of the most effective treatments (like vaccines) are treated like a lethal-injection drug.
Nothing is, or ever will be, a miracle cure. There will always be nonresponders and those who have adverse effects. In that respect, what goes for one treatment goes for all of them.
But that doesn’t stop these things from being pushed in the most unreliable ways. On Yelp, Groupon, Facebook, and countless other nonmedical sites that aren’t required to back up their claims with hard evidence.
Anything I prescribe, and all over-the-counter medications, are subject to far more scrutiny. They have known risks and benefits. They’ve been through trials, and most have years of data to review when questions arise.
Granted, CBD oil has been approved, as Epidiolex, for different forms of epilepsy. That kind of regulation is a step forward, but the majority of people selling CBD oil are doing so with unregulated OTC forms.
These may work, but the lack of regulation means every one of these places can make their own formulations, purities, and strengths. In some respects it’s a throwback to the era of patent medicines, where each pharmacy was free to whip up their own concoctions, label them as treatments for whatever they wished, and advertise and sell them.
The Food and Drug Administration, however, continues to take an ostrich approach. At their level these OTC agents are illegal and cannot be sold or marketed. At the same time, though, the restrictions overall are not being enforced. This gives the impression that there is nothing wrong with selling them.
Let’s look at morphine, an effective pain reliever and controlled substance. It’s tightly regulated, as it should be. But what if those regulations were ignored? What if, in addition to it being available by prescription, it were sold OTC in perhaps weaker but unregulated strengths and forms, with a variety of unscientific claims made for its benefits?
I don’t see anyone getting away with doing that.
Like I said earlier, I have nothing against CBD oil. But I do think it should have to go through the same approval process as any other medication, with specific strengths, dosing, benefits, and side effects determined, and enforceable regulations around its manufacturing, sale, and use.
Anything less is snake oil.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
My vet sells cannabidiol (CBD) oil for dogs and cats.
So does the vape store down the street, the pharmacy around the corner ... and pretty much every place these days.
I probably have more patients ask me about CBD than any other drug, usually because a friend/cousin/in-law/child/parent/spouse/neighbor/coworker “said I should ask you about this.” That’s the power of the Internet: The most marginally proven treatments are portrayed as definitive cures, while some of the most effective treatments (like vaccines) are treated like a lethal-injection drug.
Nothing is, or ever will be, a miracle cure. There will always be nonresponders and those who have adverse effects. In that respect, what goes for one treatment goes for all of them.
But that doesn’t stop these things from being pushed in the most unreliable ways. On Yelp, Groupon, Facebook, and countless other nonmedical sites that aren’t required to back up their claims with hard evidence.
Anything I prescribe, and all over-the-counter medications, are subject to far more scrutiny. They have known risks and benefits. They’ve been through trials, and most have years of data to review when questions arise.
Granted, CBD oil has been approved, as Epidiolex, for different forms of epilepsy. That kind of regulation is a step forward, but the majority of people selling CBD oil are doing so with unregulated OTC forms.
These may work, but the lack of regulation means every one of these places can make their own formulations, purities, and strengths. In some respects it’s a throwback to the era of patent medicines, where each pharmacy was free to whip up their own concoctions, label them as treatments for whatever they wished, and advertise and sell them.
The Food and Drug Administration, however, continues to take an ostrich approach. At their level these OTC agents are illegal and cannot be sold or marketed. At the same time, though, the restrictions overall are not being enforced. This gives the impression that there is nothing wrong with selling them.
Let’s look at morphine, an effective pain reliever and controlled substance. It’s tightly regulated, as it should be. But what if those regulations were ignored? What if, in addition to it being available by prescription, it were sold OTC in perhaps weaker but unregulated strengths and forms, with a variety of unscientific claims made for its benefits?
I don’t see anyone getting away with doing that.
Like I said earlier, I have nothing against CBD oil. But I do think it should have to go through the same approval process as any other medication, with specific strengths, dosing, benefits, and side effects determined, and enforceable regulations around its manufacturing, sale, and use.
Anything less is snake oil.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Gabapentinoids associated with suicidal behavior, overdose
Young patients might be at increased risk of suicidal behavior, unintentional overdose, injuries, and traffic incidents during treatment periods with gabapentinoids, compared with periods without treatment with those medications, a cohort study of almost 200,000 people shows. Pregabalin is associated with higher hazards of those outcomes than is gabapentin, and the associations are strongest in patients aged 15-24 years, the researchers reported.
“If our findings are triangulated with other forms of evidence, ,” wrote Yasmina Molero, PhD, and associates. “Further restrictions for off-label prescription may need consideration.” The study was published in BMJ.
The use of gabapentinoids has risen in the United States (JAMA Intern Med. 2018;178[2]:292-4), and overdose deaths tied to gabapentin have led some states to explore reclassification of the drug as a controlled substance (Risk Manag Healthc Policy. 2018;11:109-16). In the United Kingdom, gabapentinoids are being reclassified as a class C controlled drug because of concerns about the risk of addiction, overdose, and safety, wrote Dr. Molero of the department of psychiatry at Warneford Hospital at the University of Oxford, England, and associates.
To study associations between gabapentinoids and adverse outcomes related to coordination, mental health, and criminality, Dr. Molero and her associates analyzed data from 191,973 people from the Swedish Prescribed Drug Register who collected prescriptions for pregabalin or gabapentin between 2006 and 2013. The researchers included patients aged 15 years and older in their analyses.
They examined suicidal behavior, unintentional overdoses, head or body injuries, road traffic incidents and offenses, and arrests for violent crime using the Swedish Patient Register and the National Crime Register. In addition, they defined suicidal behavior as emergency hospital visits attributable to self-injurious behavior or suicide attempt, or death by suicide. Unintentional overdoses were defined as emergency hospital visits or death attributable to poisoning by illicit drugs, medications, or biologic substances; accidental poisoning by noxious substances; or acute intoxications and overdoses by alcohol and illicit drugs, excluding intentional self-poisoning, wrote Dr. Molero, who is affiliated with the Karolinska Institute in Stockholm, and her associates.
Of the nearly 192,000 participants who collected prescriptions of gabapentinoids on at least two consecutive occasions, 120,664 received pregabalin, and 85,360 received gabapentin; 14,051 of the participants received both drugs. Fifty-nine percent were women, and most patients were aged 45 or older.
During the study period, 10,026 participants (5.2%) were treated for suicidal behavior or died from suicide, 17,144 participants (8.9%) experienced an unintentional overdose, and 12,070 participants (6.3%) had a road traffic incident or offense. In addition, 70,522 participants (36.7%) had head or body injuries, and 7,984 participants (4.1%) were arrested for a violent crime.
The study used a within-individual design that compared when a person was taking a gabapentinoid with when he or she was not. During treatment periods, participants were at increased risk of suicidal behavior or death from suicide (age-adjusted hazard ratio, 1.26), unintentional overdose (1.24), head or body injuries (1.22), and road traffic incidents or offenses (1.13). Associations with arrests for violent crime were not significant.
Gabapentinoid treatment was associated with increased hazards of suicidal behavior in people young than 55 years, but hazards were reduced or not significant in participants aged 55 years and older. Participants aged 15-24 years had the highest hazards of suicidal behavior (1.67).
In a sensitivity analysis, the researchers examined participants who had a diagnosis of comorbid epilepsy, psychiatric disorders, or musculoskeletal disorders before the start of gabapentinoid treatment. Among patients with comorbid epilepsy, gabapentinoids were not significantly associated with suicidal behavior and were associated with reduced hazards for all other outcomes.
“In comorbid psychiatric disorders, gabapentinoids were associated with lower risk for all outcomes,” the researchers said. Among patients with comorbid musculoskeletal disorders, gabapentinoids were associated with reductions in head or body injuries, traffic incidents, and arrests for violent crime.
Dr. Molero and her associates noted that they lacked information about alcohol and drug use, as well as treatment adherence and the conditions for which gabapentinoids had been prescribed. Furthermore, differences in prescription practices and outcome rates might affect the generalizability of the results to other countries.
The different results for pregabalin and gabapentin “could be due to their different pharmacodynamic and pharmacokinetic profiles; pregabalin has a higher potency, greater bioavailability, and quicker absorption than gabapentin. Pregabalin also has been associated with withdrawal symptoms following rapid discontinuation, which could be related to suicidal behavior,” Dr. Molero and colleagues said. “The reduced hazards in older people could reflect pharmacodynamic differences related to age, less concurrent use of alcohol or drugs, different indications for treatment, or reduced symptom severity of underlying conditions.”
The Wellcome Trust, Swedish Research Council, and Karolinska Institute supported the study. The authors had no disclosures relevant to the study. One author reported grants from Shire and Evolan and has served as a speaker for Shire.
SOURCE: Molero Y et al. BMJ. 2019 Jun 12. doi: 10.1136/bmj.l2147.
The findings by Molero et al. advance clinical knowledge about the drug class of gabapentinoids, wrote Derek K. Tracy, MB BCh. Though the study does not establish causality, it does rely on a solid, large dataset. The study shows the importance of uncoupling pregabalin and gabapentin. Both drugs are indeed gabapentinoids, but their use can lead to different outcomes, depending on the age of patients. For example, pregabalin – not gabapentin – appears tied to higher risks of harm. The demographic group that is most vulnerable is patients aged 15-24, the researchers found. Factors driving those age-related differences in risks tied to the drugs need to be understood.
Dr. Tracy is a consultant psychiatrist at Queen Mary’s Hospital in London. He is a trustee of the charity Mentor and has received honoraria from Janssen for delivering educational talks on novel psychoactive substances. His comments were adapted from an editorial (BMJ. 2019 Jun 12. doi: 10.1136/bmj.14021 ).
The findings by Molero et al. advance clinical knowledge about the drug class of gabapentinoids, wrote Derek K. Tracy, MB BCh. Though the study does not establish causality, it does rely on a solid, large dataset. The study shows the importance of uncoupling pregabalin and gabapentin. Both drugs are indeed gabapentinoids, but their use can lead to different outcomes, depending on the age of patients. For example, pregabalin – not gabapentin – appears tied to higher risks of harm. The demographic group that is most vulnerable is patients aged 15-24, the researchers found. Factors driving those age-related differences in risks tied to the drugs need to be understood.
Dr. Tracy is a consultant psychiatrist at Queen Mary’s Hospital in London. He is a trustee of the charity Mentor and has received honoraria from Janssen for delivering educational talks on novel psychoactive substances. His comments were adapted from an editorial (BMJ. 2019 Jun 12. doi: 10.1136/bmj.14021 ).
The findings by Molero et al. advance clinical knowledge about the drug class of gabapentinoids, wrote Derek K. Tracy, MB BCh. Though the study does not establish causality, it does rely on a solid, large dataset. The study shows the importance of uncoupling pregabalin and gabapentin. Both drugs are indeed gabapentinoids, but their use can lead to different outcomes, depending on the age of patients. For example, pregabalin – not gabapentin – appears tied to higher risks of harm. The demographic group that is most vulnerable is patients aged 15-24, the researchers found. Factors driving those age-related differences in risks tied to the drugs need to be understood.
Dr. Tracy is a consultant psychiatrist at Queen Mary’s Hospital in London. He is a trustee of the charity Mentor and has received honoraria from Janssen for delivering educational talks on novel psychoactive substances. His comments were adapted from an editorial (BMJ. 2019 Jun 12. doi: 10.1136/bmj.14021 ).
Young patients might be at increased risk of suicidal behavior, unintentional overdose, injuries, and traffic incidents during treatment periods with gabapentinoids, compared with periods without treatment with those medications, a cohort study of almost 200,000 people shows. Pregabalin is associated with higher hazards of those outcomes than is gabapentin, and the associations are strongest in patients aged 15-24 years, the researchers reported.
“If our findings are triangulated with other forms of evidence, ,” wrote Yasmina Molero, PhD, and associates. “Further restrictions for off-label prescription may need consideration.” The study was published in BMJ.
The use of gabapentinoids has risen in the United States (JAMA Intern Med. 2018;178[2]:292-4), and overdose deaths tied to gabapentin have led some states to explore reclassification of the drug as a controlled substance (Risk Manag Healthc Policy. 2018;11:109-16). In the United Kingdom, gabapentinoids are being reclassified as a class C controlled drug because of concerns about the risk of addiction, overdose, and safety, wrote Dr. Molero of the department of psychiatry at Warneford Hospital at the University of Oxford, England, and associates.
To study associations between gabapentinoids and adverse outcomes related to coordination, mental health, and criminality, Dr. Molero and her associates analyzed data from 191,973 people from the Swedish Prescribed Drug Register who collected prescriptions for pregabalin or gabapentin between 2006 and 2013. The researchers included patients aged 15 years and older in their analyses.
They examined suicidal behavior, unintentional overdoses, head or body injuries, road traffic incidents and offenses, and arrests for violent crime using the Swedish Patient Register and the National Crime Register. In addition, they defined suicidal behavior as emergency hospital visits attributable to self-injurious behavior or suicide attempt, or death by suicide. Unintentional overdoses were defined as emergency hospital visits or death attributable to poisoning by illicit drugs, medications, or biologic substances; accidental poisoning by noxious substances; or acute intoxications and overdoses by alcohol and illicit drugs, excluding intentional self-poisoning, wrote Dr. Molero, who is affiliated with the Karolinska Institute in Stockholm, and her associates.
Of the nearly 192,000 participants who collected prescriptions of gabapentinoids on at least two consecutive occasions, 120,664 received pregabalin, and 85,360 received gabapentin; 14,051 of the participants received both drugs. Fifty-nine percent were women, and most patients were aged 45 or older.
During the study period, 10,026 participants (5.2%) were treated for suicidal behavior or died from suicide, 17,144 participants (8.9%) experienced an unintentional overdose, and 12,070 participants (6.3%) had a road traffic incident or offense. In addition, 70,522 participants (36.7%) had head or body injuries, and 7,984 participants (4.1%) were arrested for a violent crime.
The study used a within-individual design that compared when a person was taking a gabapentinoid with when he or she was not. During treatment periods, participants were at increased risk of suicidal behavior or death from suicide (age-adjusted hazard ratio, 1.26), unintentional overdose (1.24), head or body injuries (1.22), and road traffic incidents or offenses (1.13). Associations with arrests for violent crime were not significant.
Gabapentinoid treatment was associated with increased hazards of suicidal behavior in people young than 55 years, but hazards were reduced or not significant in participants aged 55 years and older. Participants aged 15-24 years had the highest hazards of suicidal behavior (1.67).
In a sensitivity analysis, the researchers examined participants who had a diagnosis of comorbid epilepsy, psychiatric disorders, or musculoskeletal disorders before the start of gabapentinoid treatment. Among patients with comorbid epilepsy, gabapentinoids were not significantly associated with suicidal behavior and were associated with reduced hazards for all other outcomes.
“In comorbid psychiatric disorders, gabapentinoids were associated with lower risk for all outcomes,” the researchers said. Among patients with comorbid musculoskeletal disorders, gabapentinoids were associated with reductions in head or body injuries, traffic incidents, and arrests for violent crime.
Dr. Molero and her associates noted that they lacked information about alcohol and drug use, as well as treatment adherence and the conditions for which gabapentinoids had been prescribed. Furthermore, differences in prescription practices and outcome rates might affect the generalizability of the results to other countries.
The different results for pregabalin and gabapentin “could be due to their different pharmacodynamic and pharmacokinetic profiles; pregabalin has a higher potency, greater bioavailability, and quicker absorption than gabapentin. Pregabalin also has been associated with withdrawal symptoms following rapid discontinuation, which could be related to suicidal behavior,” Dr. Molero and colleagues said. “The reduced hazards in older people could reflect pharmacodynamic differences related to age, less concurrent use of alcohol or drugs, different indications for treatment, or reduced symptom severity of underlying conditions.”
The Wellcome Trust, Swedish Research Council, and Karolinska Institute supported the study. The authors had no disclosures relevant to the study. One author reported grants from Shire and Evolan and has served as a speaker for Shire.
SOURCE: Molero Y et al. BMJ. 2019 Jun 12. doi: 10.1136/bmj.l2147.
Young patients might be at increased risk of suicidal behavior, unintentional overdose, injuries, and traffic incidents during treatment periods with gabapentinoids, compared with periods without treatment with those medications, a cohort study of almost 200,000 people shows. Pregabalin is associated with higher hazards of those outcomes than is gabapentin, and the associations are strongest in patients aged 15-24 years, the researchers reported.
“If our findings are triangulated with other forms of evidence, ,” wrote Yasmina Molero, PhD, and associates. “Further restrictions for off-label prescription may need consideration.” The study was published in BMJ.
The use of gabapentinoids has risen in the United States (JAMA Intern Med. 2018;178[2]:292-4), and overdose deaths tied to gabapentin have led some states to explore reclassification of the drug as a controlled substance (Risk Manag Healthc Policy. 2018;11:109-16). In the United Kingdom, gabapentinoids are being reclassified as a class C controlled drug because of concerns about the risk of addiction, overdose, and safety, wrote Dr. Molero of the department of psychiatry at Warneford Hospital at the University of Oxford, England, and associates.
To study associations between gabapentinoids and adverse outcomes related to coordination, mental health, and criminality, Dr. Molero and her associates analyzed data from 191,973 people from the Swedish Prescribed Drug Register who collected prescriptions for pregabalin or gabapentin between 2006 and 2013. The researchers included patients aged 15 years and older in their analyses.
They examined suicidal behavior, unintentional overdoses, head or body injuries, road traffic incidents and offenses, and arrests for violent crime using the Swedish Patient Register and the National Crime Register. In addition, they defined suicidal behavior as emergency hospital visits attributable to self-injurious behavior or suicide attempt, or death by suicide. Unintentional overdoses were defined as emergency hospital visits or death attributable to poisoning by illicit drugs, medications, or biologic substances; accidental poisoning by noxious substances; or acute intoxications and overdoses by alcohol and illicit drugs, excluding intentional self-poisoning, wrote Dr. Molero, who is affiliated with the Karolinska Institute in Stockholm, and her associates.
Of the nearly 192,000 participants who collected prescriptions of gabapentinoids on at least two consecutive occasions, 120,664 received pregabalin, and 85,360 received gabapentin; 14,051 of the participants received both drugs. Fifty-nine percent were women, and most patients were aged 45 or older.
During the study period, 10,026 participants (5.2%) were treated for suicidal behavior or died from suicide, 17,144 participants (8.9%) experienced an unintentional overdose, and 12,070 participants (6.3%) had a road traffic incident or offense. In addition, 70,522 participants (36.7%) had head or body injuries, and 7,984 participants (4.1%) were arrested for a violent crime.
The study used a within-individual design that compared when a person was taking a gabapentinoid with when he or she was not. During treatment periods, participants were at increased risk of suicidal behavior or death from suicide (age-adjusted hazard ratio, 1.26), unintentional overdose (1.24), head or body injuries (1.22), and road traffic incidents or offenses (1.13). Associations with arrests for violent crime were not significant.
Gabapentinoid treatment was associated with increased hazards of suicidal behavior in people young than 55 years, but hazards were reduced or not significant in participants aged 55 years and older. Participants aged 15-24 years had the highest hazards of suicidal behavior (1.67).
In a sensitivity analysis, the researchers examined participants who had a diagnosis of comorbid epilepsy, psychiatric disorders, or musculoskeletal disorders before the start of gabapentinoid treatment. Among patients with comorbid epilepsy, gabapentinoids were not significantly associated with suicidal behavior and were associated with reduced hazards for all other outcomes.
“In comorbid psychiatric disorders, gabapentinoids were associated with lower risk for all outcomes,” the researchers said. Among patients with comorbid musculoskeletal disorders, gabapentinoids were associated with reductions in head or body injuries, traffic incidents, and arrests for violent crime.
Dr. Molero and her associates noted that they lacked information about alcohol and drug use, as well as treatment adherence and the conditions for which gabapentinoids had been prescribed. Furthermore, differences in prescription practices and outcome rates might affect the generalizability of the results to other countries.
The different results for pregabalin and gabapentin “could be due to their different pharmacodynamic and pharmacokinetic profiles; pregabalin has a higher potency, greater bioavailability, and quicker absorption than gabapentin. Pregabalin also has been associated with withdrawal symptoms following rapid discontinuation, which could be related to suicidal behavior,” Dr. Molero and colleagues said. “The reduced hazards in older people could reflect pharmacodynamic differences related to age, less concurrent use of alcohol or drugs, different indications for treatment, or reduced symptom severity of underlying conditions.”
The Wellcome Trust, Swedish Research Council, and Karolinska Institute supported the study. The authors had no disclosures relevant to the study. One author reported grants from Shire and Evolan and has served as a speaker for Shire.
SOURCE: Molero Y et al. BMJ. 2019 Jun 12. doi: 10.1136/bmj.l2147.
FROM BMJ
Key clinical point: Patients might be at increased risk of suicidal behavior, unintentional overdose, head and body injuries, and traffic incidents during periods of treatment with gabapentinoids. Pregabalin is associated with higher hazards of these outcomes than is gabapentin, and the associations are strongest in patients aged 15-24 years.
Major finding: During treatment periods, patients were at increased risk of suicidal behavior or death from suicide (age-adjusted hazard ratio, 1.26), unintentional overdose (1.24), head or body injuries (1.22), and road traffic incidents or offenses (1.13).
Study details: An analysis of data from 191,973 people from the Swedish Prescribed Drug Register, which collected prescriptions for pregabalin or gabapentin between 2006 and 2013.
Disclosures: The Wellcome Trust, Swedish Research Council, and Karolinska Institute supported the study. The authors had no relevant disclosures. One author reported grants from Shire and Evolan, and has served as a speaker for Shire.
Source: Molero Y et al. BMJ. 2019 Jun 12. doi: 10.1136/bmj.l2147.
Induced seizures as effective as spontaneous in identifying epileptic generator
according to a study of patients with focal drug-resistant epilepsy.
“This finding might lead to a more time-efficient intracranial presurgical investigation of focal epilepsy by reducing the need to record spontaneous seizures,” wrote Carolina Cuello Oderiz, MD, formerly of McGill University, and her coauthors. The study was published in JAMA Neurology.
To determine if cortical stimulation-induced seizures and subsequent removal of the informed seizure-onset zone (SOZ) could lead to good surgical outcomes, the researchers selected 103 patients with focal drug-resistant epilepsy who underwent stereoelectroencephalography (SEEG). All participants had to have undergone cortical stimulation during SEEG, followed by open epilepsy surgical procedure with a minimum 1-year follow-up. In addition, complete brain imaging for exact localization of individual electrode contacts and resection cavity was also required.
Of the 103 patients, 59 (57.3%) had cortical stimulation-induced seizures. The percentage of these patients in the good outcome group was higher than in the poor outcome group (70.5% versus 47.5%). The median percentage of resected cortical stimulation-informed SOZ contacts was also higher in the good than in the poor outcome group (63.2% versus 33.3%). The results were similar for spontaneous seizures, where the median percentage of resected contacts of the spontaneous SOZ was 57.1% in the good outcome group and 32.7% in the poor outcome group.
The coauthors noted their study’s limitations, including the exclusion of many patients due to the need for hi-resolution neuroimaging and sufficient postsurgical imaging and follow-up. They added that the strict criteria were “key to the main outcome of this study,” however, and noted that generalizability of the data was supported by similar rates in excluded patients.
The study was supported by grants from the Canadian Institute of Health Research and the Savoy Epilepsy Foundation. Numerous authors reported receiving grants, personal fees, and other funding from organizations like the Montreal Neurological Institute and various pharmaceutical companies.
Dr. Cuello Oderiz is now at SUNY Upstate Medical University, Syracuse, N.Y.
SOURCE: Cuello Oderiz C et al. JAMA Neurol. 2019 Jun 10. doi: 10.1001/jamaneurol.2019.1464.
according to a study of patients with focal drug-resistant epilepsy.
“This finding might lead to a more time-efficient intracranial presurgical investigation of focal epilepsy by reducing the need to record spontaneous seizures,” wrote Carolina Cuello Oderiz, MD, formerly of McGill University, and her coauthors. The study was published in JAMA Neurology.
To determine if cortical stimulation-induced seizures and subsequent removal of the informed seizure-onset zone (SOZ) could lead to good surgical outcomes, the researchers selected 103 patients with focal drug-resistant epilepsy who underwent stereoelectroencephalography (SEEG). All participants had to have undergone cortical stimulation during SEEG, followed by open epilepsy surgical procedure with a minimum 1-year follow-up. In addition, complete brain imaging for exact localization of individual electrode contacts and resection cavity was also required.
Of the 103 patients, 59 (57.3%) had cortical stimulation-induced seizures. The percentage of these patients in the good outcome group was higher than in the poor outcome group (70.5% versus 47.5%). The median percentage of resected cortical stimulation-informed SOZ contacts was also higher in the good than in the poor outcome group (63.2% versus 33.3%). The results were similar for spontaneous seizures, where the median percentage of resected contacts of the spontaneous SOZ was 57.1% in the good outcome group and 32.7% in the poor outcome group.
The coauthors noted their study’s limitations, including the exclusion of many patients due to the need for hi-resolution neuroimaging and sufficient postsurgical imaging and follow-up. They added that the strict criteria were “key to the main outcome of this study,” however, and noted that generalizability of the data was supported by similar rates in excluded patients.
The study was supported by grants from the Canadian Institute of Health Research and the Savoy Epilepsy Foundation. Numerous authors reported receiving grants, personal fees, and other funding from organizations like the Montreal Neurological Institute and various pharmaceutical companies.
Dr. Cuello Oderiz is now at SUNY Upstate Medical University, Syracuse, N.Y.
SOURCE: Cuello Oderiz C et al. JAMA Neurol. 2019 Jun 10. doi: 10.1001/jamaneurol.2019.1464.
according to a study of patients with focal drug-resistant epilepsy.
“This finding might lead to a more time-efficient intracranial presurgical investigation of focal epilepsy by reducing the need to record spontaneous seizures,” wrote Carolina Cuello Oderiz, MD, formerly of McGill University, and her coauthors. The study was published in JAMA Neurology.
To determine if cortical stimulation-induced seizures and subsequent removal of the informed seizure-onset zone (SOZ) could lead to good surgical outcomes, the researchers selected 103 patients with focal drug-resistant epilepsy who underwent stereoelectroencephalography (SEEG). All participants had to have undergone cortical stimulation during SEEG, followed by open epilepsy surgical procedure with a minimum 1-year follow-up. In addition, complete brain imaging for exact localization of individual electrode contacts and resection cavity was also required.
Of the 103 patients, 59 (57.3%) had cortical stimulation-induced seizures. The percentage of these patients in the good outcome group was higher than in the poor outcome group (70.5% versus 47.5%). The median percentage of resected cortical stimulation-informed SOZ contacts was also higher in the good than in the poor outcome group (63.2% versus 33.3%). The results were similar for spontaneous seizures, where the median percentage of resected contacts of the spontaneous SOZ was 57.1% in the good outcome group and 32.7% in the poor outcome group.
The coauthors noted their study’s limitations, including the exclusion of many patients due to the need for hi-resolution neuroimaging and sufficient postsurgical imaging and follow-up. They added that the strict criteria were “key to the main outcome of this study,” however, and noted that generalizability of the data was supported by similar rates in excluded patients.
The study was supported by grants from the Canadian Institute of Health Research and the Savoy Epilepsy Foundation. Numerous authors reported receiving grants, personal fees, and other funding from organizations like the Montreal Neurological Institute and various pharmaceutical companies.
Dr. Cuello Oderiz is now at SUNY Upstate Medical University, Syracuse, N.Y.
SOURCE: Cuello Oderiz C et al. JAMA Neurol. 2019 Jun 10. doi: 10.1001/jamaneurol.2019.1464.
FROM JAMA NEUROLOGY
Key clinical point: Seizures induced by cortical stimulation and spontaneous seizures both led to a similar percentage of good surgical outcomes in patients with epilepsy.
Major finding: The percentage of patients who received cortical stimulation-induced seizures in the good outcome group was higher than in the poor outcome group (70.5% versus 47.5%).
Study details: A cohort study of 103 patients with focal drug-resistant epilepsy who underwent stereoelectroencephalography.
Disclosures: The study was supported by grants from the Canadian Institute of Health Research and the Savoy Epilepsy Foundation. Numerous authors reported receiving grants, personal fees, and other funding from organizations like the Montreal Neurological Institute and various pharmaceutical companies.
Source: Cuello Oderiz C et al. JAMA Neurol. 2019 Jun 10. doi: 10.1001/jamaneurol.2019.1464.