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Newly approved drug improves sleep onset in insomnia
In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.
Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.
“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.
The findings were published in the February issue of The Lancet Neurology.
Two trials, three doses
Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.
To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.
In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.
During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.
Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.
The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.
The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
Dose-dependent effects
At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.
LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.
At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.
In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.
Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
Longer studies needed
In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.
However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”
He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.
Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.
Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.
Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.
The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.
A version of this article first appeared on Medscape.com.
In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.
Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.
“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.
The findings were published in the February issue of The Lancet Neurology.
Two trials, three doses
Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.
To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.
In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.
During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.
Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.
The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.
The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
Dose-dependent effects
At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.
LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.
At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.
In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.
Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
Longer studies needed
In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.
However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”
He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.
Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.
Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.
Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.
The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.
A version of this article first appeared on Medscape.com.
In the first of two studies, a 50-mg dose of daridorexant was associated with a reduction in latency to persistent sleep (LPS) of 11.7 minutes at month 3 versus placebo. The drug also was associated with improved daytime function.
Based on these results, the Food and Drug Administration approved daridorexant for the treatment of insomnia in adults earlier in January.
“The study shows that it is a really good drug that works differently from most other drugs,” said Emmanuel Mignot, MD, PhD, professor of sleep medicine at Stanford (Calif.) University. “It’s more specific to sleep,” Dr. Mignot added.
The findings were published in the February issue of The Lancet Neurology.
Two trials, three doses
Daridorexant is a dual orexin receptor antagonist intended to reduce excessive wakefulness. The investigators hypothesized that, because of its therapeutic target, the drug would not cause sleepiness on the morning after administration.
To examine daridorexant’s safety and efficacy, the researchers conducted two double-blind, parallel-group, phase 3 trials. Eligible participants were aged 18 years or older, had moderate to severe insomnia disorder, and had a self-reported history of disturbed sleep at least 3 nights per week for at least 3 months before screening.
In study 1, investigators randomly assigned participants in groups of equal size to daridorexant 25 mg, 50 mg, or placebo. In study 2, participants were randomly assigned to daridorexant 10 mg, 25 mg, or placebo.
During a placebo run-in period, participants underwent polysomnography on two consecutive nights to define baseline values. At the end of months 1 and 3 of the treatment period, participants again underwent 2 nights of polysomnography. A final night of polysomnography occurred during the placebo run-out period.
Self-assessments included the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). This questionnaire, to which participants responded daily, is designed to measure the daytime impairments related to insomnia. The IDSIQ questions focus on sleepiness, mood, alertness, and cognition.
The study’s primary endpoints were change from baseline in wake after sleep onset (WASO) and LPS at months 1 and 3. Secondary endpoints were change from baseline in self-reported total sleep time and change in the IDSIQ sleepiness domain score at months 1 and 3.
The investigators enrolled 930 participants in study 1 and 924 in study 2. In each study, more than two-thirds of participants were women, 39% were aged 65 or older, and demographic and baseline characteristics were similar between treatment groups.
Dose-dependent effects
At month 1 in study 1, WASO was reduced by 22.8 minutes (P < .0001) in patients who received the 50-mg dose and by 12.2 minutes (P < .0001) in the 25-mg dose. At month 3, WASO was reduced by 18.3 minutes (P < .0001) in those assigned to 50 mg and by 11.9 minutes (P < .0001) in those assigned to 25 mg.
LPS was reduced by 11.4 minutes (P < .0001) at month 1 and by 11.7 minutes (P < .0001) at month 3 with the 50-mg dose versus placebo. LPS was reduced by 8.3 minutes (P = .0005) at month 1 and by 7.6 minutes (P = .0015) at month 3 with the 25-mg dose versus placebo.
At both time points, self-reported total sleep time was significantly increased and the IDSIQ sleepiness score significantly improved with the 50-mg dose. The 25-mg dose was associated with significant improvements in self-reported total sleep time at both time points, but not with significant improvements in IDSIQ sleepiness score.
In study 2, the 25-mg dose was associated with significant reductions in WASO at month 1 (11.6 minutes, P = .0001) and month 3 (10.3 minutes, P = .0028) compared with placebo. The 25-mg dose was not associated with significant differences in LPS at either time point, however.
Similarly, the 25-mg dose was associated with improvements in self-reported total sleep time, but not with the IDSIQ sleepiness score. The 10-mg dose was not associated with improvements on any endpoint compared with placebo.
Longer studies needed
In an accompanying editorial, Kai Spiegelhalder, PhD, University of Freiburg, Germany, and colleagues pointed out that although insomnia disorder is defined by self-reported difficulty initiating or maintaining sleep, none of the primary or secondary endpoints in these trials addressed these symptoms.
However, Dr. Mignot noted the use of the IDSIQ scale is the most interesting aspect of the study. Although difficulty with concentration and mood impairment are major symptoms of insomnia, they are often neglected. “This drug was reversing the daytime impairment that insomniacs have,” said Dr. Mignot. “We now need to systematically study people not only for the effect on sleep, but also that it makes them feel better the day after.”
He added that most of the current hypnotics were not developed to treat insomnia. Daridorexant, in contrast, targets the wake-promoting orexin system. “It works more selectively on sleep and not on other things. Most of the other sleeping pills have more complex effects on the brain,” Dr. Mignot said.
Commenting on the study, John Winkelman, MD, PhD, professor of psychiatry at Harvard Medical School, Boston, said the low prevalence of side effects associated with daridorexant was remarkable. “This is not what most of the benzodiazepine receptor agonists looked like,” said Dr. Winkelman, who was not involved with the research.
Many insomnia drugs affect transmitter systems that are widespread in the brain, thus provoking side effects. But orexin-receptor antagonists “don’t seem to produce a lot of side effects,” he noted.
Although the study duration was reasonable, longer studies will be necessary, he added. “And it would be nice to see comparative data. Prescribers want to see some context.” said Dr. Winkelman.
The study was funded by Idorsia Pharmaceuticals. Dr. Mignot reported receiving research or clinical trial funding from Axsome, Jazz Pharmaceuticals, Avadel, Apple, Huami, Sunovion, and Takeda. He has also received consulting fees or speakers’ conference reimbursement from Idorsia, Centessa Pharmaceuticals, Jazz Pharmaceuticals, Avadel, Dreem, and Takeda. Dr. Winkelman has consulted for Idorsia and has participated in investigator-initiated studies supported by Merck.
A version of this article first appeared on Medscape.com.
FROM THE LANCET NEUROLOGY
Dairy intake may increase risk of Parkinson’s disease in men
according to investigators. Men of European ancestry with a genetic marker predicting dairy consumption had significantly greater risk of Parkinson’s disease than individuals without the marker, suggesting a causal relationship between dairy intake and Parkinson’s disease, lead author Cloé Domenighetti, MSc, a PhD student at UVSQ, Université Paris Sud, and colleagues reported.
“Previous studies highlighted dairy intake as a risk factor of Parkinson’s disease,” the investigators wrote in Movement Disorders. “A meta-analysis of prospective studies reported a 40% increased Parkinson’s disease risk in participants with the highest intake. It is unclear whether the association is causal or explained by confounding or reverse causation, given the long prodromal phase of Parkinson’s disease.”
A Mendelian randomization study
The investigators evaluated this link by comparing 9,823 cases of Parkinson’s disease with 8,376 controls, all individuals of European ancestry from the Courage-Parkinson’s disease consortium, comprising 23 studies. Data were analyzed by two-sample Mendelian randomization, a technique that uses genotype to predict behavior, thereby replacing conventional methods of capturing behavior, such as questionnaires. In this case, the investigators screened all participants for rs4988235, a single-nucleotide polymorphism (SNP) upstream of the lactase gene that is well documented to predict dairy intake among individuals of European ancestry.
“Mendelian randomization uses genetic variants associated with exposures as instrumental variables to estimate causal relationships between exposures and outcomes,” the investigators wrote. “Mendelian randomization analyses are less likely to be biased by confounding or reverse causation than observational studies if a set of assumptions are met.”
The approach uncovered a significant association between rs4988235 and Parkinson’s disease, with a 70% increase in disease risk per one serving of dairy per day (odds ratio, 1.70; 95% confidence interval, 1.12-2.60; P = .013). Further analysis revealed that this finding was driven by men, who had a 2.5-fold increased risk of Parkinson’s disease per one serving per day (OR, 2.50; 95% CI, 1.37-4.56; P = .003) versus women, among whom there was no significant association (OR, 1.04; 95% CI, 0.56-1.92; P = .91). No significant associations were observed among individuals grouped by age or Parkinson’s disease duration.
“Our findings suggest that dairy intake increases Parkinson’s disease risk,” the investigators concluded. “Therefore, diets with limited milk intake (e.g., Mediterranean diet) may be beneficial with respect to Parkinson’s disease.”
Further evidence supporting a link between diet and Parkinson’s disease
According to Silke Appel-Cresswell, MD, Marg Meikle Professor for Parkinson’s Research at the University of British Columbia, Vancouver, the findings align with previous prospective cohort studies demonstrating an increased risk of Parkinson’s disease with greater consumption of dairy.
“What the current study adds,” Dr. Appel-Cresswell said, “is a complementary approach to assess the association where the risk of reverse causation and of confounding are minimized. Like in some of the previous studies, the authors find sex differences with an increased risk for men but not women.”
Dr. Appel-Cresswell noted that an increasing body of evidence supports a link between diet and Parkinson’s disease, including a study of her own published last year, which showed later onset of Parkinson’s disease among individuals with a Mediterranean-style diet.
“We are accumulating evidence for a role of diet (or more broadly, the food exposome) for the risk to develop Parkinson’s disease,” Dr. Appel-Cresswell said, noting that “key pieces are still missing, including mechanisms underlying associations, clinical trials in individuals with established Parkinson’s disease and – eventually – preventive interventions. This research is urgently needed and analyses will need to take sex differences and a large range of potential other factors into account.”
A ‘modest’ contributing factor?
Vikas Kotagal, MD, associate professor of neurology at the University of Michigan, Ann Arbor, offered a perspective on the study methodology, and suggested that a causal link between dairy intake and Parkinson’s disease, if present, is likely minimal.
“Limitations to the study include the fact that participants weren’t actually asked or tested for how much dairy they truly consumed,” Dr. Kotagal said*. “Their dairy intake was estimated based on their genetic background – there are certainly many assumptions baked into this analytic approach which may or may not be true. It is also worth noting the fact that this causal association was seen in men and not women, suggesting that even if dairy intake was truly causal, it is likely to be a modest contributing factor and not a significant cause of Parkinson’s disease in the broader population in general.”
Still, Dr. Kotagal agreed with Dr. Appel-Cresswell that underlying mechanisms need further investigation.
“The biggest takeaway here is to heighten the urgency for researchers and funders to explore whether factors that might cluster with dairy intake – including pesticide exposure in milk or even the make-up of bacterial populations in different peoples’ intestines – might deserve closer scrutiny as a missing link connecting dairy consumption to increased Parkinson’s disease risk,” Dr. Kotagal said.
Dietary advice
Considering all available evidence, Dr. Appel-Cresswell offered some dietary advice with benefits that may extend beyond prevention of Parkinson’s disease.
“From a clinical point of view, I suggest to limit dairy intake to a moderate amount,” she said. “Mediterranean diets so far have the best supporting evidence for a lower Parkinson’s disease risk, although data is lacking for benefits in established Parkinson’s disease. Given the low risk of the Mediterranean diet and the established benefits for a host of other medical conditions, this is generally a safe and delicious recommendation whether one is living with Parkinson’s or not.”
The study was supported by the European Union Joint Program for Neurodegenerative Disease Research, the National Centre of Excellence in Research on Parkinson’s Disease, the National Institutes of Health, and others. The investigators disclosed additional relationships with Astellas Pharma, Sanofi, Pfizer, and others. Dr. Kotagal and Dr. Appel-Cresswell reported no relevant conflicts of interest.
*Correction, 2/10/22: An earlier version of this article misstated Dr. Kotagal's name in certain instances, including a photo caption.
according to investigators. Men of European ancestry with a genetic marker predicting dairy consumption had significantly greater risk of Parkinson’s disease than individuals without the marker, suggesting a causal relationship between dairy intake and Parkinson’s disease, lead author Cloé Domenighetti, MSc, a PhD student at UVSQ, Université Paris Sud, and colleagues reported.
“Previous studies highlighted dairy intake as a risk factor of Parkinson’s disease,” the investigators wrote in Movement Disorders. “A meta-analysis of prospective studies reported a 40% increased Parkinson’s disease risk in participants with the highest intake. It is unclear whether the association is causal or explained by confounding or reverse causation, given the long prodromal phase of Parkinson’s disease.”
A Mendelian randomization study
The investigators evaluated this link by comparing 9,823 cases of Parkinson’s disease with 8,376 controls, all individuals of European ancestry from the Courage-Parkinson’s disease consortium, comprising 23 studies. Data were analyzed by two-sample Mendelian randomization, a technique that uses genotype to predict behavior, thereby replacing conventional methods of capturing behavior, such as questionnaires. In this case, the investigators screened all participants for rs4988235, a single-nucleotide polymorphism (SNP) upstream of the lactase gene that is well documented to predict dairy intake among individuals of European ancestry.
“Mendelian randomization uses genetic variants associated with exposures as instrumental variables to estimate causal relationships between exposures and outcomes,” the investigators wrote. “Mendelian randomization analyses are less likely to be biased by confounding or reverse causation than observational studies if a set of assumptions are met.”
The approach uncovered a significant association between rs4988235 and Parkinson’s disease, with a 70% increase in disease risk per one serving of dairy per day (odds ratio, 1.70; 95% confidence interval, 1.12-2.60; P = .013). Further analysis revealed that this finding was driven by men, who had a 2.5-fold increased risk of Parkinson’s disease per one serving per day (OR, 2.50; 95% CI, 1.37-4.56; P = .003) versus women, among whom there was no significant association (OR, 1.04; 95% CI, 0.56-1.92; P = .91). No significant associations were observed among individuals grouped by age or Parkinson’s disease duration.
“Our findings suggest that dairy intake increases Parkinson’s disease risk,” the investigators concluded. “Therefore, diets with limited milk intake (e.g., Mediterranean diet) may be beneficial with respect to Parkinson’s disease.”
Further evidence supporting a link between diet and Parkinson’s disease
According to Silke Appel-Cresswell, MD, Marg Meikle Professor for Parkinson’s Research at the University of British Columbia, Vancouver, the findings align with previous prospective cohort studies demonstrating an increased risk of Parkinson’s disease with greater consumption of dairy.
“What the current study adds,” Dr. Appel-Cresswell said, “is a complementary approach to assess the association where the risk of reverse causation and of confounding are minimized. Like in some of the previous studies, the authors find sex differences with an increased risk for men but not women.”
Dr. Appel-Cresswell noted that an increasing body of evidence supports a link between diet and Parkinson’s disease, including a study of her own published last year, which showed later onset of Parkinson’s disease among individuals with a Mediterranean-style diet.
“We are accumulating evidence for a role of diet (or more broadly, the food exposome) for the risk to develop Parkinson’s disease,” Dr. Appel-Cresswell said, noting that “key pieces are still missing, including mechanisms underlying associations, clinical trials in individuals with established Parkinson’s disease and – eventually – preventive interventions. This research is urgently needed and analyses will need to take sex differences and a large range of potential other factors into account.”
A ‘modest’ contributing factor?
Vikas Kotagal, MD, associate professor of neurology at the University of Michigan, Ann Arbor, offered a perspective on the study methodology, and suggested that a causal link between dairy intake and Parkinson’s disease, if present, is likely minimal.
“Limitations to the study include the fact that participants weren’t actually asked or tested for how much dairy they truly consumed,” Dr. Kotagal said*. “Their dairy intake was estimated based on their genetic background – there are certainly many assumptions baked into this analytic approach which may or may not be true. It is also worth noting the fact that this causal association was seen in men and not women, suggesting that even if dairy intake was truly causal, it is likely to be a modest contributing factor and not a significant cause of Parkinson’s disease in the broader population in general.”
Still, Dr. Kotagal agreed with Dr. Appel-Cresswell that underlying mechanisms need further investigation.
“The biggest takeaway here is to heighten the urgency for researchers and funders to explore whether factors that might cluster with dairy intake – including pesticide exposure in milk or even the make-up of bacterial populations in different peoples’ intestines – might deserve closer scrutiny as a missing link connecting dairy consumption to increased Parkinson’s disease risk,” Dr. Kotagal said.
Dietary advice
Considering all available evidence, Dr. Appel-Cresswell offered some dietary advice with benefits that may extend beyond prevention of Parkinson’s disease.
“From a clinical point of view, I suggest to limit dairy intake to a moderate amount,” she said. “Mediterranean diets so far have the best supporting evidence for a lower Parkinson’s disease risk, although data is lacking for benefits in established Parkinson’s disease. Given the low risk of the Mediterranean diet and the established benefits for a host of other medical conditions, this is generally a safe and delicious recommendation whether one is living with Parkinson’s or not.”
The study was supported by the European Union Joint Program for Neurodegenerative Disease Research, the National Centre of Excellence in Research on Parkinson’s Disease, the National Institutes of Health, and others. The investigators disclosed additional relationships with Astellas Pharma, Sanofi, Pfizer, and others. Dr. Kotagal and Dr. Appel-Cresswell reported no relevant conflicts of interest.
*Correction, 2/10/22: An earlier version of this article misstated Dr. Kotagal's name in certain instances, including a photo caption.
according to investigators. Men of European ancestry with a genetic marker predicting dairy consumption had significantly greater risk of Parkinson’s disease than individuals without the marker, suggesting a causal relationship between dairy intake and Parkinson’s disease, lead author Cloé Domenighetti, MSc, a PhD student at UVSQ, Université Paris Sud, and colleagues reported.
“Previous studies highlighted dairy intake as a risk factor of Parkinson’s disease,” the investigators wrote in Movement Disorders. “A meta-analysis of prospective studies reported a 40% increased Parkinson’s disease risk in participants with the highest intake. It is unclear whether the association is causal or explained by confounding or reverse causation, given the long prodromal phase of Parkinson’s disease.”
A Mendelian randomization study
The investigators evaluated this link by comparing 9,823 cases of Parkinson’s disease with 8,376 controls, all individuals of European ancestry from the Courage-Parkinson’s disease consortium, comprising 23 studies. Data were analyzed by two-sample Mendelian randomization, a technique that uses genotype to predict behavior, thereby replacing conventional methods of capturing behavior, such as questionnaires. In this case, the investigators screened all participants for rs4988235, a single-nucleotide polymorphism (SNP) upstream of the lactase gene that is well documented to predict dairy intake among individuals of European ancestry.
“Mendelian randomization uses genetic variants associated with exposures as instrumental variables to estimate causal relationships between exposures and outcomes,” the investigators wrote. “Mendelian randomization analyses are less likely to be biased by confounding or reverse causation than observational studies if a set of assumptions are met.”
The approach uncovered a significant association between rs4988235 and Parkinson’s disease, with a 70% increase in disease risk per one serving of dairy per day (odds ratio, 1.70; 95% confidence interval, 1.12-2.60; P = .013). Further analysis revealed that this finding was driven by men, who had a 2.5-fold increased risk of Parkinson’s disease per one serving per day (OR, 2.50; 95% CI, 1.37-4.56; P = .003) versus women, among whom there was no significant association (OR, 1.04; 95% CI, 0.56-1.92; P = .91). No significant associations were observed among individuals grouped by age or Parkinson’s disease duration.
“Our findings suggest that dairy intake increases Parkinson’s disease risk,” the investigators concluded. “Therefore, diets with limited milk intake (e.g., Mediterranean diet) may be beneficial with respect to Parkinson’s disease.”
Further evidence supporting a link between diet and Parkinson’s disease
According to Silke Appel-Cresswell, MD, Marg Meikle Professor for Parkinson’s Research at the University of British Columbia, Vancouver, the findings align with previous prospective cohort studies demonstrating an increased risk of Parkinson’s disease with greater consumption of dairy.
“What the current study adds,” Dr. Appel-Cresswell said, “is a complementary approach to assess the association where the risk of reverse causation and of confounding are minimized. Like in some of the previous studies, the authors find sex differences with an increased risk for men but not women.”
Dr. Appel-Cresswell noted that an increasing body of evidence supports a link between diet and Parkinson’s disease, including a study of her own published last year, which showed later onset of Parkinson’s disease among individuals with a Mediterranean-style diet.
“We are accumulating evidence for a role of diet (or more broadly, the food exposome) for the risk to develop Parkinson’s disease,” Dr. Appel-Cresswell said, noting that “key pieces are still missing, including mechanisms underlying associations, clinical trials in individuals with established Parkinson’s disease and – eventually – preventive interventions. This research is urgently needed and analyses will need to take sex differences and a large range of potential other factors into account.”
A ‘modest’ contributing factor?
Vikas Kotagal, MD, associate professor of neurology at the University of Michigan, Ann Arbor, offered a perspective on the study methodology, and suggested that a causal link between dairy intake and Parkinson’s disease, if present, is likely minimal.
“Limitations to the study include the fact that participants weren’t actually asked or tested for how much dairy they truly consumed,” Dr. Kotagal said*. “Their dairy intake was estimated based on their genetic background – there are certainly many assumptions baked into this analytic approach which may or may not be true. It is also worth noting the fact that this causal association was seen in men and not women, suggesting that even if dairy intake was truly causal, it is likely to be a modest contributing factor and not a significant cause of Parkinson’s disease in the broader population in general.”
Still, Dr. Kotagal agreed with Dr. Appel-Cresswell that underlying mechanisms need further investigation.
“The biggest takeaway here is to heighten the urgency for researchers and funders to explore whether factors that might cluster with dairy intake – including pesticide exposure in milk or even the make-up of bacterial populations in different peoples’ intestines – might deserve closer scrutiny as a missing link connecting dairy consumption to increased Parkinson’s disease risk,” Dr. Kotagal said.
Dietary advice
Considering all available evidence, Dr. Appel-Cresswell offered some dietary advice with benefits that may extend beyond prevention of Parkinson’s disease.
“From a clinical point of view, I suggest to limit dairy intake to a moderate amount,” she said. “Mediterranean diets so far have the best supporting evidence for a lower Parkinson’s disease risk, although data is lacking for benefits in established Parkinson’s disease. Given the low risk of the Mediterranean diet and the established benefits for a host of other medical conditions, this is generally a safe and delicious recommendation whether one is living with Parkinson’s or not.”
The study was supported by the European Union Joint Program for Neurodegenerative Disease Research, the National Centre of Excellence in Research on Parkinson’s Disease, the National Institutes of Health, and others. The investigators disclosed additional relationships with Astellas Pharma, Sanofi, Pfizer, and others. Dr. Kotagal and Dr. Appel-Cresswell reported no relevant conflicts of interest.
*Correction, 2/10/22: An earlier version of this article misstated Dr. Kotagal's name in certain instances, including a photo caption.
FROM MOVEMENT DISORDERS
COVID brain fog is a ‘true neurologic condition’
early research suggests. Investigators found abnormalities in cerebrospinal fluid (CSF) and other risk factors, including diabetes and hypertension, present in individuals with mild COVID-19 experiencing persistent cognitive problems, often referred to as “brain fog.”
“We’re seeing changes to the [CSF] in the brain of most people who report cognitive changes,” said Joanna Hellmuth, MD, assistant professor of neurology, Memory and Aging Center, University of California, San Francisco. “We’re just in the beginning stages, but I hope this study will provide some legitimacy to this being a true neurologic condition.”
The study was published online Jan. 18, 2022, in Annals of Clinical and Translational Neurology.
No guidance
There is currently no guidance on how to identify patients with COVID-related cognitive changes, said Dr. Hellmuth. “The term ‘brain fog’ is not based in science or medicine, but that’s the most common term we use to describe this.”
The analysis included adults with confirmed SARS-CoV-2 infection not requiring hospitalization who were enrolled in the Long-term Impact of Infection with Novel Coronavirus study.
Participants underwent a structured interview that covered COVID-19 illness, past medical history, preexisting cognitive risk factors, medications, and cognitive symptoms following onset of COVID-19. They also completed an in-person battery of cognitive tests.
The analysis included 22 participants with at least one new cognitive symptom who had cognitive post-acute sequelae of SARS-CoV-2 infection (PASC). Ten cognitive controls reported no new cognitive symptoms after acute infection.
Participants were a median age of 41 years, had a median of 16 years of education, and were assessed a median of 10.1 months from their first COVID-19 symptom. There were no group differences in terms of age, gender, years of education, or distribution of race/ethnicity (all P > .05).
Among those with cognitive PASC, 43% reported cognitive symptoms starting 1 or more months after the first COVID symptom. About 29% reported cognitive changes started 2 or more months after their first COVID symptom.
“The immune system could be altered in some way after the infection, and perhaps that’s what’s contributing to these delayed onset cognitive changes,” said Dr. Hellmuth.
Compared with controls, participants with cognitive PASC had more preexisting cognitive risk factors (a median of 2.5 vs. 0; P = .03). These included hypertension and diabetes, which increase the risk of stroke, mild cognitive impairment, vascular dementia, traumatic brain injury, (TBI), learning disabilities, anxiety, depression, stimulant use, and ADHD, which may make the brain more vulnerable to executive functioning problems.
Dr. Hellmuth noted that the study wasn’t powered to determine whether any individual risk factor was associated with risk of cognitive changes.
As there are no published neuropsychological testing criteria for cognitive PASC, the researchers applied the equivalent criteria for HIV-associated neurocognitive disorder (HAND), a similar, virally associated cognitive disorder. Only 59% of those with cognitive PASC met equivalent HAND criteria for objective cognitive impairment versus 70% of cognitive controls. This, the investigators noted, highlights “the challenges and incongruities of using subjective, versus objective cognitive assessments for diagnosis.”
Is self-report enough?
While there is currently “nothing objective doctors can hang their hats on to say ‘you do’ or ‘you don’t’ have cognitive changes related to COVID,” using the HAND criteria is “not particularly helpful,” said Dr. Hellmuth. “Comparing an individual to a population-based norm in this case is really nuanced, and we shouldn’t rely on this solely to determine whether they do, or don’t, have cognitive changes.”
Perhaps self-reports in this case are “enough” said Dr. Hellmuth. “People know their brains better than anyone else, better than any doctor will.”
A total of 13 in the cognitive PASC group and 4 in the control group consented to a lumbar puncture. Cognitive PASC participants were older than controls (median of 47 vs. 28 years; P = .03) with no other between-group differences.
Overall, 77% of participants with cognitive PASC had a CSF abnormality, compared with 0% of cognitive controls (P = .01). CSF abnormalities included elevated protein levels with no other explainable cause in 2 of the 13 subjects with PASC, which Dr. Hellmuth said is typically a marker of inflammation.
Researchers also noted abnormal oligoclonal banding, a collection of antibodies, in the blood or brain fluid. These were identified in 69% of participants with cognitive PASC, compared with 0% of cognitive controls (P = .03).
“When we find this pattern in both blood and brain, it suggests a systemic inflammatory disorder,” although “we have no idea what these antibodies are targeting,” said Dr. Hellmuth.
The study represents “the very beginning stages” of PASC becoming a medical diagnosis “where doctors know what to call it, how to treat it, and how to do blood and cerebrospinal fluid tests to diagnose it,” said Dr. Hellmuth.
She hopes PASC will receive medical legitimacy just as TBI has. In years past, a player was hit on the head or had their “bell rung,” simply returned to the field. “Now that we understand the science, we call it a mild TBI or concussion, and we have a very different medical approach to it.”
A limitation of the study was the small sample size, which may hinder the results’ validity. In addition, the study demographics may not reflect the broader population of those impacted by PASC.
‘A first substantial step’
Commenting on the research, William Schaffner, MD, professor, division of infectious diseases, Vanderbilt University Medical Center, Nashville, Tenn., said the new results represent “a first substantial step on the road to trying to find out what’s going on” with COVID patients dealing with cognitive issues.
Dr. Schaffner noted that elevated protein levels, identified in some study subjects, “is usually a consequence of previous inflammation” and is “a very interesting” finding. “In people who are otherwise normal, if you do a lumbar puncture, you don’t find elevated proteins.”
However, he noted the “diversity of results” from CSF examinations. “A single pattern does not leap out.”
What the researchers are observing “is not just a phenomenon of the mind or just something psychological,” said Dr. Schaffner. “Something physical is going on here.”
The study was funded by grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. Dr. Hellmuth received grant support from the National Institutes of Health/NIMH supporting this work and personal fees for medical-legal consultation outside of the submitted work. Dr. Schaffner has disclosed not relevant financial relationships.
A version of this article first appeared on Medscape.com.
early research suggests. Investigators found abnormalities in cerebrospinal fluid (CSF) and other risk factors, including diabetes and hypertension, present in individuals with mild COVID-19 experiencing persistent cognitive problems, often referred to as “brain fog.”
“We’re seeing changes to the [CSF] in the brain of most people who report cognitive changes,” said Joanna Hellmuth, MD, assistant professor of neurology, Memory and Aging Center, University of California, San Francisco. “We’re just in the beginning stages, but I hope this study will provide some legitimacy to this being a true neurologic condition.”
The study was published online Jan. 18, 2022, in Annals of Clinical and Translational Neurology.
No guidance
There is currently no guidance on how to identify patients with COVID-related cognitive changes, said Dr. Hellmuth. “The term ‘brain fog’ is not based in science or medicine, but that’s the most common term we use to describe this.”
The analysis included adults with confirmed SARS-CoV-2 infection not requiring hospitalization who were enrolled in the Long-term Impact of Infection with Novel Coronavirus study.
Participants underwent a structured interview that covered COVID-19 illness, past medical history, preexisting cognitive risk factors, medications, and cognitive symptoms following onset of COVID-19. They also completed an in-person battery of cognitive tests.
The analysis included 22 participants with at least one new cognitive symptom who had cognitive post-acute sequelae of SARS-CoV-2 infection (PASC). Ten cognitive controls reported no new cognitive symptoms after acute infection.
Participants were a median age of 41 years, had a median of 16 years of education, and were assessed a median of 10.1 months from their first COVID-19 symptom. There were no group differences in terms of age, gender, years of education, or distribution of race/ethnicity (all P > .05).
Among those with cognitive PASC, 43% reported cognitive symptoms starting 1 or more months after the first COVID symptom. About 29% reported cognitive changes started 2 or more months after their first COVID symptom.
“The immune system could be altered in some way after the infection, and perhaps that’s what’s contributing to these delayed onset cognitive changes,” said Dr. Hellmuth.
Compared with controls, participants with cognitive PASC had more preexisting cognitive risk factors (a median of 2.5 vs. 0; P = .03). These included hypertension and diabetes, which increase the risk of stroke, mild cognitive impairment, vascular dementia, traumatic brain injury, (TBI), learning disabilities, anxiety, depression, stimulant use, and ADHD, which may make the brain more vulnerable to executive functioning problems.
Dr. Hellmuth noted that the study wasn’t powered to determine whether any individual risk factor was associated with risk of cognitive changes.
As there are no published neuropsychological testing criteria for cognitive PASC, the researchers applied the equivalent criteria for HIV-associated neurocognitive disorder (HAND), a similar, virally associated cognitive disorder. Only 59% of those with cognitive PASC met equivalent HAND criteria for objective cognitive impairment versus 70% of cognitive controls. This, the investigators noted, highlights “the challenges and incongruities of using subjective, versus objective cognitive assessments for diagnosis.”
Is self-report enough?
While there is currently “nothing objective doctors can hang their hats on to say ‘you do’ or ‘you don’t’ have cognitive changes related to COVID,” using the HAND criteria is “not particularly helpful,” said Dr. Hellmuth. “Comparing an individual to a population-based norm in this case is really nuanced, and we shouldn’t rely on this solely to determine whether they do, or don’t, have cognitive changes.”
Perhaps self-reports in this case are “enough” said Dr. Hellmuth. “People know their brains better than anyone else, better than any doctor will.”
A total of 13 in the cognitive PASC group and 4 in the control group consented to a lumbar puncture. Cognitive PASC participants were older than controls (median of 47 vs. 28 years; P = .03) with no other between-group differences.
Overall, 77% of participants with cognitive PASC had a CSF abnormality, compared with 0% of cognitive controls (P = .01). CSF abnormalities included elevated protein levels with no other explainable cause in 2 of the 13 subjects with PASC, which Dr. Hellmuth said is typically a marker of inflammation.
Researchers also noted abnormal oligoclonal banding, a collection of antibodies, in the blood or brain fluid. These were identified in 69% of participants with cognitive PASC, compared with 0% of cognitive controls (P = .03).
“When we find this pattern in both blood and brain, it suggests a systemic inflammatory disorder,” although “we have no idea what these antibodies are targeting,” said Dr. Hellmuth.
The study represents “the very beginning stages” of PASC becoming a medical diagnosis “where doctors know what to call it, how to treat it, and how to do blood and cerebrospinal fluid tests to diagnose it,” said Dr. Hellmuth.
She hopes PASC will receive medical legitimacy just as TBI has. In years past, a player was hit on the head or had their “bell rung,” simply returned to the field. “Now that we understand the science, we call it a mild TBI or concussion, and we have a very different medical approach to it.”
A limitation of the study was the small sample size, which may hinder the results’ validity. In addition, the study demographics may not reflect the broader population of those impacted by PASC.
‘A first substantial step’
Commenting on the research, William Schaffner, MD, professor, division of infectious diseases, Vanderbilt University Medical Center, Nashville, Tenn., said the new results represent “a first substantial step on the road to trying to find out what’s going on” with COVID patients dealing with cognitive issues.
Dr. Schaffner noted that elevated protein levels, identified in some study subjects, “is usually a consequence of previous inflammation” and is “a very interesting” finding. “In people who are otherwise normal, if you do a lumbar puncture, you don’t find elevated proteins.”
However, he noted the “diversity of results” from CSF examinations. “A single pattern does not leap out.”
What the researchers are observing “is not just a phenomenon of the mind or just something psychological,” said Dr. Schaffner. “Something physical is going on here.”
The study was funded by grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. Dr. Hellmuth received grant support from the National Institutes of Health/NIMH supporting this work and personal fees for medical-legal consultation outside of the submitted work. Dr. Schaffner has disclosed not relevant financial relationships.
A version of this article first appeared on Medscape.com.
early research suggests. Investigators found abnormalities in cerebrospinal fluid (CSF) and other risk factors, including diabetes and hypertension, present in individuals with mild COVID-19 experiencing persistent cognitive problems, often referred to as “brain fog.”
“We’re seeing changes to the [CSF] in the brain of most people who report cognitive changes,” said Joanna Hellmuth, MD, assistant professor of neurology, Memory and Aging Center, University of California, San Francisco. “We’re just in the beginning stages, but I hope this study will provide some legitimacy to this being a true neurologic condition.”
The study was published online Jan. 18, 2022, in Annals of Clinical and Translational Neurology.
No guidance
There is currently no guidance on how to identify patients with COVID-related cognitive changes, said Dr. Hellmuth. “The term ‘brain fog’ is not based in science or medicine, but that’s the most common term we use to describe this.”
The analysis included adults with confirmed SARS-CoV-2 infection not requiring hospitalization who were enrolled in the Long-term Impact of Infection with Novel Coronavirus study.
Participants underwent a structured interview that covered COVID-19 illness, past medical history, preexisting cognitive risk factors, medications, and cognitive symptoms following onset of COVID-19. They also completed an in-person battery of cognitive tests.
The analysis included 22 participants with at least one new cognitive symptom who had cognitive post-acute sequelae of SARS-CoV-2 infection (PASC). Ten cognitive controls reported no new cognitive symptoms after acute infection.
Participants were a median age of 41 years, had a median of 16 years of education, and were assessed a median of 10.1 months from their first COVID-19 symptom. There were no group differences in terms of age, gender, years of education, or distribution of race/ethnicity (all P > .05).
Among those with cognitive PASC, 43% reported cognitive symptoms starting 1 or more months after the first COVID symptom. About 29% reported cognitive changes started 2 or more months after their first COVID symptom.
“The immune system could be altered in some way after the infection, and perhaps that’s what’s contributing to these delayed onset cognitive changes,” said Dr. Hellmuth.
Compared with controls, participants with cognitive PASC had more preexisting cognitive risk factors (a median of 2.5 vs. 0; P = .03). These included hypertension and diabetes, which increase the risk of stroke, mild cognitive impairment, vascular dementia, traumatic brain injury, (TBI), learning disabilities, anxiety, depression, stimulant use, and ADHD, which may make the brain more vulnerable to executive functioning problems.
Dr. Hellmuth noted that the study wasn’t powered to determine whether any individual risk factor was associated with risk of cognitive changes.
As there are no published neuropsychological testing criteria for cognitive PASC, the researchers applied the equivalent criteria for HIV-associated neurocognitive disorder (HAND), a similar, virally associated cognitive disorder. Only 59% of those with cognitive PASC met equivalent HAND criteria for objective cognitive impairment versus 70% of cognitive controls. This, the investigators noted, highlights “the challenges and incongruities of using subjective, versus objective cognitive assessments for diagnosis.”
Is self-report enough?
While there is currently “nothing objective doctors can hang their hats on to say ‘you do’ or ‘you don’t’ have cognitive changes related to COVID,” using the HAND criteria is “not particularly helpful,” said Dr. Hellmuth. “Comparing an individual to a population-based norm in this case is really nuanced, and we shouldn’t rely on this solely to determine whether they do, or don’t, have cognitive changes.”
Perhaps self-reports in this case are “enough” said Dr. Hellmuth. “People know their brains better than anyone else, better than any doctor will.”
A total of 13 in the cognitive PASC group and 4 in the control group consented to a lumbar puncture. Cognitive PASC participants were older than controls (median of 47 vs. 28 years; P = .03) with no other between-group differences.
Overall, 77% of participants with cognitive PASC had a CSF abnormality, compared with 0% of cognitive controls (P = .01). CSF abnormalities included elevated protein levels with no other explainable cause in 2 of the 13 subjects with PASC, which Dr. Hellmuth said is typically a marker of inflammation.
Researchers also noted abnormal oligoclonal banding, a collection of antibodies, in the blood or brain fluid. These were identified in 69% of participants with cognitive PASC, compared with 0% of cognitive controls (P = .03).
“When we find this pattern in both blood and brain, it suggests a systemic inflammatory disorder,” although “we have no idea what these antibodies are targeting,” said Dr. Hellmuth.
The study represents “the very beginning stages” of PASC becoming a medical diagnosis “where doctors know what to call it, how to treat it, and how to do blood and cerebrospinal fluid tests to diagnose it,” said Dr. Hellmuth.
She hopes PASC will receive medical legitimacy just as TBI has. In years past, a player was hit on the head or had their “bell rung,” simply returned to the field. “Now that we understand the science, we call it a mild TBI or concussion, and we have a very different medical approach to it.”
A limitation of the study was the small sample size, which may hinder the results’ validity. In addition, the study demographics may not reflect the broader population of those impacted by PASC.
‘A first substantial step’
Commenting on the research, William Schaffner, MD, professor, division of infectious diseases, Vanderbilt University Medical Center, Nashville, Tenn., said the new results represent “a first substantial step on the road to trying to find out what’s going on” with COVID patients dealing with cognitive issues.
Dr. Schaffner noted that elevated protein levels, identified in some study subjects, “is usually a consequence of previous inflammation” and is “a very interesting” finding. “In people who are otherwise normal, if you do a lumbar puncture, you don’t find elevated proteins.”
However, he noted the “diversity of results” from CSF examinations. “A single pattern does not leap out.”
What the researchers are observing “is not just a phenomenon of the mind or just something psychological,” said Dr. Schaffner. “Something physical is going on here.”
The study was funded by grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. Dr. Hellmuth received grant support from the National Institutes of Health/NIMH supporting this work and personal fees for medical-legal consultation outside of the submitted work. Dr. Schaffner has disclosed not relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
Ketamine nasal spray provides slow-acting relief for cluster headache attacks
, a pilot study has found, though it did not reduce pain intensity as quickly as initially anticipated.
“In clinical practice, intranasal ketamine might be a valuable tool for severely affected patients with insufficient response or intolerance to current first-line treatment,” wrote Anja S. Petersen, MD, of the Danish Headache Center at Rigshospitalet-Glostrup (Denmark) and her coauthors. The study was published online ahead of print in Headache.
To assess ketamine’s safety and efficacy in treating cluster headache attacks, the researchers launched a single-center, open-label, proof-of-concept study of 23 Danish patients with chronic cluster headache. Their average age was 51, 70% were males, and their mean disease duration was 18 years. Twenty of the participants suffered a spontaneous attack while under in-hospital observation and were treated with 15 mg of intranasal ketamine every 6 minutes to a maximum of five times.
Fifteen minutes after ketamine was administered, mean pain intensity (±SD) was reduced from 7.2 (±1.3) to 6.1 (±3.1) on an 11-point numeric rating scale, equivalent to a 15% reduction and well below the primary endpoint of a 50% or greater reduction. Only 4 of the 20 participants had a reduction of 50% or more, and 4 patients chose rescue medication at 15 minutes. However, at 30 minutes pain intensity was reduced by 59% (mean difference 4.3, 95% confidence interval, 2.4-6.2, P > 0.001), with 11 out of 16 participants scoring a 4 or below.
Eight of the 20 participants reported feeling complete relief from the ketamine nasal spray, while 6 participants reported feeling no effects. Half of the patients said they preferred ketamine to oxygen and/or sumatriptan injection. Seventeen patients (83%) reported side effects, but 12 of them classified their side effects as “few.” No serious adverse events were identified, with the most common adverse events being dizziness, lightheadedness, nausea/vomiting, and paresthesia.
Debating ketamine’s potential for cluster headache patients
“I’m not crazy about the prospects,” said Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H., in an interview. “It was an admirable proof-of-concept trial, and well worth doing. These are desperate patients. But if the aim was to decrease pain intensity within 15 minutes for cluster patients without side effects, this clearly did not do that,” Dr. Tepper said.
“In a sense, this study was to evaluate whether glutamate might be a target for chronic cluster headache, to determine if blocking NMDA glutamate receptors by ketamine would be effective,” Dr. Tepper said. “And I must say, I’m not very impressed.”
He noted his concerns about the study – including 30 minutes being an “unacceptable” wait for patients undergoing a cluster attack, the 20% of patients who required a rescue at 15 minutes, and the various side effects that come with ketamine in nasal form – and said the results did not sway him to consider ketamine a practical option for cluster headache patients.
“You add all of that up, and I would say this was an equivocal study,” he said. “There might be enough there to be worth studying in episodic cluster rather than chronic cluster; there might be enough to consider a randomized, placebo-controlled trial. But it’s not something that I would ring the bell at Wall Street about.”
“The acute treatment of a patient with chronic cluster headache is a real problem for us headache specialists,” added Alan Rapoport, MD, professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, in an interview. “Cluster headache is probably the worst pain we deal with; women who’ve gone through childbirth say that cluster headache is worse. So it’s very reasonable to have tried.”
“It’s not an impressive finding,” he said, “but it does indicate that there’s some value here. Maybe they need to change the dose; maybe they need to get it in faster by doing something tricky like combining the drug with another substance that will make it attach to the nasal mucosa better. I urge them to study it again, and I hope that they come up with better results the next time, because what they attempted to study is absolutely vital.”
The authors acknowledged their study’s limitations, including a homogeneous patient population and the lack of placebo-controlled verification of effect after 30 minutes. They added, however, that a pilot study like this provides “critical information and paves the way for subsequent placebo-controlled studies.” They also admitted that “daily usage [of ketamine] seems suboptimal” because of the potential of patients becoming addicted.
The study was funded by CCH Pharmaceuticals. Several authors reported receiving speaker’s fees and being subinvestigators in trials run by various pharmaceutical companies, including CCH Pharmaceuticals.
, a pilot study has found, though it did not reduce pain intensity as quickly as initially anticipated.
“In clinical practice, intranasal ketamine might be a valuable tool for severely affected patients with insufficient response or intolerance to current first-line treatment,” wrote Anja S. Petersen, MD, of the Danish Headache Center at Rigshospitalet-Glostrup (Denmark) and her coauthors. The study was published online ahead of print in Headache.
To assess ketamine’s safety and efficacy in treating cluster headache attacks, the researchers launched a single-center, open-label, proof-of-concept study of 23 Danish patients with chronic cluster headache. Their average age was 51, 70% were males, and their mean disease duration was 18 years. Twenty of the participants suffered a spontaneous attack while under in-hospital observation and were treated with 15 mg of intranasal ketamine every 6 minutes to a maximum of five times.
Fifteen minutes after ketamine was administered, mean pain intensity (±SD) was reduced from 7.2 (±1.3) to 6.1 (±3.1) on an 11-point numeric rating scale, equivalent to a 15% reduction and well below the primary endpoint of a 50% or greater reduction. Only 4 of the 20 participants had a reduction of 50% or more, and 4 patients chose rescue medication at 15 minutes. However, at 30 minutes pain intensity was reduced by 59% (mean difference 4.3, 95% confidence interval, 2.4-6.2, P > 0.001), with 11 out of 16 participants scoring a 4 or below.
Eight of the 20 participants reported feeling complete relief from the ketamine nasal spray, while 6 participants reported feeling no effects. Half of the patients said they preferred ketamine to oxygen and/or sumatriptan injection. Seventeen patients (83%) reported side effects, but 12 of them classified their side effects as “few.” No serious adverse events were identified, with the most common adverse events being dizziness, lightheadedness, nausea/vomiting, and paresthesia.
Debating ketamine’s potential for cluster headache patients
“I’m not crazy about the prospects,” said Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H., in an interview. “It was an admirable proof-of-concept trial, and well worth doing. These are desperate patients. But if the aim was to decrease pain intensity within 15 minutes for cluster patients without side effects, this clearly did not do that,” Dr. Tepper said.
“In a sense, this study was to evaluate whether glutamate might be a target for chronic cluster headache, to determine if blocking NMDA glutamate receptors by ketamine would be effective,” Dr. Tepper said. “And I must say, I’m not very impressed.”
He noted his concerns about the study – including 30 minutes being an “unacceptable” wait for patients undergoing a cluster attack, the 20% of patients who required a rescue at 15 minutes, and the various side effects that come with ketamine in nasal form – and said the results did not sway him to consider ketamine a practical option for cluster headache patients.
“You add all of that up, and I would say this was an equivocal study,” he said. “There might be enough there to be worth studying in episodic cluster rather than chronic cluster; there might be enough to consider a randomized, placebo-controlled trial. But it’s not something that I would ring the bell at Wall Street about.”
“The acute treatment of a patient with chronic cluster headache is a real problem for us headache specialists,” added Alan Rapoport, MD, professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, in an interview. “Cluster headache is probably the worst pain we deal with; women who’ve gone through childbirth say that cluster headache is worse. So it’s very reasonable to have tried.”
“It’s not an impressive finding,” he said, “but it does indicate that there’s some value here. Maybe they need to change the dose; maybe they need to get it in faster by doing something tricky like combining the drug with another substance that will make it attach to the nasal mucosa better. I urge them to study it again, and I hope that they come up with better results the next time, because what they attempted to study is absolutely vital.”
The authors acknowledged their study’s limitations, including a homogeneous patient population and the lack of placebo-controlled verification of effect after 30 minutes. They added, however, that a pilot study like this provides “critical information and paves the way for subsequent placebo-controlled studies.” They also admitted that “daily usage [of ketamine] seems suboptimal” because of the potential of patients becoming addicted.
The study was funded by CCH Pharmaceuticals. Several authors reported receiving speaker’s fees and being subinvestigators in trials run by various pharmaceutical companies, including CCH Pharmaceuticals.
, a pilot study has found, though it did not reduce pain intensity as quickly as initially anticipated.
“In clinical practice, intranasal ketamine might be a valuable tool for severely affected patients with insufficient response or intolerance to current first-line treatment,” wrote Anja S. Petersen, MD, of the Danish Headache Center at Rigshospitalet-Glostrup (Denmark) and her coauthors. The study was published online ahead of print in Headache.
To assess ketamine’s safety and efficacy in treating cluster headache attacks, the researchers launched a single-center, open-label, proof-of-concept study of 23 Danish patients with chronic cluster headache. Their average age was 51, 70% were males, and their mean disease duration was 18 years. Twenty of the participants suffered a spontaneous attack while under in-hospital observation and were treated with 15 mg of intranasal ketamine every 6 minutes to a maximum of five times.
Fifteen minutes after ketamine was administered, mean pain intensity (±SD) was reduced from 7.2 (±1.3) to 6.1 (±3.1) on an 11-point numeric rating scale, equivalent to a 15% reduction and well below the primary endpoint of a 50% or greater reduction. Only 4 of the 20 participants had a reduction of 50% or more, and 4 patients chose rescue medication at 15 minutes. However, at 30 minutes pain intensity was reduced by 59% (mean difference 4.3, 95% confidence interval, 2.4-6.2, P > 0.001), with 11 out of 16 participants scoring a 4 or below.
Eight of the 20 participants reported feeling complete relief from the ketamine nasal spray, while 6 participants reported feeling no effects. Half of the patients said they preferred ketamine to oxygen and/or sumatriptan injection. Seventeen patients (83%) reported side effects, but 12 of them classified their side effects as “few.” No serious adverse events were identified, with the most common adverse events being dizziness, lightheadedness, nausea/vomiting, and paresthesia.
Debating ketamine’s potential for cluster headache patients
“I’m not crazy about the prospects,” said Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H., in an interview. “It was an admirable proof-of-concept trial, and well worth doing. These are desperate patients. But if the aim was to decrease pain intensity within 15 minutes for cluster patients without side effects, this clearly did not do that,” Dr. Tepper said.
“In a sense, this study was to evaluate whether glutamate might be a target for chronic cluster headache, to determine if blocking NMDA glutamate receptors by ketamine would be effective,” Dr. Tepper said. “And I must say, I’m not very impressed.”
He noted his concerns about the study – including 30 minutes being an “unacceptable” wait for patients undergoing a cluster attack, the 20% of patients who required a rescue at 15 minutes, and the various side effects that come with ketamine in nasal form – and said the results did not sway him to consider ketamine a practical option for cluster headache patients.
“You add all of that up, and I would say this was an equivocal study,” he said. “There might be enough there to be worth studying in episodic cluster rather than chronic cluster; there might be enough to consider a randomized, placebo-controlled trial. But it’s not something that I would ring the bell at Wall Street about.”
“The acute treatment of a patient with chronic cluster headache is a real problem for us headache specialists,” added Alan Rapoport, MD, professor of neurology at University of California, Los Angeles, and past president of the International Headache Society, in an interview. “Cluster headache is probably the worst pain we deal with; women who’ve gone through childbirth say that cluster headache is worse. So it’s very reasonable to have tried.”
“It’s not an impressive finding,” he said, “but it does indicate that there’s some value here. Maybe they need to change the dose; maybe they need to get it in faster by doing something tricky like combining the drug with another substance that will make it attach to the nasal mucosa better. I urge them to study it again, and I hope that they come up with better results the next time, because what they attempted to study is absolutely vital.”
The authors acknowledged their study’s limitations, including a homogeneous patient population and the lack of placebo-controlled verification of effect after 30 minutes. They added, however, that a pilot study like this provides “critical information and paves the way for subsequent placebo-controlled studies.” They also admitted that “daily usage [of ketamine] seems suboptimal” because of the potential of patients becoming addicted.
The study was funded by CCH Pharmaceuticals. Several authors reported receiving speaker’s fees and being subinvestigators in trials run by various pharmaceutical companies, including CCH Pharmaceuticals.
FROM HEADACHE
Global dementia cases may triple by 2050 unless risk factors are reduced
new research suggests.
Results from a study of 195 countries and territories estimates that by 2050, 153 million people are expected to have dementia worldwide – up from 57 million in 2019. In the United States, the number is expected to increase 100%, from an estimated 5.3 million in 2019 to 10.5 million in 2050.
The increase is largely driven by population growth and population aging, but researchers noted that expanding access to education and addressing risk factors such as obesity, high blood sugar, and smoking could blunt the rise in cases.
The study predicts increases in dementia in every country included in the analysis. The sharpest rise is expected in north Africa and the Middle East (367%) and sub-Saharan Africa (357%). The smallest increases will be in high-income countries in Asia Pacific (53%) and western Europe (74%).
Although the United States had the 37th lowest percentage increase across all countries considered, “this expected increase is still large and requires attention from policy and decision-makers,” said coinvestigator Emma Nichols, MPH, a researcher with the Institute for Health Metrics and Evaluation at the University of Washington, Seattle.
The findings were published online Jan. 6, 2022, in The Lancet Public Health (doi: 10.1016/S2468-2667[21]00249-8).
Dementia prevalence
For the study, researchers used country-specific estimates of dementia prevalence from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 study to project dementia prevalence globally, by world region, and at the country level.
They also used information on projected trends in four important dementia risk factors (high body mass index, high fasting plasma glucose, smoking, and education) to estimate how changes in these risk factors might impact dementia prevalence between 2019 and 2050.
Despite large increases in the projected number of people living with dementia, age-standardized both-sex prevalence remained stable between 2019 and 2050, with a global percentage change of 0.1% (95% uncertainty interval, –7.5 to 10.8).
Dementia prevalence was higher in women than in men and increased with age, doubling about every 5 years until 85 years of age in both 2019 and 2050 (female-to-male ratio, 1.67; 95% UI, 1.52-1.85).
Projected increases in cases could largely be attributed to population growth and population aging, although their relative importance varied by world region. Population growth contributed most to the increases in sub-Saharan Africa and population aging contributed most to the increases in east Asia.
The countries with the highest expected percentage change in total number of dementia cases between 2019 and 2050 were: Qatar (1,926%), United Arab Emirates (1,795%), Bahrain (1,084%), Oman (943%), Saudi Arabia (898%), Kuwait (850%), Iraq (559%), Maldives (554%), Jordan (522%), and Equatorial Guinea (498%).
The countries with the lowest expected percentage change in total number of dementia cases between 2019 and 2050 were Japan (27%), Bulgaria (37%), Serbia (38%), Lithuania (44%), Greece (45%), Latvia (47%), Croatia (55%), Ukraine (55%), Italy (56%), and Finland (58%).
Modifiable risk factors
Researchers also calculated how changes in risk factors might affect dementia prevalence. They found that improvements in global education access would reduce dementia prevalence by an estimated 6.2 million cases worldwide by 2050. However, that decrease would be offset by expected increases in obesity, high blood sugar, and smoking, which investigators estimate will result in an additional 6.8 million dementia cases.
The projections are based on expected trends in population aging, population growth, and risk factor trajectories, but “projections could change if effective interventions for modifiable risk factors are developed and deployed,” Ms. Nichols said.
In 2020, the Lancet Commission on Dementia Prevention, Intervention, and Care issued an update of its 2017 report, identifying 12 modifiable risk factors that could delay or prevent 40% of dementia cases. The risk factors were low education, hypertension, hearing impairment, smoking, midlife obesity, depression, physical inactivity, diabetes, social isolation, excessive alcohol consumption, head injury, and air pollution.
“Countries, including the U.S., should look to develop effective interventions for modifiable risk factors, but also should invest in the resources needed to support those with dementia and their caregivers,” Ms. Nichols said. She added that additional support for research and resources to develop therapeutic interventions is also warranted.
Oversimplifying mechanisms?
In an accompanying commentary, Michaël Schwarzinger, MD, and Carole Dufouil, PhD, of Bordeaux (France) University Hospital, noted that the authors’ efforts to build on GBD 2019 oversimplify the underlying mechanisms that cause dementia. The authors “provide somehow apocalyptic projections that do not factor in advisable changes in lifestyle over the lifetime,” they wrote.
“There is a considerable and urgent need to reinforce a public health approach towards dementia to better inform the people and decision-makers about the appropriate means to delay or avoid these dire projections,” the editorialists added.
The study was funded by the Bill and Melinda Gates Foundation and Gates Ventures. Ms. Nichols and the editorialists disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
Results from a study of 195 countries and territories estimates that by 2050, 153 million people are expected to have dementia worldwide – up from 57 million in 2019. In the United States, the number is expected to increase 100%, from an estimated 5.3 million in 2019 to 10.5 million in 2050.
The increase is largely driven by population growth and population aging, but researchers noted that expanding access to education and addressing risk factors such as obesity, high blood sugar, and smoking could blunt the rise in cases.
The study predicts increases in dementia in every country included in the analysis. The sharpest rise is expected in north Africa and the Middle East (367%) and sub-Saharan Africa (357%). The smallest increases will be in high-income countries in Asia Pacific (53%) and western Europe (74%).
Although the United States had the 37th lowest percentage increase across all countries considered, “this expected increase is still large and requires attention from policy and decision-makers,” said coinvestigator Emma Nichols, MPH, a researcher with the Institute for Health Metrics and Evaluation at the University of Washington, Seattle.
The findings were published online Jan. 6, 2022, in The Lancet Public Health (doi: 10.1016/S2468-2667[21]00249-8).
Dementia prevalence
For the study, researchers used country-specific estimates of dementia prevalence from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 study to project dementia prevalence globally, by world region, and at the country level.
They also used information on projected trends in four important dementia risk factors (high body mass index, high fasting plasma glucose, smoking, and education) to estimate how changes in these risk factors might impact dementia prevalence between 2019 and 2050.
Despite large increases in the projected number of people living with dementia, age-standardized both-sex prevalence remained stable between 2019 and 2050, with a global percentage change of 0.1% (95% uncertainty interval, –7.5 to 10.8).
Dementia prevalence was higher in women than in men and increased with age, doubling about every 5 years until 85 years of age in both 2019 and 2050 (female-to-male ratio, 1.67; 95% UI, 1.52-1.85).
Projected increases in cases could largely be attributed to population growth and population aging, although their relative importance varied by world region. Population growth contributed most to the increases in sub-Saharan Africa and population aging contributed most to the increases in east Asia.
The countries with the highest expected percentage change in total number of dementia cases between 2019 and 2050 were: Qatar (1,926%), United Arab Emirates (1,795%), Bahrain (1,084%), Oman (943%), Saudi Arabia (898%), Kuwait (850%), Iraq (559%), Maldives (554%), Jordan (522%), and Equatorial Guinea (498%).
The countries with the lowest expected percentage change in total number of dementia cases between 2019 and 2050 were Japan (27%), Bulgaria (37%), Serbia (38%), Lithuania (44%), Greece (45%), Latvia (47%), Croatia (55%), Ukraine (55%), Italy (56%), and Finland (58%).
Modifiable risk factors
Researchers also calculated how changes in risk factors might affect dementia prevalence. They found that improvements in global education access would reduce dementia prevalence by an estimated 6.2 million cases worldwide by 2050. However, that decrease would be offset by expected increases in obesity, high blood sugar, and smoking, which investigators estimate will result in an additional 6.8 million dementia cases.
The projections are based on expected trends in population aging, population growth, and risk factor trajectories, but “projections could change if effective interventions for modifiable risk factors are developed and deployed,” Ms. Nichols said.
In 2020, the Lancet Commission on Dementia Prevention, Intervention, and Care issued an update of its 2017 report, identifying 12 modifiable risk factors that could delay or prevent 40% of dementia cases. The risk factors were low education, hypertension, hearing impairment, smoking, midlife obesity, depression, physical inactivity, diabetes, social isolation, excessive alcohol consumption, head injury, and air pollution.
“Countries, including the U.S., should look to develop effective interventions for modifiable risk factors, but also should invest in the resources needed to support those with dementia and their caregivers,” Ms. Nichols said. She added that additional support for research and resources to develop therapeutic interventions is also warranted.
Oversimplifying mechanisms?
In an accompanying commentary, Michaël Schwarzinger, MD, and Carole Dufouil, PhD, of Bordeaux (France) University Hospital, noted that the authors’ efforts to build on GBD 2019 oversimplify the underlying mechanisms that cause dementia. The authors “provide somehow apocalyptic projections that do not factor in advisable changes in lifestyle over the lifetime,” they wrote.
“There is a considerable and urgent need to reinforce a public health approach towards dementia to better inform the people and decision-makers about the appropriate means to delay or avoid these dire projections,” the editorialists added.
The study was funded by the Bill and Melinda Gates Foundation and Gates Ventures. Ms. Nichols and the editorialists disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
Results from a study of 195 countries and territories estimates that by 2050, 153 million people are expected to have dementia worldwide – up from 57 million in 2019. In the United States, the number is expected to increase 100%, from an estimated 5.3 million in 2019 to 10.5 million in 2050.
The increase is largely driven by population growth and population aging, but researchers noted that expanding access to education and addressing risk factors such as obesity, high blood sugar, and smoking could blunt the rise in cases.
The study predicts increases in dementia in every country included in the analysis. The sharpest rise is expected in north Africa and the Middle East (367%) and sub-Saharan Africa (357%). The smallest increases will be in high-income countries in Asia Pacific (53%) and western Europe (74%).
Although the United States had the 37th lowest percentage increase across all countries considered, “this expected increase is still large and requires attention from policy and decision-makers,” said coinvestigator Emma Nichols, MPH, a researcher with the Institute for Health Metrics and Evaluation at the University of Washington, Seattle.
The findings were published online Jan. 6, 2022, in The Lancet Public Health (doi: 10.1016/S2468-2667[21]00249-8).
Dementia prevalence
For the study, researchers used country-specific estimates of dementia prevalence from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 study to project dementia prevalence globally, by world region, and at the country level.
They also used information on projected trends in four important dementia risk factors (high body mass index, high fasting plasma glucose, smoking, and education) to estimate how changes in these risk factors might impact dementia prevalence between 2019 and 2050.
Despite large increases in the projected number of people living with dementia, age-standardized both-sex prevalence remained stable between 2019 and 2050, with a global percentage change of 0.1% (95% uncertainty interval, –7.5 to 10.8).
Dementia prevalence was higher in women than in men and increased with age, doubling about every 5 years until 85 years of age in both 2019 and 2050 (female-to-male ratio, 1.67; 95% UI, 1.52-1.85).
Projected increases in cases could largely be attributed to population growth and population aging, although their relative importance varied by world region. Population growth contributed most to the increases in sub-Saharan Africa and population aging contributed most to the increases in east Asia.
The countries with the highest expected percentage change in total number of dementia cases between 2019 and 2050 were: Qatar (1,926%), United Arab Emirates (1,795%), Bahrain (1,084%), Oman (943%), Saudi Arabia (898%), Kuwait (850%), Iraq (559%), Maldives (554%), Jordan (522%), and Equatorial Guinea (498%).
The countries with the lowest expected percentage change in total number of dementia cases between 2019 and 2050 were Japan (27%), Bulgaria (37%), Serbia (38%), Lithuania (44%), Greece (45%), Latvia (47%), Croatia (55%), Ukraine (55%), Italy (56%), and Finland (58%).
Modifiable risk factors
Researchers also calculated how changes in risk factors might affect dementia prevalence. They found that improvements in global education access would reduce dementia prevalence by an estimated 6.2 million cases worldwide by 2050. However, that decrease would be offset by expected increases in obesity, high blood sugar, and smoking, which investigators estimate will result in an additional 6.8 million dementia cases.
The projections are based on expected trends in population aging, population growth, and risk factor trajectories, but “projections could change if effective interventions for modifiable risk factors are developed and deployed,” Ms. Nichols said.
In 2020, the Lancet Commission on Dementia Prevention, Intervention, and Care issued an update of its 2017 report, identifying 12 modifiable risk factors that could delay or prevent 40% of dementia cases. The risk factors were low education, hypertension, hearing impairment, smoking, midlife obesity, depression, physical inactivity, diabetes, social isolation, excessive alcohol consumption, head injury, and air pollution.
“Countries, including the U.S., should look to develop effective interventions for modifiable risk factors, but also should invest in the resources needed to support those with dementia and their caregivers,” Ms. Nichols said. She added that additional support for research and resources to develop therapeutic interventions is also warranted.
Oversimplifying mechanisms?
In an accompanying commentary, Michaël Schwarzinger, MD, and Carole Dufouil, PhD, of Bordeaux (France) University Hospital, noted that the authors’ efforts to build on GBD 2019 oversimplify the underlying mechanisms that cause dementia. The authors “provide somehow apocalyptic projections that do not factor in advisable changes in lifestyle over the lifetime,” they wrote.
“There is a considerable and urgent need to reinforce a public health approach towards dementia to better inform the people and decision-makers about the appropriate means to delay or avoid these dire projections,” the editorialists added.
The study was funded by the Bill and Melinda Gates Foundation and Gates Ventures. Ms. Nichols and the editorialists disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LANCET PUBLIC HEALTH
Is outpatient care as safe as inpatient for TIA, minor stroke?
In a meta-analysis of more than 200,000 patients with TIA or mIS, risk for subsequent stroke within 90 days was 2.1% for those treated in a TIA clinic versus 2.8% for patients treated in inpatient settings, which was not significantly different. The risk for patients treated in an emergency department was higher, at 3.5%.
“The message is that if you do the correct risk stratification and then triage patients based on their risk profile, you can safely discharge and have a timely follow-up for the patients who have low risk for a subsequent event,” said coinvestigator Ramin Zand, MD, vascular neurologist and stroke attending physician at Geisinger Health System, Danville, Pennsylvania.
The findings were published online Jan. 5 in JAMA Network Open.
Higher risk in EDs
There is currently no consensus on the care protocol for patients with TIA or mIS, and the rate at which these patients are hospitalized varies by region, hospital, and practitioner, the investigators noted.
Previous studies have indicated that outpatient management of certain individuals with TIA can be safe and cost-effective.
The current researchers searched for retrospective and prospective studies of adult patients that provided information about ischemic stroke after TIA or mIS. Studies that used time- and tissue-based definitions of TIA were included, as well as studies that used various definitions of mIS.
The investigators examined care provided at TIA clinics, inpatient settings (such as medical-surgical units, stroke units, or observation units), EDs, and unspecified settings. Their main aim was to compare outcomes between TIA clinics and inpatient settings.
In all, 226,683 patients (recruited between 1981 and 2018) from 71 studies were included in the meta-analysis. The studies examined 101 cohorts, 24 of which were studied prospectively. Among the 5,636 patients who received care in TIA clinics, the mean age was 65.7 years, and 50.8% of this group were men. Among the 130,139 inpatients, the mean age was 78.3 years, and 61.6% of the group were women.
Results showed no significant difference in risk for subsequent stroke between patients treated in the inpatient and outpatient settings.
Among patients treated in a TIA clinic, risk for subsequent stroke following a TIA or mIS was 0.3% within 2 days, 1.0% within 7 days, 1.3% within 30 days, and 2.1% within 90 days. Among those treated as inpatients, risk for subsequent stroke was 0.5% within 2 days, 1.2% within 7 days, 1.6% within 30 days, and 2.8% within 90 days.
Risk for subsequent stroke was higher among patients treated in the ED and in unspecified settings. At the EDs, the risk was 1.9% within 2 days, 3.4% within 7 days, 3.5% within 30 days, and 3.5% within 90 days. Among those treated in unspecified settings, the risk was 2.2% within 2 days, 3.4% within 7 days, 4.2% within 30 days, and 6.0% within 90 days.
Patients treated in the ED also had a significantly higher risk for subsequent stroke at 2 and 7 days, compared with those treated in inpatient settings and a significantly higher risk for subsequent stroke at 2, 7, and 90 days, compared with those treated in TIA clinics.
‘Most comprehensive look’
“This is the most comprehensive look at all the studies to try and answer this research question,” said Dr. Zand. The results were similar to what was expected, he added.
The infrastructure and resources differed among the sites at which the various studies were conducted, and the investigators adjusted for these differences as much as possible, Dr. Zand noted. A certain amount of selection bias may remain, but it does not affect the overall conclusion, he added.
“Timely outpatient care among low-risk TIA patients is both feasible and safe,” he said.
Dr. Zand noted that the findings have implications not only for patient management but also for the management of the health system. “It’s not feasible nor desirable to admit all the TIA patients, especially with the lessons that we learned from COVID, the burden on the health systems, and the fact that many hospitals are operating at full capacity right now,” he said.
The recommendation is to hospitalize high-risk patients and provide outpatient evaluation and workup to low-risk patients, he added. “This is exactly what we saw in this study,” Dr. Zand said.
Selection bias?
Commenting on the research, Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, noted that evaluation of patients with TIA or mIS “can be done very well as an outpatient” if clinicians have experienced personnel, the outpatient facilities to do the studies necessary, and criteria in place for deciding who to admit or not admit.
However, the decision on whether to choose an inpatient or outpatient approach for a particular patient is complicated, said Dr. Caplan, who was not involved with the research.
Clinicians must consider factors such as whether the patient is mobile, has a car, or has a significant other. The patient’s symptoms and past illnesses also influence the decision, he added.
Dr. Caplan noted that in the meta-analysis, far fewer patients were seen in the TIA clinics than were seen in the inpatient setting. In addition, none of the studies used uniform criteria to determine which patients should undergo workup as outpatients and which as inpatients. “There was a lot of selection bias that may have had nothing to do with how sick the person was,” Dr. Caplan said.
In addition, few hospitals in the United States have an outpatient TIA clinic, he noted. Most of the studies of TIA clinics that the researchers examined were conducted in Europe. “It’s easier to do [that] in Europe because of their socialized medicine,” said Dr. Caplan.
But TIA clinics should be more widespread in the U.S., he added. “Insurance companies should be willing to pay for comparable facilities, inpatient and outpatient,” he said.
The study was conducted without external funding. Dr. Zand reported no relevant financial relationships. Dr. Caplan was an investigator for TIAregistry.org, which analyzed the outcomes of treatment in TIA clinics in Europe.
A version of this article first appeared on Medscape.com.
In a meta-analysis of more than 200,000 patients with TIA or mIS, risk for subsequent stroke within 90 days was 2.1% for those treated in a TIA clinic versus 2.8% for patients treated in inpatient settings, which was not significantly different. The risk for patients treated in an emergency department was higher, at 3.5%.
“The message is that if you do the correct risk stratification and then triage patients based on their risk profile, you can safely discharge and have a timely follow-up for the patients who have low risk for a subsequent event,” said coinvestigator Ramin Zand, MD, vascular neurologist and stroke attending physician at Geisinger Health System, Danville, Pennsylvania.
The findings were published online Jan. 5 in JAMA Network Open.
Higher risk in EDs
There is currently no consensus on the care protocol for patients with TIA or mIS, and the rate at which these patients are hospitalized varies by region, hospital, and practitioner, the investigators noted.
Previous studies have indicated that outpatient management of certain individuals with TIA can be safe and cost-effective.
The current researchers searched for retrospective and prospective studies of adult patients that provided information about ischemic stroke after TIA or mIS. Studies that used time- and tissue-based definitions of TIA were included, as well as studies that used various definitions of mIS.
The investigators examined care provided at TIA clinics, inpatient settings (such as medical-surgical units, stroke units, or observation units), EDs, and unspecified settings. Their main aim was to compare outcomes between TIA clinics and inpatient settings.
In all, 226,683 patients (recruited between 1981 and 2018) from 71 studies were included in the meta-analysis. The studies examined 101 cohorts, 24 of which were studied prospectively. Among the 5,636 patients who received care in TIA clinics, the mean age was 65.7 years, and 50.8% of this group were men. Among the 130,139 inpatients, the mean age was 78.3 years, and 61.6% of the group were women.
Results showed no significant difference in risk for subsequent stroke between patients treated in the inpatient and outpatient settings.
Among patients treated in a TIA clinic, risk for subsequent stroke following a TIA or mIS was 0.3% within 2 days, 1.0% within 7 days, 1.3% within 30 days, and 2.1% within 90 days. Among those treated as inpatients, risk for subsequent stroke was 0.5% within 2 days, 1.2% within 7 days, 1.6% within 30 days, and 2.8% within 90 days.
Risk for subsequent stroke was higher among patients treated in the ED and in unspecified settings. At the EDs, the risk was 1.9% within 2 days, 3.4% within 7 days, 3.5% within 30 days, and 3.5% within 90 days. Among those treated in unspecified settings, the risk was 2.2% within 2 days, 3.4% within 7 days, 4.2% within 30 days, and 6.0% within 90 days.
Patients treated in the ED also had a significantly higher risk for subsequent stroke at 2 and 7 days, compared with those treated in inpatient settings and a significantly higher risk for subsequent stroke at 2, 7, and 90 days, compared with those treated in TIA clinics.
‘Most comprehensive look’
“This is the most comprehensive look at all the studies to try and answer this research question,” said Dr. Zand. The results were similar to what was expected, he added.
The infrastructure and resources differed among the sites at which the various studies were conducted, and the investigators adjusted for these differences as much as possible, Dr. Zand noted. A certain amount of selection bias may remain, but it does not affect the overall conclusion, he added.
“Timely outpatient care among low-risk TIA patients is both feasible and safe,” he said.
Dr. Zand noted that the findings have implications not only for patient management but also for the management of the health system. “It’s not feasible nor desirable to admit all the TIA patients, especially with the lessons that we learned from COVID, the burden on the health systems, and the fact that many hospitals are operating at full capacity right now,” he said.
The recommendation is to hospitalize high-risk patients and provide outpatient evaluation and workup to low-risk patients, he added. “This is exactly what we saw in this study,” Dr. Zand said.
Selection bias?
Commenting on the research, Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, noted that evaluation of patients with TIA or mIS “can be done very well as an outpatient” if clinicians have experienced personnel, the outpatient facilities to do the studies necessary, and criteria in place for deciding who to admit or not admit.
However, the decision on whether to choose an inpatient or outpatient approach for a particular patient is complicated, said Dr. Caplan, who was not involved with the research.
Clinicians must consider factors such as whether the patient is mobile, has a car, or has a significant other. The patient’s symptoms and past illnesses also influence the decision, he added.
Dr. Caplan noted that in the meta-analysis, far fewer patients were seen in the TIA clinics than were seen in the inpatient setting. In addition, none of the studies used uniform criteria to determine which patients should undergo workup as outpatients and which as inpatients. “There was a lot of selection bias that may have had nothing to do with how sick the person was,” Dr. Caplan said.
In addition, few hospitals in the United States have an outpatient TIA clinic, he noted. Most of the studies of TIA clinics that the researchers examined were conducted in Europe. “It’s easier to do [that] in Europe because of their socialized medicine,” said Dr. Caplan.
But TIA clinics should be more widespread in the U.S., he added. “Insurance companies should be willing to pay for comparable facilities, inpatient and outpatient,” he said.
The study was conducted without external funding. Dr. Zand reported no relevant financial relationships. Dr. Caplan was an investigator for TIAregistry.org, which analyzed the outcomes of treatment in TIA clinics in Europe.
A version of this article first appeared on Medscape.com.
In a meta-analysis of more than 200,000 patients with TIA or mIS, risk for subsequent stroke within 90 days was 2.1% for those treated in a TIA clinic versus 2.8% for patients treated in inpatient settings, which was not significantly different. The risk for patients treated in an emergency department was higher, at 3.5%.
“The message is that if you do the correct risk stratification and then triage patients based on their risk profile, you can safely discharge and have a timely follow-up for the patients who have low risk for a subsequent event,” said coinvestigator Ramin Zand, MD, vascular neurologist and stroke attending physician at Geisinger Health System, Danville, Pennsylvania.
The findings were published online Jan. 5 in JAMA Network Open.
Higher risk in EDs
There is currently no consensus on the care protocol for patients with TIA or mIS, and the rate at which these patients are hospitalized varies by region, hospital, and practitioner, the investigators noted.
Previous studies have indicated that outpatient management of certain individuals with TIA can be safe and cost-effective.
The current researchers searched for retrospective and prospective studies of adult patients that provided information about ischemic stroke after TIA or mIS. Studies that used time- and tissue-based definitions of TIA were included, as well as studies that used various definitions of mIS.
The investigators examined care provided at TIA clinics, inpatient settings (such as medical-surgical units, stroke units, or observation units), EDs, and unspecified settings. Their main aim was to compare outcomes between TIA clinics and inpatient settings.
In all, 226,683 patients (recruited between 1981 and 2018) from 71 studies were included in the meta-analysis. The studies examined 101 cohorts, 24 of which were studied prospectively. Among the 5,636 patients who received care in TIA clinics, the mean age was 65.7 years, and 50.8% of this group were men. Among the 130,139 inpatients, the mean age was 78.3 years, and 61.6% of the group were women.
Results showed no significant difference in risk for subsequent stroke between patients treated in the inpatient and outpatient settings.
Among patients treated in a TIA clinic, risk for subsequent stroke following a TIA or mIS was 0.3% within 2 days, 1.0% within 7 days, 1.3% within 30 days, and 2.1% within 90 days. Among those treated as inpatients, risk for subsequent stroke was 0.5% within 2 days, 1.2% within 7 days, 1.6% within 30 days, and 2.8% within 90 days.
Risk for subsequent stroke was higher among patients treated in the ED and in unspecified settings. At the EDs, the risk was 1.9% within 2 days, 3.4% within 7 days, 3.5% within 30 days, and 3.5% within 90 days. Among those treated in unspecified settings, the risk was 2.2% within 2 days, 3.4% within 7 days, 4.2% within 30 days, and 6.0% within 90 days.
Patients treated in the ED also had a significantly higher risk for subsequent stroke at 2 and 7 days, compared with those treated in inpatient settings and a significantly higher risk for subsequent stroke at 2, 7, and 90 days, compared with those treated in TIA clinics.
‘Most comprehensive look’
“This is the most comprehensive look at all the studies to try and answer this research question,” said Dr. Zand. The results were similar to what was expected, he added.
The infrastructure and resources differed among the sites at which the various studies were conducted, and the investigators adjusted for these differences as much as possible, Dr. Zand noted. A certain amount of selection bias may remain, but it does not affect the overall conclusion, he added.
“Timely outpatient care among low-risk TIA patients is both feasible and safe,” he said.
Dr. Zand noted that the findings have implications not only for patient management but also for the management of the health system. “It’s not feasible nor desirable to admit all the TIA patients, especially with the lessons that we learned from COVID, the burden on the health systems, and the fact that many hospitals are operating at full capacity right now,” he said.
The recommendation is to hospitalize high-risk patients and provide outpatient evaluation and workup to low-risk patients, he added. “This is exactly what we saw in this study,” Dr. Zand said.
Selection bias?
Commenting on the research, Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, noted that evaluation of patients with TIA or mIS “can be done very well as an outpatient” if clinicians have experienced personnel, the outpatient facilities to do the studies necessary, and criteria in place for deciding who to admit or not admit.
However, the decision on whether to choose an inpatient or outpatient approach for a particular patient is complicated, said Dr. Caplan, who was not involved with the research.
Clinicians must consider factors such as whether the patient is mobile, has a car, or has a significant other. The patient’s symptoms and past illnesses also influence the decision, he added.
Dr. Caplan noted that in the meta-analysis, far fewer patients were seen in the TIA clinics than were seen in the inpatient setting. In addition, none of the studies used uniform criteria to determine which patients should undergo workup as outpatients and which as inpatients. “There was a lot of selection bias that may have had nothing to do with how sick the person was,” Dr. Caplan said.
In addition, few hospitals in the United States have an outpatient TIA clinic, he noted. Most of the studies of TIA clinics that the researchers examined were conducted in Europe. “It’s easier to do [that] in Europe because of their socialized medicine,” said Dr. Caplan.
But TIA clinics should be more widespread in the U.S., he added. “Insurance companies should be willing to pay for comparable facilities, inpatient and outpatient,” he said.
The study was conducted without external funding. Dr. Zand reported no relevant financial relationships. Dr. Caplan was an investigator for TIAregistry.org, which analyzed the outcomes of treatment in TIA clinics in Europe.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
MRI is key to diagnosing CTE in living patients?
, new research suggests.
“These new results offer some hope for clinicians who are really struggling to confidently diagnose or detect CTE during life,” said lead author Michael L. Alosco, PhD, associate professor of neurology, codirector of the Boston University Alzheimer’s Disease Research Center, and investigator at the Boston University CTE Center.
The findings were published online Dec. 7, 2021, in Alzheimer’s Research & Therapy.
A new way to diagnose?
CTE is a neurodegenerative disease associated with exposure to repetitive blows to the head, such as those sustained playing contact sports. Currently, the condition can only be reliably diagnosed at autopsy using neuropathological diagnostic criteria.
There are four pathological stages of CTE, ranging from mild to severe. Each progressive stage reflects mounting accumulation of hyperphosphorylated tau (p-tau).
The study included 55 male brain donors with confirmed CTE, all with a history of repetitive head injury. Most (n = 52) played football, but two played ice hockey and one had military and combat exposure. The analysis also included 31 men with normal cognition (NC). Of these, some were living and some were deceased.
The study sample was restricted to participants age 60 and older and to those who had an MRI obtained through a medical record request.
Most referrals for MRI in the CTE group were related to dementia or neurodegenerative disease (65%). In the NC group, MRI indications were mostly related to cerebrovascular causes (22.6%), memory complaints (16.1%), or vertigo (9.7%).
From MRIs, neuroradiologists visually rated patterns of shrinkage in the brain, microvascular disease, and presence of cavum septum pellucidum (CSP) – a large hole in the tissue separating ventricles of the brain.
More atrophy
Results showed that compared with the NC group, the CTE group had significantly greater atrophy in several brain regions, including the orbital-frontal cortex, dorsolateral frontal cortex, superior frontal cortex, anterior temporal lobes, and medial temporal lobe.
The dorsolateral frontal cortex showed the largest group difference (estimated marginal mean difference, 1.31; 95% confidence interval, .42-2.19; false discovery rate-adjusted P = .01).
Previous research has shown early p-tau involvement in this area among CTE patients. Although the hippocampus is also affected in CTE, this occurs later in the disease course, the investigators noted.
The unique pattern, type, and distribution of p-tau pathology in CTE is different from Alzheimer’s disease. CTE is also distinct from Alzheimer’s disease in that there is no accumulation of beta-amyloid plaque.
The new results add to “converging evidence” for frontotemporal and medial temporal lobe atrophy in CTE “that might be able to be visualized on MRI,” the investigators noted.
Almost two-thirds of the CTE group had an additional neurodegenerative disease. Furthermore, the effect sizes remained similar in analyses that excluded CTE donors with frontotemporal lobar degeneration or Alzheimer’s disease.
“This suggests to us that these other diseases were not accounting for the atrophy,” Dr. Alosco said.
Individuals with CTE were 6.7 times more likely to have a CSP versus those with NC (odds ratio, 6.7; 95% CI, 1.5-50.1; P = .049).
Although previous research suggested an association between CSP and repetitive concussion, CSP is also frequently found in the general adult population. However, when combined with data on frontal lobe shrinkage, it may be a supportive differential diagnostic feature for CTE, Dr. Alosco said.
An important first step
The investigators also examined ventricle size. The lateral ventricles in the CTE group were significantly larger (mean difference, 1.72; 95% CI, .62-2.82; P = .01), as was the third ventricle (mean difference, .80; 95% CI, .26-1.35; P = .01).
When neuropathologists rated tau severity and atrophy at autopsy, they found that more severe p-tau pathology was associated with greater atrophy among those with CTE (beta = .68; P < .01).
Dr. Alosco called the finding “exciting,” noting that it suggests “this tau is a precipitant for neurodegeneration.”
He noted that, although some researchers have used positron emission tomography (PET) tau tracers to uncover a CTE pattern, MRI is relatively inexpensive and routinely used as part of dementia assessment.
While the new study is “an important first step” in using MRI to diagnose CTE, larger sample sizes are needed, Dr. Alosco said. “We also need to look at other disease groups and really nail down the difference with CTE in terms of patterns” (vs. Alzheimer’s disease and vs. frontotemporal lobar degeneration), he added.
“Once those differences are cleared, we will be ready to be more confident when we interpret these images.”.
‘Not unexpected’
Commenting on the research, neurologist and concussion expert Francis X. Conidi, DO, director, Florida Center for Headache and Sports Neurology, Port St. Lucie, said that, although the study was “well thought out and interesting,” the results were “not completely unexpected.”
Frontal and anterior temporal lobe atrophy and prominent third ventricles are very common in patients with traumatic brain injury (TBI), which is “a prerequisite to develop CTE,” said Dr. Conidi, who was not involved with the research.
The current study’s findings mirror observations found in a National Football League cohort he and his colleagues are following – and in his patients with TBI in general.
Dr. Conidi noted that there is a “significant subjective component” to the study results because they relied on the opinion of neuroradiologists. He is not convinced MRI findings of frontotemporal and medial temporal lobe atrophy necessarily represent CTE and not TBI. In fact, he noted that patients with TBI have a significantly greater chance of not developing a neurodegenerative disorder.
Dr. Conidi added that he doesn’t think MRI will ever be the gold standard for diagnosing or even assessing risk of developing CTE. “That lies in tau PET imaging,” he said.
Overstated conclusion?
Also commenting on the research findings, Kristen Dams-O’Connor, PhD, professor, vice chair of research, and director, Brain Injury Research Center, Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai in New York, said the sensitivity analyses, particularly those designed to clarify contributions of Alzheimer’s disease and other neuropathological contributions to associations between p-tau and atrophy, “increase our confidence” in the findings.
“What’s exciting about this paper is that it provides very preliminary support for adding another tool to our arsenal as we try to establish a constellation of in vivo diagnostic markers that, together, will help us rule in a post-traumatic neurodegenerative process and rule out other brain diseases.”
A possible study limitation is that the MRI scans were from low-field strength magnets, although that makes the study more “ecologically valid”, said Dr. Dams-O’Connor. “Many clinical scanners are built around a 1.5T magnet, so what the researchers see in this study is what a radiologist may see in the clinic.”
The conclusion that frontal-temporal atrophy is an MRI marker of CTE is “an overstatement” as this pattern of atrophy is not specific to CTE, said Dr. Dams-O’Connor. “The association of p-tau with atrophy is unsurprising and doesn’t bring us much closer to understanding how, or whether, the patterns of p-tau accumulation observed in CTE contribute to the clinical expression of symptoms.”
Dr. Alosco and Dr. Conidi report no relevant financial relationships. Disclosures for the other study authors are listed in the original journal article. The study was funded by grants from the National Institute on Aging, the National Institute on Neurological Disorders and Stroke, National Institute of Aging Boston University AD Center, Department of Veterans Affairs Merit Award, the Nick and Lynn Buoniconti Foundation, and BU-CTSI.
A version of this article first appeared on Medscape.com.
, new research suggests.
“These new results offer some hope for clinicians who are really struggling to confidently diagnose or detect CTE during life,” said lead author Michael L. Alosco, PhD, associate professor of neurology, codirector of the Boston University Alzheimer’s Disease Research Center, and investigator at the Boston University CTE Center.
The findings were published online Dec. 7, 2021, in Alzheimer’s Research & Therapy.
A new way to diagnose?
CTE is a neurodegenerative disease associated with exposure to repetitive blows to the head, such as those sustained playing contact sports. Currently, the condition can only be reliably diagnosed at autopsy using neuropathological diagnostic criteria.
There are four pathological stages of CTE, ranging from mild to severe. Each progressive stage reflects mounting accumulation of hyperphosphorylated tau (p-tau).
The study included 55 male brain donors with confirmed CTE, all with a history of repetitive head injury. Most (n = 52) played football, but two played ice hockey and one had military and combat exposure. The analysis also included 31 men with normal cognition (NC). Of these, some were living and some were deceased.
The study sample was restricted to participants age 60 and older and to those who had an MRI obtained through a medical record request.
Most referrals for MRI in the CTE group were related to dementia or neurodegenerative disease (65%). In the NC group, MRI indications were mostly related to cerebrovascular causes (22.6%), memory complaints (16.1%), or vertigo (9.7%).
From MRIs, neuroradiologists visually rated patterns of shrinkage in the brain, microvascular disease, and presence of cavum septum pellucidum (CSP) – a large hole in the tissue separating ventricles of the brain.
More atrophy
Results showed that compared with the NC group, the CTE group had significantly greater atrophy in several brain regions, including the orbital-frontal cortex, dorsolateral frontal cortex, superior frontal cortex, anterior temporal lobes, and medial temporal lobe.
The dorsolateral frontal cortex showed the largest group difference (estimated marginal mean difference, 1.31; 95% confidence interval, .42-2.19; false discovery rate-adjusted P = .01).
Previous research has shown early p-tau involvement in this area among CTE patients. Although the hippocampus is also affected in CTE, this occurs later in the disease course, the investigators noted.
The unique pattern, type, and distribution of p-tau pathology in CTE is different from Alzheimer’s disease. CTE is also distinct from Alzheimer’s disease in that there is no accumulation of beta-amyloid plaque.
The new results add to “converging evidence” for frontotemporal and medial temporal lobe atrophy in CTE “that might be able to be visualized on MRI,” the investigators noted.
Almost two-thirds of the CTE group had an additional neurodegenerative disease. Furthermore, the effect sizes remained similar in analyses that excluded CTE donors with frontotemporal lobar degeneration or Alzheimer’s disease.
“This suggests to us that these other diseases were not accounting for the atrophy,” Dr. Alosco said.
Individuals with CTE were 6.7 times more likely to have a CSP versus those with NC (odds ratio, 6.7; 95% CI, 1.5-50.1; P = .049).
Although previous research suggested an association between CSP and repetitive concussion, CSP is also frequently found in the general adult population. However, when combined with data on frontal lobe shrinkage, it may be a supportive differential diagnostic feature for CTE, Dr. Alosco said.
An important first step
The investigators also examined ventricle size. The lateral ventricles in the CTE group were significantly larger (mean difference, 1.72; 95% CI, .62-2.82; P = .01), as was the third ventricle (mean difference, .80; 95% CI, .26-1.35; P = .01).
When neuropathologists rated tau severity and atrophy at autopsy, they found that more severe p-tau pathology was associated with greater atrophy among those with CTE (beta = .68; P < .01).
Dr. Alosco called the finding “exciting,” noting that it suggests “this tau is a precipitant for neurodegeneration.”
He noted that, although some researchers have used positron emission tomography (PET) tau tracers to uncover a CTE pattern, MRI is relatively inexpensive and routinely used as part of dementia assessment.
While the new study is “an important first step” in using MRI to diagnose CTE, larger sample sizes are needed, Dr. Alosco said. “We also need to look at other disease groups and really nail down the difference with CTE in terms of patterns” (vs. Alzheimer’s disease and vs. frontotemporal lobar degeneration), he added.
“Once those differences are cleared, we will be ready to be more confident when we interpret these images.”.
‘Not unexpected’
Commenting on the research, neurologist and concussion expert Francis X. Conidi, DO, director, Florida Center for Headache and Sports Neurology, Port St. Lucie, said that, although the study was “well thought out and interesting,” the results were “not completely unexpected.”
Frontal and anterior temporal lobe atrophy and prominent third ventricles are very common in patients with traumatic brain injury (TBI), which is “a prerequisite to develop CTE,” said Dr. Conidi, who was not involved with the research.
The current study’s findings mirror observations found in a National Football League cohort he and his colleagues are following – and in his patients with TBI in general.
Dr. Conidi noted that there is a “significant subjective component” to the study results because they relied on the opinion of neuroradiologists. He is not convinced MRI findings of frontotemporal and medial temporal lobe atrophy necessarily represent CTE and not TBI. In fact, he noted that patients with TBI have a significantly greater chance of not developing a neurodegenerative disorder.
Dr. Conidi added that he doesn’t think MRI will ever be the gold standard for diagnosing or even assessing risk of developing CTE. “That lies in tau PET imaging,” he said.
Overstated conclusion?
Also commenting on the research findings, Kristen Dams-O’Connor, PhD, professor, vice chair of research, and director, Brain Injury Research Center, Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai in New York, said the sensitivity analyses, particularly those designed to clarify contributions of Alzheimer’s disease and other neuropathological contributions to associations between p-tau and atrophy, “increase our confidence” in the findings.
“What’s exciting about this paper is that it provides very preliminary support for adding another tool to our arsenal as we try to establish a constellation of in vivo diagnostic markers that, together, will help us rule in a post-traumatic neurodegenerative process and rule out other brain diseases.”
A possible study limitation is that the MRI scans were from low-field strength magnets, although that makes the study more “ecologically valid”, said Dr. Dams-O’Connor. “Many clinical scanners are built around a 1.5T magnet, so what the researchers see in this study is what a radiologist may see in the clinic.”
The conclusion that frontal-temporal atrophy is an MRI marker of CTE is “an overstatement” as this pattern of atrophy is not specific to CTE, said Dr. Dams-O’Connor. “The association of p-tau with atrophy is unsurprising and doesn’t bring us much closer to understanding how, or whether, the patterns of p-tau accumulation observed in CTE contribute to the clinical expression of symptoms.”
Dr. Alosco and Dr. Conidi report no relevant financial relationships. Disclosures for the other study authors are listed in the original journal article. The study was funded by grants from the National Institute on Aging, the National Institute on Neurological Disorders and Stroke, National Institute of Aging Boston University AD Center, Department of Veterans Affairs Merit Award, the Nick and Lynn Buoniconti Foundation, and BU-CTSI.
A version of this article first appeared on Medscape.com.
, new research suggests.
“These new results offer some hope for clinicians who are really struggling to confidently diagnose or detect CTE during life,” said lead author Michael L. Alosco, PhD, associate professor of neurology, codirector of the Boston University Alzheimer’s Disease Research Center, and investigator at the Boston University CTE Center.
The findings were published online Dec. 7, 2021, in Alzheimer’s Research & Therapy.
A new way to diagnose?
CTE is a neurodegenerative disease associated with exposure to repetitive blows to the head, such as those sustained playing contact sports. Currently, the condition can only be reliably diagnosed at autopsy using neuropathological diagnostic criteria.
There are four pathological stages of CTE, ranging from mild to severe. Each progressive stage reflects mounting accumulation of hyperphosphorylated tau (p-tau).
The study included 55 male brain donors with confirmed CTE, all with a history of repetitive head injury. Most (n = 52) played football, but two played ice hockey and one had military and combat exposure. The analysis also included 31 men with normal cognition (NC). Of these, some were living and some were deceased.
The study sample was restricted to participants age 60 and older and to those who had an MRI obtained through a medical record request.
Most referrals for MRI in the CTE group were related to dementia or neurodegenerative disease (65%). In the NC group, MRI indications were mostly related to cerebrovascular causes (22.6%), memory complaints (16.1%), or vertigo (9.7%).
From MRIs, neuroradiologists visually rated patterns of shrinkage in the brain, microvascular disease, and presence of cavum septum pellucidum (CSP) – a large hole in the tissue separating ventricles of the brain.
More atrophy
Results showed that compared with the NC group, the CTE group had significantly greater atrophy in several brain regions, including the orbital-frontal cortex, dorsolateral frontal cortex, superior frontal cortex, anterior temporal lobes, and medial temporal lobe.
The dorsolateral frontal cortex showed the largest group difference (estimated marginal mean difference, 1.31; 95% confidence interval, .42-2.19; false discovery rate-adjusted P = .01).
Previous research has shown early p-tau involvement in this area among CTE patients. Although the hippocampus is also affected in CTE, this occurs later in the disease course, the investigators noted.
The unique pattern, type, and distribution of p-tau pathology in CTE is different from Alzheimer’s disease. CTE is also distinct from Alzheimer’s disease in that there is no accumulation of beta-amyloid plaque.
The new results add to “converging evidence” for frontotemporal and medial temporal lobe atrophy in CTE “that might be able to be visualized on MRI,” the investigators noted.
Almost two-thirds of the CTE group had an additional neurodegenerative disease. Furthermore, the effect sizes remained similar in analyses that excluded CTE donors with frontotemporal lobar degeneration or Alzheimer’s disease.
“This suggests to us that these other diseases were not accounting for the atrophy,” Dr. Alosco said.
Individuals with CTE were 6.7 times more likely to have a CSP versus those with NC (odds ratio, 6.7; 95% CI, 1.5-50.1; P = .049).
Although previous research suggested an association between CSP and repetitive concussion, CSP is also frequently found in the general adult population. However, when combined with data on frontal lobe shrinkage, it may be a supportive differential diagnostic feature for CTE, Dr. Alosco said.
An important first step
The investigators also examined ventricle size. The lateral ventricles in the CTE group were significantly larger (mean difference, 1.72; 95% CI, .62-2.82; P = .01), as was the third ventricle (mean difference, .80; 95% CI, .26-1.35; P = .01).
When neuropathologists rated tau severity and atrophy at autopsy, they found that more severe p-tau pathology was associated with greater atrophy among those with CTE (beta = .68; P < .01).
Dr. Alosco called the finding “exciting,” noting that it suggests “this tau is a precipitant for neurodegeneration.”
He noted that, although some researchers have used positron emission tomography (PET) tau tracers to uncover a CTE pattern, MRI is relatively inexpensive and routinely used as part of dementia assessment.
While the new study is “an important first step” in using MRI to diagnose CTE, larger sample sizes are needed, Dr. Alosco said. “We also need to look at other disease groups and really nail down the difference with CTE in terms of patterns” (vs. Alzheimer’s disease and vs. frontotemporal lobar degeneration), he added.
“Once those differences are cleared, we will be ready to be more confident when we interpret these images.”.
‘Not unexpected’
Commenting on the research, neurologist and concussion expert Francis X. Conidi, DO, director, Florida Center for Headache and Sports Neurology, Port St. Lucie, said that, although the study was “well thought out and interesting,” the results were “not completely unexpected.”
Frontal and anterior temporal lobe atrophy and prominent third ventricles are very common in patients with traumatic brain injury (TBI), which is “a prerequisite to develop CTE,” said Dr. Conidi, who was not involved with the research.
The current study’s findings mirror observations found in a National Football League cohort he and his colleagues are following – and in his patients with TBI in general.
Dr. Conidi noted that there is a “significant subjective component” to the study results because they relied on the opinion of neuroradiologists. He is not convinced MRI findings of frontotemporal and medial temporal lobe atrophy necessarily represent CTE and not TBI. In fact, he noted that patients with TBI have a significantly greater chance of not developing a neurodegenerative disorder.
Dr. Conidi added that he doesn’t think MRI will ever be the gold standard for diagnosing or even assessing risk of developing CTE. “That lies in tau PET imaging,” he said.
Overstated conclusion?
Also commenting on the research findings, Kristen Dams-O’Connor, PhD, professor, vice chair of research, and director, Brain Injury Research Center, Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai in New York, said the sensitivity analyses, particularly those designed to clarify contributions of Alzheimer’s disease and other neuropathological contributions to associations between p-tau and atrophy, “increase our confidence” in the findings.
“What’s exciting about this paper is that it provides very preliminary support for adding another tool to our arsenal as we try to establish a constellation of in vivo diagnostic markers that, together, will help us rule in a post-traumatic neurodegenerative process and rule out other brain diseases.”
A possible study limitation is that the MRI scans were from low-field strength magnets, although that makes the study more “ecologically valid”, said Dr. Dams-O’Connor. “Many clinical scanners are built around a 1.5T magnet, so what the researchers see in this study is what a radiologist may see in the clinic.”
The conclusion that frontal-temporal atrophy is an MRI marker of CTE is “an overstatement” as this pattern of atrophy is not specific to CTE, said Dr. Dams-O’Connor. “The association of p-tau with atrophy is unsurprising and doesn’t bring us much closer to understanding how, or whether, the patterns of p-tau accumulation observed in CTE contribute to the clinical expression of symptoms.”
Dr. Alosco and Dr. Conidi report no relevant financial relationships. Disclosures for the other study authors are listed in the original journal article. The study was funded by grants from the National Institute on Aging, the National Institute on Neurological Disorders and Stroke, National Institute of Aging Boston University AD Center, Department of Veterans Affairs Merit Award, the Nick and Lynn Buoniconti Foundation, and BU-CTSI.
A version of this article first appeared on Medscape.com.
Gene mutations may drive sudden unexplained deaths in children
, researchers have found.
Previous studies have found de novo genetic variants – those not found in either parent but which occur for the first time in their offspring – that increase the risk of cardiac and seizure disorders, but research on sudden unexplained deaths in children (SUDC) is limited, according to Matthew Halvorsen, PhD, of the University of North Carolina at Chapel Hill, and colleagues. Most cases of SUDC occur in children aged 1-4 years, and a lack of standardized investigation systems likely leads to misclassification of these deaths, they said.
Compared with sudden infant death syndrome (SIDS), which occurs in approximately 1,400 children in the United States each year, approximately 400 children aged 1 year and older die from SUDC annually. A major obstacle to studying these cases is that so-called molecular autopsies – which incorporate genetic analysis into the postmortem examination – typically do not assess the parents’ genetic information and thus limit the ability to identify de novo mutations, they added.
In a study published in the Proceedings of the National Academy of Sciences, Dr. Halvorsen’s group obtained whole exome sequence data from 124 “trios,” meaning a dead child and two living parents. They tested for excessive de novo mutations for different genes involved in conditions that included cardiac arrhythmias and epilepsy. The average age at the time of death for the children was 34.2 months; 54% were male, and 82% were White.
Children who died of SUDC were nearly 10 times as likely to have de novo mutations in genes associated with cardiac and seizure disorders as were unrelated healthy controls (odds ratio, 9.76). Most pathogenic variants were de novo, which highlights the importance of trio studies, the researchers noted.
The researchers identified 11 variants associated with increased risk of SUDC, 7 of which were de novo. Three of the 124 cases carried mutations (two for RYR2 and 1 for TNNI3) affecting genes in the CardiacEpilepsy dataset proposed by the American College of Medical Genetics and Genomics, strengthening the connection to seizure disorders.
Another notable finding was the identification of six de novo mutations involved in altering calcium-related regulation, which suggests a cardiac susceptibility to sudden death.
The data support “novel genetic causes of pediatric sudden deaths that could be discovered with larger cohorts,” the researchers noted. Taken together, they say, the gene mutations could play a role in approximately 9% of SUDC cases.
The study findings were limited by several factors, including lack of population-based case ascertainment, exclusive focus on unexplained deaths, potentially missed mutations, and use of DNA from blood as opposed to organs, the researchers noted.
However, they concluded, “the data indicate that deleterious de novo mutations are significant genetic risk factors for childhood sudden unexplained death, and that their identification may lead to medical intervention that ultimately saves lives.”
Findings highlight impact of SUDC
“This study is important because SUDC is a much more pressing medical need than most people realize,” said Richard Tsien, PhD, of New York University Langone Medical Center, and the corresponding author of the study.
Although SUDC is less common than SIDS, SUDC has essentially no targeted research funding, Dr. Tsien said. Study coauthor Laura Gould, MA, a researcher and mother who lost a young child to SUDC, worked with Orrin Devinsky, MD, to create a registry for families with cases of SUDC. This registry was instrumental in allowing the researchers to “do the molecular detective work we need to do” to see whether a genetic basis exists for SUDC, Dr. Tsien said.
“The detective work comes up with a consistent story,” he said. “More than half of the genes that we found are involved in the normal function of the heart and brain,” performing such functions as delivering calcium ions to the inside of the heart cells and nerve cells.
The study “is the first of its kind,” given the difficulty of acquiring DNA from the child and two parents in SUDC cases, Dr. Tsien said.
Overall, approximately 10% of the cases have a compelling explanation based on the coding of DNA, Dr. Tsien said. From a clinical standpoint, that information might affect what a clinician says to a parent.
A key takeaway is that most of the genetic mutations are spontaneous and are not inherited from the parents, Dr. Tsien said. The study findings indicate that parents who suffer an SUDC loss need not be discouraged from having children, he added.
For the long term, “the more we understand about these disorders, the more information we can offer to families,” he said. Eventually, clinicians might be able to use genetics to identify signs of when SUDC might be more likely. “For example, if a child shows a very mild seizure, this would alert them that there might be potential for a more drastic outcome.”
Meanwhile, families with SUDC cases may find support and benefit in signing up for the registry and knowing that other families have been through a similar experience, Dr. Tsien said.
Genetic studies create opportunities
A significant portion of pediatric mortality remains unexplained, according to Richard D. Goldstein, MD, of Boston Children’s Hospital. One reason is the lack of a formal diagnostic code to identify these deaths.
Research to date has suggested links between SUDC and a family history of febrile seizures, as well as differences in brain structure associated with epilepsy, Dr. Goldstein said.
“An important hypothesis is that these deaths are part of a continuum that also includes stillbirths, SIDS, and sudden unexpected death in epilepsy [SUDEP],” Dr. Goldstein said. “By mandate, investigations of these deaths occur under the jurisdiction of medical examiners and coroners and have, for the most part, been insulated from developments in modern medicine like genomics and proteomics, elements of what are referred to as the molecular autopsy, and studies such as the current study bring attention to what is being missed.”
Dr. Goldstein said the new study buttresses the “conventional clinical suspicion” about the likely causes of SUDC, “but also strengthens the association between sudden unexpected death in pediatrics (SUDP) and SUDEP that we and others have been positing. I think the researchers very nicely make the point that epilepsy and cardiac arrhythmia genes are not as separated in their effects as many would believe.”
As for the clinical applicability of the findings, Dr. Goldstein said medicine needs to offer parents more: “Pediatric deaths without explanation deserve more than a forensic investigation that concerns itself mostly with whether there has been foul play,” he said. “We need to figure out how to engage families, at an incredibly vulnerable time, in helping find the cause of the child’s death and also contributing to needed research. Most of the reported variants were de novo, which means that parent participation is needed to figure out these genetic factors but also that we can offer reassurance to families that other children are not at risk.”
The study was supported by the SUDC Foundation and Finding a Cure for Epilepsy and Seizures (New York University). Dr. Tsien disclosed support from the National Institutes of Health and a grant from FACES. Dr. Goldstein reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, researchers have found.
Previous studies have found de novo genetic variants – those not found in either parent but which occur for the first time in their offspring – that increase the risk of cardiac and seizure disorders, but research on sudden unexplained deaths in children (SUDC) is limited, according to Matthew Halvorsen, PhD, of the University of North Carolina at Chapel Hill, and colleagues. Most cases of SUDC occur in children aged 1-4 years, and a lack of standardized investigation systems likely leads to misclassification of these deaths, they said.
Compared with sudden infant death syndrome (SIDS), which occurs in approximately 1,400 children in the United States each year, approximately 400 children aged 1 year and older die from SUDC annually. A major obstacle to studying these cases is that so-called molecular autopsies – which incorporate genetic analysis into the postmortem examination – typically do not assess the parents’ genetic information and thus limit the ability to identify de novo mutations, they added.
In a study published in the Proceedings of the National Academy of Sciences, Dr. Halvorsen’s group obtained whole exome sequence data from 124 “trios,” meaning a dead child and two living parents. They tested for excessive de novo mutations for different genes involved in conditions that included cardiac arrhythmias and epilepsy. The average age at the time of death for the children was 34.2 months; 54% were male, and 82% were White.
Children who died of SUDC were nearly 10 times as likely to have de novo mutations in genes associated with cardiac and seizure disorders as were unrelated healthy controls (odds ratio, 9.76). Most pathogenic variants were de novo, which highlights the importance of trio studies, the researchers noted.
The researchers identified 11 variants associated with increased risk of SUDC, 7 of which were de novo. Three of the 124 cases carried mutations (two for RYR2 and 1 for TNNI3) affecting genes in the CardiacEpilepsy dataset proposed by the American College of Medical Genetics and Genomics, strengthening the connection to seizure disorders.
Another notable finding was the identification of six de novo mutations involved in altering calcium-related regulation, which suggests a cardiac susceptibility to sudden death.
The data support “novel genetic causes of pediatric sudden deaths that could be discovered with larger cohorts,” the researchers noted. Taken together, they say, the gene mutations could play a role in approximately 9% of SUDC cases.
The study findings were limited by several factors, including lack of population-based case ascertainment, exclusive focus on unexplained deaths, potentially missed mutations, and use of DNA from blood as opposed to organs, the researchers noted.
However, they concluded, “the data indicate that deleterious de novo mutations are significant genetic risk factors for childhood sudden unexplained death, and that their identification may lead to medical intervention that ultimately saves lives.”
Findings highlight impact of SUDC
“This study is important because SUDC is a much more pressing medical need than most people realize,” said Richard Tsien, PhD, of New York University Langone Medical Center, and the corresponding author of the study.
Although SUDC is less common than SIDS, SUDC has essentially no targeted research funding, Dr. Tsien said. Study coauthor Laura Gould, MA, a researcher and mother who lost a young child to SUDC, worked with Orrin Devinsky, MD, to create a registry for families with cases of SUDC. This registry was instrumental in allowing the researchers to “do the molecular detective work we need to do” to see whether a genetic basis exists for SUDC, Dr. Tsien said.
“The detective work comes up with a consistent story,” he said. “More than half of the genes that we found are involved in the normal function of the heart and brain,” performing such functions as delivering calcium ions to the inside of the heart cells and nerve cells.
The study “is the first of its kind,” given the difficulty of acquiring DNA from the child and two parents in SUDC cases, Dr. Tsien said.
Overall, approximately 10% of the cases have a compelling explanation based on the coding of DNA, Dr. Tsien said. From a clinical standpoint, that information might affect what a clinician says to a parent.
A key takeaway is that most of the genetic mutations are spontaneous and are not inherited from the parents, Dr. Tsien said. The study findings indicate that parents who suffer an SUDC loss need not be discouraged from having children, he added.
For the long term, “the more we understand about these disorders, the more information we can offer to families,” he said. Eventually, clinicians might be able to use genetics to identify signs of when SUDC might be more likely. “For example, if a child shows a very mild seizure, this would alert them that there might be potential for a more drastic outcome.”
Meanwhile, families with SUDC cases may find support and benefit in signing up for the registry and knowing that other families have been through a similar experience, Dr. Tsien said.
Genetic studies create opportunities
A significant portion of pediatric mortality remains unexplained, according to Richard D. Goldstein, MD, of Boston Children’s Hospital. One reason is the lack of a formal diagnostic code to identify these deaths.
Research to date has suggested links between SUDC and a family history of febrile seizures, as well as differences in brain structure associated with epilepsy, Dr. Goldstein said.
“An important hypothesis is that these deaths are part of a continuum that also includes stillbirths, SIDS, and sudden unexpected death in epilepsy [SUDEP],” Dr. Goldstein said. “By mandate, investigations of these deaths occur under the jurisdiction of medical examiners and coroners and have, for the most part, been insulated from developments in modern medicine like genomics and proteomics, elements of what are referred to as the molecular autopsy, and studies such as the current study bring attention to what is being missed.”
Dr. Goldstein said the new study buttresses the “conventional clinical suspicion” about the likely causes of SUDC, “but also strengthens the association between sudden unexpected death in pediatrics (SUDP) and SUDEP that we and others have been positing. I think the researchers very nicely make the point that epilepsy and cardiac arrhythmia genes are not as separated in their effects as many would believe.”
As for the clinical applicability of the findings, Dr. Goldstein said medicine needs to offer parents more: “Pediatric deaths without explanation deserve more than a forensic investigation that concerns itself mostly with whether there has been foul play,” he said. “We need to figure out how to engage families, at an incredibly vulnerable time, in helping find the cause of the child’s death and also contributing to needed research. Most of the reported variants were de novo, which means that parent participation is needed to figure out these genetic factors but also that we can offer reassurance to families that other children are not at risk.”
The study was supported by the SUDC Foundation and Finding a Cure for Epilepsy and Seizures (New York University). Dr. Tsien disclosed support from the National Institutes of Health and a grant from FACES. Dr. Goldstein reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, researchers have found.
Previous studies have found de novo genetic variants – those not found in either parent but which occur for the first time in their offspring – that increase the risk of cardiac and seizure disorders, but research on sudden unexplained deaths in children (SUDC) is limited, according to Matthew Halvorsen, PhD, of the University of North Carolina at Chapel Hill, and colleagues. Most cases of SUDC occur in children aged 1-4 years, and a lack of standardized investigation systems likely leads to misclassification of these deaths, they said.
Compared with sudden infant death syndrome (SIDS), which occurs in approximately 1,400 children in the United States each year, approximately 400 children aged 1 year and older die from SUDC annually. A major obstacle to studying these cases is that so-called molecular autopsies – which incorporate genetic analysis into the postmortem examination – typically do not assess the parents’ genetic information and thus limit the ability to identify de novo mutations, they added.
In a study published in the Proceedings of the National Academy of Sciences, Dr. Halvorsen’s group obtained whole exome sequence data from 124 “trios,” meaning a dead child and two living parents. They tested for excessive de novo mutations for different genes involved in conditions that included cardiac arrhythmias and epilepsy. The average age at the time of death for the children was 34.2 months; 54% were male, and 82% were White.
Children who died of SUDC were nearly 10 times as likely to have de novo mutations in genes associated with cardiac and seizure disorders as were unrelated healthy controls (odds ratio, 9.76). Most pathogenic variants were de novo, which highlights the importance of trio studies, the researchers noted.
The researchers identified 11 variants associated with increased risk of SUDC, 7 of which were de novo. Three of the 124 cases carried mutations (two for RYR2 and 1 for TNNI3) affecting genes in the CardiacEpilepsy dataset proposed by the American College of Medical Genetics and Genomics, strengthening the connection to seizure disorders.
Another notable finding was the identification of six de novo mutations involved in altering calcium-related regulation, which suggests a cardiac susceptibility to sudden death.
The data support “novel genetic causes of pediatric sudden deaths that could be discovered with larger cohorts,” the researchers noted. Taken together, they say, the gene mutations could play a role in approximately 9% of SUDC cases.
The study findings were limited by several factors, including lack of population-based case ascertainment, exclusive focus on unexplained deaths, potentially missed mutations, and use of DNA from blood as opposed to organs, the researchers noted.
However, they concluded, “the data indicate that deleterious de novo mutations are significant genetic risk factors for childhood sudden unexplained death, and that their identification may lead to medical intervention that ultimately saves lives.”
Findings highlight impact of SUDC
“This study is important because SUDC is a much more pressing medical need than most people realize,” said Richard Tsien, PhD, of New York University Langone Medical Center, and the corresponding author of the study.
Although SUDC is less common than SIDS, SUDC has essentially no targeted research funding, Dr. Tsien said. Study coauthor Laura Gould, MA, a researcher and mother who lost a young child to SUDC, worked with Orrin Devinsky, MD, to create a registry for families with cases of SUDC. This registry was instrumental in allowing the researchers to “do the molecular detective work we need to do” to see whether a genetic basis exists for SUDC, Dr. Tsien said.
“The detective work comes up with a consistent story,” he said. “More than half of the genes that we found are involved in the normal function of the heart and brain,” performing such functions as delivering calcium ions to the inside of the heart cells and nerve cells.
The study “is the first of its kind,” given the difficulty of acquiring DNA from the child and two parents in SUDC cases, Dr. Tsien said.
Overall, approximately 10% of the cases have a compelling explanation based on the coding of DNA, Dr. Tsien said. From a clinical standpoint, that information might affect what a clinician says to a parent.
A key takeaway is that most of the genetic mutations are spontaneous and are not inherited from the parents, Dr. Tsien said. The study findings indicate that parents who suffer an SUDC loss need not be discouraged from having children, he added.
For the long term, “the more we understand about these disorders, the more information we can offer to families,” he said. Eventually, clinicians might be able to use genetics to identify signs of when SUDC might be more likely. “For example, if a child shows a very mild seizure, this would alert them that there might be potential for a more drastic outcome.”
Meanwhile, families with SUDC cases may find support and benefit in signing up for the registry and knowing that other families have been through a similar experience, Dr. Tsien said.
Genetic studies create opportunities
A significant portion of pediatric mortality remains unexplained, according to Richard D. Goldstein, MD, of Boston Children’s Hospital. One reason is the lack of a formal diagnostic code to identify these deaths.
Research to date has suggested links between SUDC and a family history of febrile seizures, as well as differences in brain structure associated with epilepsy, Dr. Goldstein said.
“An important hypothesis is that these deaths are part of a continuum that also includes stillbirths, SIDS, and sudden unexpected death in epilepsy [SUDEP],” Dr. Goldstein said. “By mandate, investigations of these deaths occur under the jurisdiction of medical examiners and coroners and have, for the most part, been insulated from developments in modern medicine like genomics and proteomics, elements of what are referred to as the molecular autopsy, and studies such as the current study bring attention to what is being missed.”
Dr. Goldstein said the new study buttresses the “conventional clinical suspicion” about the likely causes of SUDC, “but also strengthens the association between sudden unexpected death in pediatrics (SUDP) and SUDEP that we and others have been positing. I think the researchers very nicely make the point that epilepsy and cardiac arrhythmia genes are not as separated in their effects as many would believe.”
As for the clinical applicability of the findings, Dr. Goldstein said medicine needs to offer parents more: “Pediatric deaths without explanation deserve more than a forensic investigation that concerns itself mostly with whether there has been foul play,” he said. “We need to figure out how to engage families, at an incredibly vulnerable time, in helping find the cause of the child’s death and also contributing to needed research. Most of the reported variants were de novo, which means that parent participation is needed to figure out these genetic factors but also that we can offer reassurance to families that other children are not at risk.”
The study was supported by the SUDC Foundation and Finding a Cure for Epilepsy and Seizures (New York University). Dr. Tsien disclosed support from the National Institutes of Health and a grant from FACES. Dr. Goldstein reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AAN updates treatment guidance on painful diabetic neuropathy
Painful diabetic neuropathy is very common and can greatly affect an individual’s quality of life, guideline author Brian Callaghan, MD, University of Michigan, Ann Arbor, noted in a news release.
“This guideline aims to help neurologists and other doctors provide the highest quality patient care based on the latest evidence,” Dr. Callaghan said.
The recommendations update the 2011 AAN guideline on the treatment of painful diabetic neuropathy. The new guidance was published online Dec. 27, 2021, in Neurology and has been endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine.
Multiple options
To update the guideline, an expert panel reviewed data from more than 100 randomized controlled trials published from January 2008 to April 2020.
The panel noted that more than 16% of individuals with diabetes experience painful diabetic neuropathy, but it often goes unrecognized and untreated. The guideline recommends clinicians assess patients with diabetes for peripheral neuropathic pain and its effect on their function and quality of life.
Before prescribing treatment, health providers should determine if the patient also has mood or sleep problems as both can influence pain perception.
The guideline recommends offering one of four classes of oral medications found to be effective for neuropathic pain: tricyclic antidepressants such as amitriptyline, nortriptyline, or imipramine; serotonin norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, or desvenlafaxine; gabapentinoids such as gabapentin or pregabalin; and/or sodium channel blockers such as carbamazepine, oxcarbazepine, lamotrigine, or lacosamide.
All four classes of medications have “comparable effect sizes just above or just below our cutoff for a medium effect size” (standardized median difference, 0.5), the panel noted.
In addition, “new studies on sodium channel blockers published since the last guideline have resulted in these drugs now being recommended and considered as effective at providing pain relief as the other drug classes recommended in this guideline,” said Dr. Callaghan.
When an initial medication fails to provide meaningful improvement in pain, or produces significant side effects, a trial of another medication from a different class is recommended.
Pain reduction, not elimination
Opioids are not recommended for painful diabetic neuropathy. Not only do they come with risks, there is also no strong evidence they are effective for painful diabetic neuropathy in the long term, the panel wrote. Tramadol and tapentadol are also not recommended for the treatment of painful diabetic neuropathy.
“Current evidence suggests that the risks of the use of opioids for painful diabetic neuropathy therapy outweigh the benefits, so they should not be prescribed,” Dr. Callaghan said.
For patients interested in trying topical, nontraditional, or nondrug interventions to reduce pain, the guideline recommends a number of options including capsaicin, glyceryl trinitrate spray, and Citrullus colocynthis. Ginkgo biloba, exercise, mindfulness, cognitive-behavioral therapy, and tai chi are also suggested.
“It is important to note that the recommended drugs and topical treatments in this guideline may not eliminate pain, but they have been shown to reduce pain,” Dr. Callaghan said. “The good news is there are many treatment options for painful diabetic neuropathy, so a treatment plan can be tailored specifically to each person living with this condition.”
Along with the updated guideline, the AAN has also published a new Polyneuropathy Quality Measurement Set to assist neurologists and other health care providers in treating patients with painful diabetic neuropathy.
The updated guideline was developed with financial support from the AAN.
A version of this article first appeared on Medscape.com.
Painful diabetic neuropathy is very common and can greatly affect an individual’s quality of life, guideline author Brian Callaghan, MD, University of Michigan, Ann Arbor, noted in a news release.
“This guideline aims to help neurologists and other doctors provide the highest quality patient care based on the latest evidence,” Dr. Callaghan said.
The recommendations update the 2011 AAN guideline on the treatment of painful diabetic neuropathy. The new guidance was published online Dec. 27, 2021, in Neurology and has been endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine.
Multiple options
To update the guideline, an expert panel reviewed data from more than 100 randomized controlled trials published from January 2008 to April 2020.
The panel noted that more than 16% of individuals with diabetes experience painful diabetic neuropathy, but it often goes unrecognized and untreated. The guideline recommends clinicians assess patients with diabetes for peripheral neuropathic pain and its effect on their function and quality of life.
Before prescribing treatment, health providers should determine if the patient also has mood or sleep problems as both can influence pain perception.
The guideline recommends offering one of four classes of oral medications found to be effective for neuropathic pain: tricyclic antidepressants such as amitriptyline, nortriptyline, or imipramine; serotonin norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, or desvenlafaxine; gabapentinoids such as gabapentin or pregabalin; and/or sodium channel blockers such as carbamazepine, oxcarbazepine, lamotrigine, or lacosamide.
All four classes of medications have “comparable effect sizes just above or just below our cutoff for a medium effect size” (standardized median difference, 0.5), the panel noted.
In addition, “new studies on sodium channel blockers published since the last guideline have resulted in these drugs now being recommended and considered as effective at providing pain relief as the other drug classes recommended in this guideline,” said Dr. Callaghan.
When an initial medication fails to provide meaningful improvement in pain, or produces significant side effects, a trial of another medication from a different class is recommended.
Pain reduction, not elimination
Opioids are not recommended for painful diabetic neuropathy. Not only do they come with risks, there is also no strong evidence they are effective for painful diabetic neuropathy in the long term, the panel wrote. Tramadol and tapentadol are also not recommended for the treatment of painful diabetic neuropathy.
“Current evidence suggests that the risks of the use of opioids for painful diabetic neuropathy therapy outweigh the benefits, so they should not be prescribed,” Dr. Callaghan said.
For patients interested in trying topical, nontraditional, or nondrug interventions to reduce pain, the guideline recommends a number of options including capsaicin, glyceryl trinitrate spray, and Citrullus colocynthis. Ginkgo biloba, exercise, mindfulness, cognitive-behavioral therapy, and tai chi are also suggested.
“It is important to note that the recommended drugs and topical treatments in this guideline may not eliminate pain, but they have been shown to reduce pain,” Dr. Callaghan said. “The good news is there are many treatment options for painful diabetic neuropathy, so a treatment plan can be tailored specifically to each person living with this condition.”
Along with the updated guideline, the AAN has also published a new Polyneuropathy Quality Measurement Set to assist neurologists and other health care providers in treating patients with painful diabetic neuropathy.
The updated guideline was developed with financial support from the AAN.
A version of this article first appeared on Medscape.com.
Painful diabetic neuropathy is very common and can greatly affect an individual’s quality of life, guideline author Brian Callaghan, MD, University of Michigan, Ann Arbor, noted in a news release.
“This guideline aims to help neurologists and other doctors provide the highest quality patient care based on the latest evidence,” Dr. Callaghan said.
The recommendations update the 2011 AAN guideline on the treatment of painful diabetic neuropathy. The new guidance was published online Dec. 27, 2021, in Neurology and has been endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine.
Multiple options
To update the guideline, an expert panel reviewed data from more than 100 randomized controlled trials published from January 2008 to April 2020.
The panel noted that more than 16% of individuals with diabetes experience painful diabetic neuropathy, but it often goes unrecognized and untreated. The guideline recommends clinicians assess patients with diabetes for peripheral neuropathic pain and its effect on their function and quality of life.
Before prescribing treatment, health providers should determine if the patient also has mood or sleep problems as both can influence pain perception.
The guideline recommends offering one of four classes of oral medications found to be effective for neuropathic pain: tricyclic antidepressants such as amitriptyline, nortriptyline, or imipramine; serotonin norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, or desvenlafaxine; gabapentinoids such as gabapentin or pregabalin; and/or sodium channel blockers such as carbamazepine, oxcarbazepine, lamotrigine, or lacosamide.
All four classes of medications have “comparable effect sizes just above or just below our cutoff for a medium effect size” (standardized median difference, 0.5), the panel noted.
In addition, “new studies on sodium channel blockers published since the last guideline have resulted in these drugs now being recommended and considered as effective at providing pain relief as the other drug classes recommended in this guideline,” said Dr. Callaghan.
When an initial medication fails to provide meaningful improvement in pain, or produces significant side effects, a trial of another medication from a different class is recommended.
Pain reduction, not elimination
Opioids are not recommended for painful diabetic neuropathy. Not only do they come with risks, there is also no strong evidence they are effective for painful diabetic neuropathy in the long term, the panel wrote. Tramadol and tapentadol are also not recommended for the treatment of painful diabetic neuropathy.
“Current evidence suggests that the risks of the use of opioids for painful diabetic neuropathy therapy outweigh the benefits, so they should not be prescribed,” Dr. Callaghan said.
For patients interested in trying topical, nontraditional, or nondrug interventions to reduce pain, the guideline recommends a number of options including capsaicin, glyceryl trinitrate spray, and Citrullus colocynthis. Ginkgo biloba, exercise, mindfulness, cognitive-behavioral therapy, and tai chi are also suggested.
“It is important to note that the recommended drugs and topical treatments in this guideline may not eliminate pain, but they have been shown to reduce pain,” Dr. Callaghan said. “The good news is there are many treatment options for painful diabetic neuropathy, so a treatment plan can be tailored specifically to each person living with this condition.”
Along with the updated guideline, the AAN has also published a new Polyneuropathy Quality Measurement Set to assist neurologists and other health care providers in treating patients with painful diabetic neuropathy.
The updated guideline was developed with financial support from the AAN.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Posttraumatic epilepsy is common, even after ‘mild’ TBI
, new research suggests.
Results from a multicenter, prospective cohort study showed 2.7% of nearly 1,500 participants with TBI reported also having posttraumatic epilepsy, and these patients had significantly worse outcomes than those without posttraumatic epilepsy.
“Posttraumatic epilepsy is common even in so-called mild TBI, and we should be on the lookout for patients reporting these kinds of spells,” said coinvestigator Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the TBI Clinical Research Center, University of Pennsylvania, Philadelphia.
Dr. Diaz-Arrastia said he dislikes the term “mild TBI” because many of these injuries have “pretty substantial consequences.”
The findings were published online Dec. 29 in JAMA Network Open.
Novel study
Seizures can occur after TBI, most commonly after a severe brain injury, such as those leading to coma or bleeding in the brain or requiring surgical intervention. However, there have been “hints” that some patients with milder brain injuries are also at increased risk for epilepsy, said Dr. Diaz-Arrastia.
To investigate, the researchers assessed data from the large, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) database. Participants with TBI, defined as a Glasgow Coma Scale (GCS) score of 3-15, had presented to a level I trauma center within 24 hours of a head trauma needing evaluation with a CT scan.
The study included patients with relatively mild TBI (GCS score, 13-15), which is a “novel feature” of the study, the authors noted. Most prior studies of posttraumatic epilepsy focused on moderate to severe TBI.
The researchers included two sex- and age-matched control groups. The orthopedic trauma control (OTC) group consisted of patients with isolated trauma to the limbs, pelvis, and/or ribs. The “friend” or peer control group had backgrounds and lifestyles similar to those with TBI but had no history of TBI, concussion, or traumatic injury in the previous year.
The analysis included 1,885 participants (mean age, 41.3 years; 65.8% men). Of these, 1,493 had TBI, 182 were in the OTC group, and 210 were in the friends group. At 6- and 12-month follow-ups, investigators administered the Epilepsy Screening Questionnaire (ESQ), developed by the National Institute of Neurological Disorders and Stroke (NINDS).
Confirmatory data
Participants were asked about experiencing uncontrolled movements, unexplained changes in mental state, and repeated unusual attacks or convulsions, and whether they had been told they had epilepsy or seizures. If they answered yes to any of these questions, they received second-level screening, which asked about seizures.
Patients were deemed to have posttraumatic epilepsy if they answered affirmatively to any first-level screening item, experienced seizures 7 days after injury, and were diagnosed with epilepsy.
The primary outcome was rate of positive posttraumatic epilepsy diagnoses. At 12 months, 2.7% of those with TBI reported a posttraumatic epilepsy diagnosis compared with none of either of the control groups (P < .001).
This rate is consistent with prior literature and is “pretty close to what we expected,” said Dr. Diaz-Arrastia.
Among those with TBI and posttraumatic epilepsy, 12.2% had GCS scores of 3-8 (severe), 5.3% had scores of 9-12 (moderate), and 0.9% had scores of 13-15 (mild). That figure for mild TBI is not insignificant, said Dr. Diaz-Arrastia.
“Probably 90% of all those coming to the emergency room with a brain injury are diagnosed with mild TBI not requiring admission,” he noted.
The risk for posttraumatic epilepsy was higher the more severe the head injury, and among those with hemorrhage on head CT imaging. In patients with mild TBI, hemorrhage was associated with a two- to threefold risk of developing posttraumatic epilepsy.
“This prospective observational study confirms the epidemiologic data that even after mild brain injury, there is an increased risk for epilepsy,” said Dr. Diaz-Arrastia.
Universal screening?
The researchers also looked at whether seizures worsen other outcomes. Compared with those who had TBI but not posttraumatic epilepsy, those with posttraumatic epilepsy had significantly lower Glasgow Outcome Scale Extended (GOSE) scores (mean, 4.7 vs. 6.1; P < .001), higher Brief Symptom Inventory (BSI) scores (58.6 vs. 50.2; P = .02), and higher Rivermead Cognitive Metric (RCM) scores (5.3 vs. 3.1; P = .002) at 12 months after adjustment for age, initial GCS score, and imaging findings.
Higher GOSE and RCM scores reflect better outcomes, but a higher score on the BSI, which assesses overall mood, reflects a worse outcome, the investigators noted.
Previous evidence suggests prophylactic use of antiepileptic drugs in patients with TBI does not reduce risks. These drugs “are neither 100% safe nor 100% effective,” said Dr. Diaz-Arrastia. Some studies showed that certain agents actually worsen outcomes, he added.
What the field needs instead are antiepileptogenic drugs – those that interfere with the maladaptive synaptic plasticity that ends up in an epileptic circuit, he noted.
The new results suggest screening for posttraumatic epilepsy using the NINDS-ESQ “should be done pretty much routinely as a follow-up for all brain injuries,” Dr. Diaz-Arrastia said.
The investigators plan to have study participants assessed by an epileptologist later. A significant number of people with TBI, he noted, won’t develop posttraumatic epilepsy until 1-5 years after their injury – and even later in some cases.
A limitation of the study was that some patients reporting posttraumatic epilepsy may have had psychogenic nonepileptiform seizures, which are common in TBI patients, the investigators noted.
The study was supported by grants from One Mind, National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS, and Department of Defence. Dr. Diaz-Arrastia reported receiving grants from the NIH, NINDS, and DOD during the conduct of the study.
A version of this article first appeared on Medscape.com.
, new research suggests.
Results from a multicenter, prospective cohort study showed 2.7% of nearly 1,500 participants with TBI reported also having posttraumatic epilepsy, and these patients had significantly worse outcomes than those without posttraumatic epilepsy.
“Posttraumatic epilepsy is common even in so-called mild TBI, and we should be on the lookout for patients reporting these kinds of spells,” said coinvestigator Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the TBI Clinical Research Center, University of Pennsylvania, Philadelphia.
Dr. Diaz-Arrastia said he dislikes the term “mild TBI” because many of these injuries have “pretty substantial consequences.”
The findings were published online Dec. 29 in JAMA Network Open.
Novel study
Seizures can occur after TBI, most commonly after a severe brain injury, such as those leading to coma or bleeding in the brain or requiring surgical intervention. However, there have been “hints” that some patients with milder brain injuries are also at increased risk for epilepsy, said Dr. Diaz-Arrastia.
To investigate, the researchers assessed data from the large, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) database. Participants with TBI, defined as a Glasgow Coma Scale (GCS) score of 3-15, had presented to a level I trauma center within 24 hours of a head trauma needing evaluation with a CT scan.
The study included patients with relatively mild TBI (GCS score, 13-15), which is a “novel feature” of the study, the authors noted. Most prior studies of posttraumatic epilepsy focused on moderate to severe TBI.
The researchers included two sex- and age-matched control groups. The orthopedic trauma control (OTC) group consisted of patients with isolated trauma to the limbs, pelvis, and/or ribs. The “friend” or peer control group had backgrounds and lifestyles similar to those with TBI but had no history of TBI, concussion, or traumatic injury in the previous year.
The analysis included 1,885 participants (mean age, 41.3 years; 65.8% men). Of these, 1,493 had TBI, 182 were in the OTC group, and 210 were in the friends group. At 6- and 12-month follow-ups, investigators administered the Epilepsy Screening Questionnaire (ESQ), developed by the National Institute of Neurological Disorders and Stroke (NINDS).
Confirmatory data
Participants were asked about experiencing uncontrolled movements, unexplained changes in mental state, and repeated unusual attacks or convulsions, and whether they had been told they had epilepsy or seizures. If they answered yes to any of these questions, they received second-level screening, which asked about seizures.
Patients were deemed to have posttraumatic epilepsy if they answered affirmatively to any first-level screening item, experienced seizures 7 days after injury, and were diagnosed with epilepsy.
The primary outcome was rate of positive posttraumatic epilepsy diagnoses. At 12 months, 2.7% of those with TBI reported a posttraumatic epilepsy diagnosis compared with none of either of the control groups (P < .001).
This rate is consistent with prior literature and is “pretty close to what we expected,” said Dr. Diaz-Arrastia.
Among those with TBI and posttraumatic epilepsy, 12.2% had GCS scores of 3-8 (severe), 5.3% had scores of 9-12 (moderate), and 0.9% had scores of 13-15 (mild). That figure for mild TBI is not insignificant, said Dr. Diaz-Arrastia.
“Probably 90% of all those coming to the emergency room with a brain injury are diagnosed with mild TBI not requiring admission,” he noted.
The risk for posttraumatic epilepsy was higher the more severe the head injury, and among those with hemorrhage on head CT imaging. In patients with mild TBI, hemorrhage was associated with a two- to threefold risk of developing posttraumatic epilepsy.
“This prospective observational study confirms the epidemiologic data that even after mild brain injury, there is an increased risk for epilepsy,” said Dr. Diaz-Arrastia.
Universal screening?
The researchers also looked at whether seizures worsen other outcomes. Compared with those who had TBI but not posttraumatic epilepsy, those with posttraumatic epilepsy had significantly lower Glasgow Outcome Scale Extended (GOSE) scores (mean, 4.7 vs. 6.1; P < .001), higher Brief Symptom Inventory (BSI) scores (58.6 vs. 50.2; P = .02), and higher Rivermead Cognitive Metric (RCM) scores (5.3 vs. 3.1; P = .002) at 12 months after adjustment for age, initial GCS score, and imaging findings.
Higher GOSE and RCM scores reflect better outcomes, but a higher score on the BSI, which assesses overall mood, reflects a worse outcome, the investigators noted.
Previous evidence suggests prophylactic use of antiepileptic drugs in patients with TBI does not reduce risks. These drugs “are neither 100% safe nor 100% effective,” said Dr. Diaz-Arrastia. Some studies showed that certain agents actually worsen outcomes, he added.
What the field needs instead are antiepileptogenic drugs – those that interfere with the maladaptive synaptic plasticity that ends up in an epileptic circuit, he noted.
The new results suggest screening for posttraumatic epilepsy using the NINDS-ESQ “should be done pretty much routinely as a follow-up for all brain injuries,” Dr. Diaz-Arrastia said.
The investigators plan to have study participants assessed by an epileptologist later. A significant number of people with TBI, he noted, won’t develop posttraumatic epilepsy until 1-5 years after their injury – and even later in some cases.
A limitation of the study was that some patients reporting posttraumatic epilepsy may have had psychogenic nonepileptiform seizures, which are common in TBI patients, the investigators noted.
The study was supported by grants from One Mind, National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS, and Department of Defence. Dr. Diaz-Arrastia reported receiving grants from the NIH, NINDS, and DOD during the conduct of the study.
A version of this article first appeared on Medscape.com.
, new research suggests.
Results from a multicenter, prospective cohort study showed 2.7% of nearly 1,500 participants with TBI reported also having posttraumatic epilepsy, and these patients had significantly worse outcomes than those without posttraumatic epilepsy.
“Posttraumatic epilepsy is common even in so-called mild TBI, and we should be on the lookout for patients reporting these kinds of spells,” said coinvestigator Ramon Diaz-Arrastia, MD, PhD, professor of neurology and director of the TBI Clinical Research Center, University of Pennsylvania, Philadelphia.
Dr. Diaz-Arrastia said he dislikes the term “mild TBI” because many of these injuries have “pretty substantial consequences.”
The findings were published online Dec. 29 in JAMA Network Open.
Novel study
Seizures can occur after TBI, most commonly after a severe brain injury, such as those leading to coma or bleeding in the brain or requiring surgical intervention. However, there have been “hints” that some patients with milder brain injuries are also at increased risk for epilepsy, said Dr. Diaz-Arrastia.
To investigate, the researchers assessed data from the large, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) database. Participants with TBI, defined as a Glasgow Coma Scale (GCS) score of 3-15, had presented to a level I trauma center within 24 hours of a head trauma needing evaluation with a CT scan.
The study included patients with relatively mild TBI (GCS score, 13-15), which is a “novel feature” of the study, the authors noted. Most prior studies of posttraumatic epilepsy focused on moderate to severe TBI.
The researchers included two sex- and age-matched control groups. The orthopedic trauma control (OTC) group consisted of patients with isolated trauma to the limbs, pelvis, and/or ribs. The “friend” or peer control group had backgrounds and lifestyles similar to those with TBI but had no history of TBI, concussion, or traumatic injury in the previous year.
The analysis included 1,885 participants (mean age, 41.3 years; 65.8% men). Of these, 1,493 had TBI, 182 were in the OTC group, and 210 were in the friends group. At 6- and 12-month follow-ups, investigators administered the Epilepsy Screening Questionnaire (ESQ), developed by the National Institute of Neurological Disorders and Stroke (NINDS).
Confirmatory data
Participants were asked about experiencing uncontrolled movements, unexplained changes in mental state, and repeated unusual attacks or convulsions, and whether they had been told they had epilepsy or seizures. If they answered yes to any of these questions, they received second-level screening, which asked about seizures.
Patients were deemed to have posttraumatic epilepsy if they answered affirmatively to any first-level screening item, experienced seizures 7 days after injury, and were diagnosed with epilepsy.
The primary outcome was rate of positive posttraumatic epilepsy diagnoses. At 12 months, 2.7% of those with TBI reported a posttraumatic epilepsy diagnosis compared with none of either of the control groups (P < .001).
This rate is consistent with prior literature and is “pretty close to what we expected,” said Dr. Diaz-Arrastia.
Among those with TBI and posttraumatic epilepsy, 12.2% had GCS scores of 3-8 (severe), 5.3% had scores of 9-12 (moderate), and 0.9% had scores of 13-15 (mild). That figure for mild TBI is not insignificant, said Dr. Diaz-Arrastia.
“Probably 90% of all those coming to the emergency room with a brain injury are diagnosed with mild TBI not requiring admission,” he noted.
The risk for posttraumatic epilepsy was higher the more severe the head injury, and among those with hemorrhage on head CT imaging. In patients with mild TBI, hemorrhage was associated with a two- to threefold risk of developing posttraumatic epilepsy.
“This prospective observational study confirms the epidemiologic data that even after mild brain injury, there is an increased risk for epilepsy,” said Dr. Diaz-Arrastia.
Universal screening?
The researchers also looked at whether seizures worsen other outcomes. Compared with those who had TBI but not posttraumatic epilepsy, those with posttraumatic epilepsy had significantly lower Glasgow Outcome Scale Extended (GOSE) scores (mean, 4.7 vs. 6.1; P < .001), higher Brief Symptom Inventory (BSI) scores (58.6 vs. 50.2; P = .02), and higher Rivermead Cognitive Metric (RCM) scores (5.3 vs. 3.1; P = .002) at 12 months after adjustment for age, initial GCS score, and imaging findings.
Higher GOSE and RCM scores reflect better outcomes, but a higher score on the BSI, which assesses overall mood, reflects a worse outcome, the investigators noted.
Previous evidence suggests prophylactic use of antiepileptic drugs in patients with TBI does not reduce risks. These drugs “are neither 100% safe nor 100% effective,” said Dr. Diaz-Arrastia. Some studies showed that certain agents actually worsen outcomes, he added.
What the field needs instead are antiepileptogenic drugs – those that interfere with the maladaptive synaptic plasticity that ends up in an epileptic circuit, he noted.
The new results suggest screening for posttraumatic epilepsy using the NINDS-ESQ “should be done pretty much routinely as a follow-up for all brain injuries,” Dr. Diaz-Arrastia said.
The investigators plan to have study participants assessed by an epileptologist later. A significant number of people with TBI, he noted, won’t develop posttraumatic epilepsy until 1-5 years after their injury – and even later in some cases.
A limitation of the study was that some patients reporting posttraumatic epilepsy may have had psychogenic nonepileptiform seizures, which are common in TBI patients, the investigators noted.
The study was supported by grants from One Mind, National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS, and Department of Defence. Dr. Diaz-Arrastia reported receiving grants from the NIH, NINDS, and DOD during the conduct of the study.
A version of this article first appeared on Medscape.com.