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Subtle visual dysfunctions often precede early-stage psychosis
A multinational group of investigators found that VisDys were reported considerably more often by patients with recent-onset psychosis and CHR than by those with recent-onset depression or a group acting as healthy control participants.
In addition, vision problems of higher severity were associated with less functional remission both for patients at CHR and those with recent-onset psychosis. Among patients with CHR, VisDys was also linked to lower quality of life (QOL), higher depressiveness, and more severe impairment of visuospatial constructability.
The researchers used fMRI imaging to compare resting-state functional brain connectivity in participants with recent-onset psychosis, CHR, and recent-onset depression. They found that the occipital (ON) and frontoparietal (FPN) subnetworks were particularly implicated in VisDys.
“Subtle VisDys should be regarded as a frequent phenomenon across the psychosis spectrum, impinging negatively on patients’ current ability to function in several settings of their daily and social life, their QOL, and visuospatial abilities,” write investigators led by Johanna Schwarzer, Institute for Translational Psychiatry, University of Muenster (Germany).
“These large-sample study findings suggest that VisDys are clinically highly relevant not only in [recent-onset psychosis] but especially in CHR,” they stated.
The findings were published online in Neuropsychopharmacology.
Subtle, underrecognized
Unlike patients with nonpsychotic disorders, approximately 50%-60% of patients diagnosed with schizophrenia report VisDys involving brightness, motion, form, color perception, or distorted perception of their own face, the researchers reported.
These “subtle” VisDys are “often underrecognized during clinical examination, despite their clinical relevance related to suicidal ideation, cognitive impairment, or poorer treatment response,” they wrote.
Most research into these vision problems in patients with schizophrenia has focused on patients in which the illness is in a stable, chronic state – although VisDys often appear years before the diagnosis of a psychotic disorder.
Moreover, there has been little research into the neurobiological underpinnings of VisDys, specifically in early states of psychosis and/or in comparison to other disorders, such as depression.
The Personalised Prognostic Indicators for Early Psychosis Management (PRONIA) Consortium studied the psychophysiological phenomenon of VisDys in a large sample of adolescents and young adults. The sample consisted of three diagnostic groups: those with recent-onset psychosis, those with CHR, and those with recent-onset depression.
VisDys in daily life were measured using the Schizophrenia Proneness Instrument–Adult Scale (SPI-A), which assesses basic symptoms that indicate increased risk for psychosis.
Visual information processing
Resting-state imaging data on intrinsic brain networks were also assessed in the PRONIA sample and were analyzed across 12,720 functional connectivities between 160 regions of interest across the whole brain.
In particular, the researchers were interested in the primary networks involved in visual information processing, especially the dorsal visual stream, with further focus on the ON and FPN intrinsic subnetworks.
The ON was chosen because it comprises “primary visual processing pathways,” while the FPN is “widely suggested to modulate attention related to visual information processing at higher cognitive levels.”
The investigators used a machine-learning multivariate pattern analysis approach that “enables the consideration of multiple interactions within brain systems.”
The current study involved 721 participants from the PRONIA database, including 147 participants with recent-onset psychosis (mean age, 28.45 years; 60.5% men), 143 with CHR (mean age, 26.97 years; about 50% men), 151 with recent-onset depression (mean age, 29.13 years; 47% men), and 280 in the healthy-controls group (mean age, 28.54 years; 39.4% men).
The researchers selected 14 items to assess from the SPI-A that represented different aspects of VisDys. Severity was defined by the maximum frequency within the past 3 months – from 1 (never) to 6 (daily).
The 14 items were as follows: oversensitivity to light and/or certain visual perception objects, photopsia, micropsia/macropsia, near and tele-vision, metamorphopsia, changes in color vision, altered perception of a patient’s own face, pseudomovements of optic stimuli, diplopia or oblique vision, disturbances of the estimation of distances or sizes, disturbances of the perception of straight lines/contours, maintenance of optic stimuli “visual echoes,” partial seeing (including tubular vision), and captivation of attention by details of the visual field.
Participants also completed the Beck Depression Inventory–II scale (BDI-II), the Positive and Negative Syndrome Scale (PANSS), the Functional Remission in General Schizophrenia, and several other scales that measure global and social functioning.
Other assessments included QOL and the Rey-Osterrieth Complex Figure Test, which is a neuropsychological measurement of visuospatial constructability.
Specific to early-stage psychosis?
Results showed that VisDys were reported more frequently in both recent-onset psychosis and CHR groups compared with the recent-onset depression and healthy control groups (50.34% and 55.94% vs. 16.56% and 4.28%, respectively).
The investigators noted that VisDys sum scores “showed high internal consistency” (Cronbachs alpha, 0.78 over all participants).
Among those with recent-onset psychosis, a higher VisDys sum score was correlated with lower scores for functional remission (P = .036) and social functioning (P = .014).
In CHR, higher VisDys sum scores were associated with lower scores for health-related functional remission (P = .024), lower physical and psychological QOL (P = .004 and P = .015, respectively), more severe depression on the BDI-II (P = .021), and more impaired visuospatial constructability (P = .027).
Among those with recent-onset depression and their healthy peers, “no relevant correlations were found between VisDys sum scores and any parameters representing functional remission, QOL, depressiveness, or visuospatial constructability,” the researchers wrote.
A total of 135 participants with recent-onset psychosis, 128 with CHR, and 134 with recent-onset depression also underwent resting-state fMRI.
ON functional connectivity predicted presence of VisDys in patients with recent-onset psychosis and those with CHR, with a balanced accuracy of 60.17% (P = .0001) and 67.38% (P = .029), respectively. In the combined recent-onset psychosis plus CHR sample, VisDys were predicted by FPN functional connectivity (balanced accuracy, 61.1%; P = .006).
“Findings from multivariate pattern analysis support a model of functional integrity within ON and FPN driving the VisDys phenomenon and being implicated in core disease mechanisms of early psychosis states,” the investigators noted.
“The main findings from this large sample study support the idea of VisDys being specific to the psychosis spectrum already at early stages,” while being less frequently reported in recent-onset depression, they wrote. VisDys also “appeared negligible” among those without psychiatric disorders.
Regular assessment needed
Steven Silverstein, PhD, professor of biopsychosocial medicine and professor of psychiatry, neuroscience, and ophthalmology, Center for Visual Science, University of Rochester (N.Y.) Medical Center, called the findings “important” because “they will increase appreciation in the field of mental health for the frequency and disabling nature of visual symptoms and the need for regular assessment in routine clinical practice with people at risk for or with psychotic disorders.”
In addition, “the brain imaging findings are providing needed information that could lead to treatments that target the brain networks generating the visual symptoms,” such as neurofeedback or brain stimulation, said Dr. Silverstein, who was not involved with the research.
The study was funded by a grant for the PRONIA Consortium. Individual researchers received funding from NARSAD Young Investigator Award of the Brain and Behavior Research Foundation, the Koeln Fortune Program/Faculty of Medicine, the University of Cologne, and the European Union’s Horizon 2020 research and innovation program. Open Access funding was enabled and organized by Projekt DEAL. Ms. Schwarzer and Dr. Silverstein reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A multinational group of investigators found that VisDys were reported considerably more often by patients with recent-onset psychosis and CHR than by those with recent-onset depression or a group acting as healthy control participants.
In addition, vision problems of higher severity were associated with less functional remission both for patients at CHR and those with recent-onset psychosis. Among patients with CHR, VisDys was also linked to lower quality of life (QOL), higher depressiveness, and more severe impairment of visuospatial constructability.
The researchers used fMRI imaging to compare resting-state functional brain connectivity in participants with recent-onset psychosis, CHR, and recent-onset depression. They found that the occipital (ON) and frontoparietal (FPN) subnetworks were particularly implicated in VisDys.
“Subtle VisDys should be regarded as a frequent phenomenon across the psychosis spectrum, impinging negatively on patients’ current ability to function in several settings of their daily and social life, their QOL, and visuospatial abilities,” write investigators led by Johanna Schwarzer, Institute for Translational Psychiatry, University of Muenster (Germany).
“These large-sample study findings suggest that VisDys are clinically highly relevant not only in [recent-onset psychosis] but especially in CHR,” they stated.
The findings were published online in Neuropsychopharmacology.
Subtle, underrecognized
Unlike patients with nonpsychotic disorders, approximately 50%-60% of patients diagnosed with schizophrenia report VisDys involving brightness, motion, form, color perception, or distorted perception of their own face, the researchers reported.
These “subtle” VisDys are “often underrecognized during clinical examination, despite their clinical relevance related to suicidal ideation, cognitive impairment, or poorer treatment response,” they wrote.
Most research into these vision problems in patients with schizophrenia has focused on patients in which the illness is in a stable, chronic state – although VisDys often appear years before the diagnosis of a psychotic disorder.
Moreover, there has been little research into the neurobiological underpinnings of VisDys, specifically in early states of psychosis and/or in comparison to other disorders, such as depression.
The Personalised Prognostic Indicators for Early Psychosis Management (PRONIA) Consortium studied the psychophysiological phenomenon of VisDys in a large sample of adolescents and young adults. The sample consisted of three diagnostic groups: those with recent-onset psychosis, those with CHR, and those with recent-onset depression.
VisDys in daily life were measured using the Schizophrenia Proneness Instrument–Adult Scale (SPI-A), which assesses basic symptoms that indicate increased risk for psychosis.
Visual information processing
Resting-state imaging data on intrinsic brain networks were also assessed in the PRONIA sample and were analyzed across 12,720 functional connectivities between 160 regions of interest across the whole brain.
In particular, the researchers were interested in the primary networks involved in visual information processing, especially the dorsal visual stream, with further focus on the ON and FPN intrinsic subnetworks.
The ON was chosen because it comprises “primary visual processing pathways,” while the FPN is “widely suggested to modulate attention related to visual information processing at higher cognitive levels.”
The investigators used a machine-learning multivariate pattern analysis approach that “enables the consideration of multiple interactions within brain systems.”
The current study involved 721 participants from the PRONIA database, including 147 participants with recent-onset psychosis (mean age, 28.45 years; 60.5% men), 143 with CHR (mean age, 26.97 years; about 50% men), 151 with recent-onset depression (mean age, 29.13 years; 47% men), and 280 in the healthy-controls group (mean age, 28.54 years; 39.4% men).
The researchers selected 14 items to assess from the SPI-A that represented different aspects of VisDys. Severity was defined by the maximum frequency within the past 3 months – from 1 (never) to 6 (daily).
The 14 items were as follows: oversensitivity to light and/or certain visual perception objects, photopsia, micropsia/macropsia, near and tele-vision, metamorphopsia, changes in color vision, altered perception of a patient’s own face, pseudomovements of optic stimuli, diplopia or oblique vision, disturbances of the estimation of distances or sizes, disturbances of the perception of straight lines/contours, maintenance of optic stimuli “visual echoes,” partial seeing (including tubular vision), and captivation of attention by details of the visual field.
Participants also completed the Beck Depression Inventory–II scale (BDI-II), the Positive and Negative Syndrome Scale (PANSS), the Functional Remission in General Schizophrenia, and several other scales that measure global and social functioning.
Other assessments included QOL and the Rey-Osterrieth Complex Figure Test, which is a neuropsychological measurement of visuospatial constructability.
Specific to early-stage psychosis?
Results showed that VisDys were reported more frequently in both recent-onset psychosis and CHR groups compared with the recent-onset depression and healthy control groups (50.34% and 55.94% vs. 16.56% and 4.28%, respectively).
The investigators noted that VisDys sum scores “showed high internal consistency” (Cronbachs alpha, 0.78 over all participants).
Among those with recent-onset psychosis, a higher VisDys sum score was correlated with lower scores for functional remission (P = .036) and social functioning (P = .014).
In CHR, higher VisDys sum scores were associated with lower scores for health-related functional remission (P = .024), lower physical and psychological QOL (P = .004 and P = .015, respectively), more severe depression on the BDI-II (P = .021), and more impaired visuospatial constructability (P = .027).
Among those with recent-onset depression and their healthy peers, “no relevant correlations were found between VisDys sum scores and any parameters representing functional remission, QOL, depressiveness, or visuospatial constructability,” the researchers wrote.
A total of 135 participants with recent-onset psychosis, 128 with CHR, and 134 with recent-onset depression also underwent resting-state fMRI.
ON functional connectivity predicted presence of VisDys in patients with recent-onset psychosis and those with CHR, with a balanced accuracy of 60.17% (P = .0001) and 67.38% (P = .029), respectively. In the combined recent-onset psychosis plus CHR sample, VisDys were predicted by FPN functional connectivity (balanced accuracy, 61.1%; P = .006).
“Findings from multivariate pattern analysis support a model of functional integrity within ON and FPN driving the VisDys phenomenon and being implicated in core disease mechanisms of early psychosis states,” the investigators noted.
“The main findings from this large sample study support the idea of VisDys being specific to the psychosis spectrum already at early stages,” while being less frequently reported in recent-onset depression, they wrote. VisDys also “appeared negligible” among those without psychiatric disorders.
Regular assessment needed
Steven Silverstein, PhD, professor of biopsychosocial medicine and professor of psychiatry, neuroscience, and ophthalmology, Center for Visual Science, University of Rochester (N.Y.) Medical Center, called the findings “important” because “they will increase appreciation in the field of mental health for the frequency and disabling nature of visual symptoms and the need for regular assessment in routine clinical practice with people at risk for or with psychotic disorders.”
In addition, “the brain imaging findings are providing needed information that could lead to treatments that target the brain networks generating the visual symptoms,” such as neurofeedback or brain stimulation, said Dr. Silverstein, who was not involved with the research.
The study was funded by a grant for the PRONIA Consortium. Individual researchers received funding from NARSAD Young Investigator Award of the Brain and Behavior Research Foundation, the Koeln Fortune Program/Faculty of Medicine, the University of Cologne, and the European Union’s Horizon 2020 research and innovation program. Open Access funding was enabled and organized by Projekt DEAL. Ms. Schwarzer and Dr. Silverstein reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A multinational group of investigators found that VisDys were reported considerably more often by patients with recent-onset psychosis and CHR than by those with recent-onset depression or a group acting as healthy control participants.
In addition, vision problems of higher severity were associated with less functional remission both for patients at CHR and those with recent-onset psychosis. Among patients with CHR, VisDys was also linked to lower quality of life (QOL), higher depressiveness, and more severe impairment of visuospatial constructability.
The researchers used fMRI imaging to compare resting-state functional brain connectivity in participants with recent-onset psychosis, CHR, and recent-onset depression. They found that the occipital (ON) and frontoparietal (FPN) subnetworks were particularly implicated in VisDys.
“Subtle VisDys should be regarded as a frequent phenomenon across the psychosis spectrum, impinging negatively on patients’ current ability to function in several settings of their daily and social life, their QOL, and visuospatial abilities,” write investigators led by Johanna Schwarzer, Institute for Translational Psychiatry, University of Muenster (Germany).
“These large-sample study findings suggest that VisDys are clinically highly relevant not only in [recent-onset psychosis] but especially in CHR,” they stated.
The findings were published online in Neuropsychopharmacology.
Subtle, underrecognized
Unlike patients with nonpsychotic disorders, approximately 50%-60% of patients diagnosed with schizophrenia report VisDys involving brightness, motion, form, color perception, or distorted perception of their own face, the researchers reported.
These “subtle” VisDys are “often underrecognized during clinical examination, despite their clinical relevance related to suicidal ideation, cognitive impairment, or poorer treatment response,” they wrote.
Most research into these vision problems in patients with schizophrenia has focused on patients in which the illness is in a stable, chronic state – although VisDys often appear years before the diagnosis of a psychotic disorder.
Moreover, there has been little research into the neurobiological underpinnings of VisDys, specifically in early states of psychosis and/or in comparison to other disorders, such as depression.
The Personalised Prognostic Indicators for Early Psychosis Management (PRONIA) Consortium studied the psychophysiological phenomenon of VisDys in a large sample of adolescents and young adults. The sample consisted of three diagnostic groups: those with recent-onset psychosis, those with CHR, and those with recent-onset depression.
VisDys in daily life were measured using the Schizophrenia Proneness Instrument–Adult Scale (SPI-A), which assesses basic symptoms that indicate increased risk for psychosis.
Visual information processing
Resting-state imaging data on intrinsic brain networks were also assessed in the PRONIA sample and were analyzed across 12,720 functional connectivities between 160 regions of interest across the whole brain.
In particular, the researchers were interested in the primary networks involved in visual information processing, especially the dorsal visual stream, with further focus on the ON and FPN intrinsic subnetworks.
The ON was chosen because it comprises “primary visual processing pathways,” while the FPN is “widely suggested to modulate attention related to visual information processing at higher cognitive levels.”
The investigators used a machine-learning multivariate pattern analysis approach that “enables the consideration of multiple interactions within brain systems.”
The current study involved 721 participants from the PRONIA database, including 147 participants with recent-onset psychosis (mean age, 28.45 years; 60.5% men), 143 with CHR (mean age, 26.97 years; about 50% men), 151 with recent-onset depression (mean age, 29.13 years; 47% men), and 280 in the healthy-controls group (mean age, 28.54 years; 39.4% men).
The researchers selected 14 items to assess from the SPI-A that represented different aspects of VisDys. Severity was defined by the maximum frequency within the past 3 months – from 1 (never) to 6 (daily).
The 14 items were as follows: oversensitivity to light and/or certain visual perception objects, photopsia, micropsia/macropsia, near and tele-vision, metamorphopsia, changes in color vision, altered perception of a patient’s own face, pseudomovements of optic stimuli, diplopia or oblique vision, disturbances of the estimation of distances or sizes, disturbances of the perception of straight lines/contours, maintenance of optic stimuli “visual echoes,” partial seeing (including tubular vision), and captivation of attention by details of the visual field.
Participants also completed the Beck Depression Inventory–II scale (BDI-II), the Positive and Negative Syndrome Scale (PANSS), the Functional Remission in General Schizophrenia, and several other scales that measure global and social functioning.
Other assessments included QOL and the Rey-Osterrieth Complex Figure Test, which is a neuropsychological measurement of visuospatial constructability.
Specific to early-stage psychosis?
Results showed that VisDys were reported more frequently in both recent-onset psychosis and CHR groups compared with the recent-onset depression and healthy control groups (50.34% and 55.94% vs. 16.56% and 4.28%, respectively).
The investigators noted that VisDys sum scores “showed high internal consistency” (Cronbachs alpha, 0.78 over all participants).
Among those with recent-onset psychosis, a higher VisDys sum score was correlated with lower scores for functional remission (P = .036) and social functioning (P = .014).
In CHR, higher VisDys sum scores were associated with lower scores for health-related functional remission (P = .024), lower physical and psychological QOL (P = .004 and P = .015, respectively), more severe depression on the BDI-II (P = .021), and more impaired visuospatial constructability (P = .027).
Among those with recent-onset depression and their healthy peers, “no relevant correlations were found between VisDys sum scores and any parameters representing functional remission, QOL, depressiveness, or visuospatial constructability,” the researchers wrote.
A total of 135 participants with recent-onset psychosis, 128 with CHR, and 134 with recent-onset depression also underwent resting-state fMRI.
ON functional connectivity predicted presence of VisDys in patients with recent-onset psychosis and those with CHR, with a balanced accuracy of 60.17% (P = .0001) and 67.38% (P = .029), respectively. In the combined recent-onset psychosis plus CHR sample, VisDys were predicted by FPN functional connectivity (balanced accuracy, 61.1%; P = .006).
“Findings from multivariate pattern analysis support a model of functional integrity within ON and FPN driving the VisDys phenomenon and being implicated in core disease mechanisms of early psychosis states,” the investigators noted.
“The main findings from this large sample study support the idea of VisDys being specific to the psychosis spectrum already at early stages,” while being less frequently reported in recent-onset depression, they wrote. VisDys also “appeared negligible” among those without psychiatric disorders.
Regular assessment needed
Steven Silverstein, PhD, professor of biopsychosocial medicine and professor of psychiatry, neuroscience, and ophthalmology, Center for Visual Science, University of Rochester (N.Y.) Medical Center, called the findings “important” because “they will increase appreciation in the field of mental health for the frequency and disabling nature of visual symptoms and the need for regular assessment in routine clinical practice with people at risk for or with psychotic disorders.”
In addition, “the brain imaging findings are providing needed information that could lead to treatments that target the brain networks generating the visual symptoms,” such as neurofeedback or brain stimulation, said Dr. Silverstein, who was not involved with the research.
The study was funded by a grant for the PRONIA Consortium. Individual researchers received funding from NARSAD Young Investigator Award of the Brain and Behavior Research Foundation, the Koeln Fortune Program/Faculty of Medicine, the University of Cologne, and the European Union’s Horizon 2020 research and innovation program. Open Access funding was enabled and organized by Projekt DEAL. Ms. Schwarzer and Dr. Silverstein reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NEUROPSYCHOPHARMACOLOGY
Blood type linked to higher risk for early onset stroke
Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.
In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.
“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.
The findings were published online in Neurology.
Strong association
The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.
Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.
Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.
Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).
Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).
Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.
While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”
“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”
He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.
“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
More research needed on younger patients
In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.
“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.
“This work has deepened our understanding of EOS pathophysiology,” they added.
The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”
Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.
“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”
A version of this article first appeared on Medscape.com.
Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.
In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.
“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.
The findings were published online in Neurology.
Strong association
The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.
Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.
Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.
Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).
Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).
Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.
While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”
“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”
He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.
“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
More research needed on younger patients
In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.
“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.
“This work has deepened our understanding of EOS pathophysiology,” they added.
The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”
Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.
“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”
A version of this article first appeared on Medscape.com.
Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.
In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.
“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.
The findings were published online in Neurology.
Strong association
The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.
Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.
Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.
Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).
Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).
Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.
While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”
“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”
He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.
“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
More research needed on younger patients
In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.
“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.
“This work has deepened our understanding of EOS pathophysiology,” they added.
The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”
Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.
“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Neuropsychiatric symptoms after stroke
Many patients experience neuropsychiatric symptoms following stroke. There is tremendous variation in the type, severity, and timeline of these symptoms, which have the potential to significantly impact patients’ quality of life. Some symptoms occur as a direct result of ischemic injury to brain structures regulating behavior, executive function, perception, or affect. Other symptoms occur indirectly due to the patient’s often-difficult experiences with the health care system, disrupted routines, or altered poststroke functional abilities. Psychiatric symptoms are not as easily recognized as classic stroke symptoms (such as hemiparesis) and are frequently overlooked, especially in the acute phase. However, these symptoms can negatively influence patients’ interpersonal relationships, rehabilitation, and employment.
Patients and families may not realize certain symptoms are stroke-related and may not discuss them with their clinicians. It is important to ask about and recognize psychiatric symptoms in patients who have experienced a stroke so you can provide optimal education and treatment. In this article, we review the types of psychiatric symptoms associated with strokes in specific brain regions (Table1-10). We also describe symptoms that do not appear directly related to the anatomical structures affected by the infarct, including delirium, psychosis, depression, anxiety, and posttraumatic stress.
Symptoms associated with stroke in specific regions
Frontal lobe strokes
The frontal lobes are the largest lobes in the brain, and damage to areas within these lobes can cause behavioral and personality changes. Lesions in the lateral frontal cortex can cause aprosodia (difficulty expressing or comprehending variations in tone of voice), which can lead to communication errors. Lateral frontal cortex injury can cause executive dysfunction and a lack of empathy1 as well as trouble with attention, planning, and self-regulation that may affect daily functioning. Strokes affecting the superior and inferior mesial cortices may result in apathy, lack of motivation, altered self-regulation, altered emotional processing, and disinhibition. Patients who experience a basal forebrain stroke may exhibit confabulation, reduced motivation, and delusions such as Capgras syndrome (the belief that a person or place has been replaced by an exact copy) and reduplicative paramnesia (the belief that a place has been either moved, duplicated, or exists in 2 places simultaneously). Strokes involving the orbital cortex can be associated with personality changes, impulsivity, poor social judgment, reduced empathy, altered self-regulation, lack of goal-directed behavior, and environmental dependency.
Some strokes may occur primarily in the subcortical white matter within the frontal lobes. Symptoms may be due to a single stroke with sudden onset, or due to repeated ischemic events that accumulate over time, as seen with microvascular disease. In the case of microvascular disease, the onset of symptoms may be insidious and the course progressive. Infarcts in the subcortical area can also cause personality changes (though typically more subtle when compared to orbitofrontal strokes), reduced emotions, poor empathy, and irritability.1 Patients may lack insight into some of or all these symptoms following a frontal lobe infarct, which makes it critical to gather collateral information from the patient’s friends or family.
Parietal lobe strokes
Symptomatology from parietal strokes depends on whether the stroke affects the dominant or nondominant hemisphere. Dominant parietal lesions cause language deficits, and psychiatric symptoms may be difficult to elucidate due to the patient’s inability to communicate.2 On the other hand, patients with nondominant parietal stroke may have neglect of, or inattention to, the opposite (typically left) side.3 This often manifests as a reluctance to use the affected limb or limbs, in some cases despite a lack of true weakness or motor dysfunction. In addition, patients may also have visual and/or tactile inattention towards the affected side, despite a lack of gross visual or sensory impairment.2 In rare cases, a patient’s stroke may be misdiagnosed as a functional disorder due to the perceived unwillingness to use a neurologically intact limb. In severe cases, patients may not recognize an affected extremity as their own. Patients are also frequently unaware of deficits affecting their nondominant side and may argue with those attempting to explain their deficit. Anosodiaphoria—an abnormal lack of concern regarding their deficits—may also be observed. Additionally, aprosodia, flat affect, and personality changes may result from strokes affecting the nondominant hemisphere, which can impact the patient’s relationships and social functioning.3
Occipital lobe strokes
While negative or loss-of-function symptomatology is one of the hallmarks of stroke, occipital lobe infarcts can pose an exception. Although vision loss is the most common symptom with occipital lobe strokes, some patients experience visual hallucinations that may occur acutely or subacutely. In the acute phase, patients may report hallucinations of varied description,4 including poorly formed areas of color, scotomas, metamorphopsia (visual distortion in which straight lines appear curved), more complex and formed hallucinations and/or palinoptic images (images or brief scenes that continue to be perceived after looking away). These hallucinations, often referred to as release phenomena or release hallucinations, are thought to result from disinhibition of the visual cortex, which then fires spontaneously.
Hallucinations are associated with either infarction or hemorrhage in the posterior cerebral artery territory. In some cases, the hallucinations may take on a formed, complex appearance, and Charles Bonnet syndrome (visual hallucinations in the setting of vision loss, with insight into the hallucinations) has been identified in a small portion of patients.5
Continue to: The duration of these...
The duration of these hallucinations varies. Some patients describe very short periods of the disturbance, lasting minutes to hours and corresponding with the onset of their stroke. Others experience prolonged hallucinations, which frequently evolve into formed, complex images, lasting from days to months.6 In the setting of cortical stroke, patients may be at risk for seizures, which could manifest as visual hallucinations. It is essential to ensure that epileptic causes of hallucinations have been ruled out, because seizures may require treatment and other precautions.
Other stroke locations
Strokes in other locations also can result in psychiatric or behavioral symptoms. Acute stroke in the subcortical midbrain or thalamus may result in peduncular hallucinosis, a syndrome of vivid visual hallucinations.7 The midbrain (most commonly the reticular formation) is usually affected; however, certain lesions of the thalamus may also cause peduncular hallucinosis. This phenomenon is theorized to be due to an increase in serotonin activity relative to acetylcholine and is often accompanied by drowsiness.
The subthalamic nucleus is most frequently associated with disordered movement such as hemiballismus, but also causes disturbances in mood and behavior, including hyperphagia and personality changes.8 Irritability, aggressiveness, disinhibition, anxiety, and obscene speech may also be seen with lesions of the subthalamic nucleus.
Finally, the caudate nucleus may cause alterations in executive functioning and behavior.9 A stroke in the dorsolateral caudate may cause abulia and psychic akinesia, decreased problem-solving ability, reduced abstract thinking, and/or diminished spontaneity, whereas an infarct in the ventromedial region of the nucleus may cause disinhibition, disorganization, impulsiveness, and, in severe cases, affective symptoms with psychosis.10 Strokes in any of these areas are at risk for being misdiagnosed because patients may not have a hemiparesis, and isolated positive or psychiatric symptoms may not be recognized as stroke.
Symptoms not related to stroke location
Delirium and psychosis
Following a stroke, a patient may exhibit neuropsychiatric symptoms that do not appear to relate directly to the anatomical structures affected by the infarct. In the acute phase, factors such as older age and medical complications (including infection, metabolic derangement, and lack of sleep due to frequent neurologic checks) create a high risk of delirium.11 Differentiating delirium from alterations in mental status due to seizure, cerebral edema, or other medical complications is essential, and delirium precautions should be exercised to the greatest extent possible. Other neuropsychiatric symptoms may manifest following hospitalization.
Continue to: Poststroke psychosis...
Poststroke psychosis often presents subacutely. Among these patients, the most common psychosis is delusion disorder, followed by schizophrenia-like psychosis and mood disorder with psychotic features.12 Some evidence suggests antipsychotics may be highly effective for many of these patients.12 Poststroke psychosis does appear to correlate somewhat with nondominant hemisphere lesions, including the frontal lobe, parietal lobe, temporal lobe, and/or caudate nucleus. Because high mortality and poor functional outcomes have been associated with poststroke psychosis, early intervention is essential.
Depression
Depression is a common problem following stroke, affecting approximately 35% of stroke patients.13 In addition to impairing quality of life, depression negatively impacts rehabilitation and increases caregiver burden. There is significant variability regarding risk factors that increases the likelihood of poststroke depression; however, psychiatric history, dysphagia, and poor social support consistently correlate with a higher risk.14,15 Characteristics of a patient’s stroke, such as lesion volume and the ability to perform activities of daily living, are also risk factors. Identifying depression among patients who recently had a stroke is sometimes difficult due to a plethora of confounding factors. Patients may not communicate well due to aphasia, while strokes in other locations may result in an altered affect. Depending on the stroke location, patients may also suffer anosognosia (a lack of awareness of their deficits), which may impair their ability to learn and use adaptive strategies and equipment. An additional confounder is the significant overlap between depressive symptoms and those seen in the setting of a major medical event or hospitalization (decreased appetite, fatigue, etc). The prevalence of depression peaks approximately 3 to 6 months after stroke, with symptoms lasting 9 to 12 months on average, although many patients experience symptoms significantly longer.14 Because symptoms can begin within hours to days following a stroke, it is essential that both hospital and outpatient clinicians assess for depression when indicated. Patients with poststroke depression should receive prompt treatment because appropriate treatment correlates with improved rehabilitation, and most patients respond well to antidepressants.16 Early treatment reduces mortality and improves compliance with secondary stroke prevention measures, including pharmacotherapy.17
Anxiety and posttraumatic stress
Anxiety and anxiety-related disorders are additional potential complications following stroke that significantly influence patient outcomes and well-being. The abrupt, unexpected onset of stroke is often frightening to patients and families. The potential for life-altering deficits as well as intense, often invasive, interactions with the health care system does little to assuage patients’ fear. Stroke patients must contend with a change in neurologic function while processing their difficult experiences, and may develop profound fear of a recurrent stroke. As many as 22% of patients have an anxiety disorder 3 months after they have a stroke.18 Phobic disorder is the most prevalent subtype, followed by generalized anxiety disorder. Younger age and previous anxiety or depression place patients at greater risk of developing poststroke anxiety. Patients suffering from poststroke anxiety have a reduced quality of life, are more dependent, and show restricted participation in rehabilitation, all of which culminate in poorer outcomes.
Many patients describe their experiences surrounding their stroke as traumatic, and posttraumatic stress disorder (PTSD) is increasingly acknowledged as a potential complication for patients with recent stroke.19 PTSD profoundly impacts patient quality of life. Interestingly, most patients who develop poststroke PTSD do not have a history of other psychiatric illness, and it is difficult to predict who may develop PTSD. Relatively little is known regarding optimal treatment strategies for poststroke PTSD, or the efficacy of pharmacotherapy and psychotherapeutic strategies to treat it.
Goals: Improve recovery and quality of life
Neuropsychiatric symptoms are common following a stroke and may manifest in a variety of ways. While some symptoms are a direct consequence of injury to a specific brain region, other symptoms may be a response to loss of independence, disability, experience with the medical system, or fear of recurrent stroke. The onset of psychiatric symptoms can be acute, beginning during hospitalization, or delayed. Understanding the association of psychiatric symptoms with the anatomical location of stroke may assist clinicians in identifying such symptoms. This knowledge informs conversations with patients and their caregivers, who may benefit from understanding that such symptoms are common after stroke. Furthermore, identifying psychiatric complications following stroke may affect rehabilitation. Additional investigation is necessary to find more effective treatment modalities and improve early intervention.
Continue to: Bottom Line
Bottom Line
Neuropsychiatric symptoms are frequently overlooked in patients with recent stroke. These symptoms include delirium, psychosis, depression, anxiety, and posttraumatic stress disorder, and can be the direct result of injury to neuroanatomical structures or a consequence of the patient’s experience. Prompt treatment can maximize stroke recovery and quality of life.
Related Resources
- Zhang S, Xu M, Liu ZJ, et al. Neuropsychiatric issues after stroke: clinical significance and therapeutic implications. World J Psychiatry. 2020;10(6):125-138. doi:10.5498/wjp. v10.i6.125
- Saha G, Chakraborty K, Pattojoshi A. Management of psychiatric disorders in patients with stroke and traumatic brain injury. Indian J Psychiatry. 2022;64(Suppl 2): S344-S354.
1. Eslinger PJ, Reichwein RK. Frontal lobe stroke syndromes. In: Caplan LR, van Gijn J, eds. Stroke Syndromes. 3rd ed. Cambridge University Press; 2012:232-241.
2. Critchley M, Russell WR, Zangwill OL. Discussion on parietal lobe syndromes. Proc R Soc Med. 1951;44(4):337-346.
3. Hier DB, Mondlock J, Caplan LR. Behavioral abnormalities after right hemisphere stroke. Neurology. 1983;33(3):337-344.
4. Brust JC, Behrens MM. “Release hallucinations” as the major symptom of posterior cerebral artery occlusion: a report of 2 cases. Ann Neurol. 1977;2(5):432-436.
5. Kumral E, Uluakay A, Donmez A. Complex visual hallucinations following stroke: epileptic origin or a deafferentiation phenomenon? Austin J Cerebrovasc Dis & Stroke. 2014;1(1):1005.
6. Lee JS, Ko KH, Oh JH, et al. Charles Bonnet syndrome after occipital infarction. J Neurosonol Neuroimag. 2018;10(2):154-157.
7. Young JB. Peduncular hallucinosis. In: Aminoff MJ, Daroff RB, eds. Encyclopedia of the Neurological Sciences. 2nd ed. Elsevier; 2014:848.
8. Etemadifar M, Abtahi SH, Abtahi SM, et al. Hemiballismus, hyperphagia, and behavioral changes following subthalamic infarct. Case Rep Med. 2012;2012:768580. doi:10.1155/2012/768580
9. Kumral E, Evyapan D, Balkir K. Acute caudate vascular lesions. Stroke. 1999;30(1):100-108.
10. Wang PY. Neurobehavioral changes following caudate infarct: a case report with literature review. Zhonghua Yi Xue Za Zhi (Taipei). 1991;47(3):199-203.
11. Ahmed S, Leurent B, Sampson EL. Risk factors for incident delirium among older people in acute hospital medical units: a systematic review and meta-analysis. Age Ageing. 2014;43(3):326-33.
12. Stangeland H, Orgeta V, Bell V. Poststroke psychosis: a systematic review. J Neurol Neurosurg Psychiatry. 2018;89(8):879-885.
13. Lenzi GL, Altieri M, Maestrini I. Post-stroke depression. Rev Neurol (Paris). 2008;164(10):837-840.
14. Whyte EM, Mulsant BH. Post stroke depression: epidemiology, pathophysiology, and biological treatment. Biol Psychiatry. 2002;52(3):253-264.
15. Pritchard KT, Hreha KP, Hong I. Dysphagia associated with risk of depressive symptoms among stroke survivors after discharge from a cluster of inpatient rehabilitation facilities. Swallowing Rehabil. 2020;3(1):33-44.
16. Wiart L, Petit H, Joseph PA, et al. Fluoxetine in early poststroke depression: a double-blind placebo-controlled study. Stroke. 2000;31(8):1829-1832.
17. Jorge RE, Robinson RG, Arndt S, et al. Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry. 2003;160(10):1823-1829.
18. Chun HY, Whiteley WN, Dennis MS, et al. Anxiety after stroke: the importance of subtyping. Stroke. 2018;49(3):556-564.
19. Garton AL, Sisti JA, Gupta VP, et al. Poststroke post-traumatic stress disorder: a review. Stroke. 2017;48(2):507-512.
Many patients experience neuropsychiatric symptoms following stroke. There is tremendous variation in the type, severity, and timeline of these symptoms, which have the potential to significantly impact patients’ quality of life. Some symptoms occur as a direct result of ischemic injury to brain structures regulating behavior, executive function, perception, or affect. Other symptoms occur indirectly due to the patient’s often-difficult experiences with the health care system, disrupted routines, or altered poststroke functional abilities. Psychiatric symptoms are not as easily recognized as classic stroke symptoms (such as hemiparesis) and are frequently overlooked, especially in the acute phase. However, these symptoms can negatively influence patients’ interpersonal relationships, rehabilitation, and employment.
Patients and families may not realize certain symptoms are stroke-related and may not discuss them with their clinicians. It is important to ask about and recognize psychiatric symptoms in patients who have experienced a stroke so you can provide optimal education and treatment. In this article, we review the types of psychiatric symptoms associated with strokes in specific brain regions (Table1-10). We also describe symptoms that do not appear directly related to the anatomical structures affected by the infarct, including delirium, psychosis, depression, anxiety, and posttraumatic stress.
Symptoms associated with stroke in specific regions
Frontal lobe strokes
The frontal lobes are the largest lobes in the brain, and damage to areas within these lobes can cause behavioral and personality changes. Lesions in the lateral frontal cortex can cause aprosodia (difficulty expressing or comprehending variations in tone of voice), which can lead to communication errors. Lateral frontal cortex injury can cause executive dysfunction and a lack of empathy1 as well as trouble with attention, planning, and self-regulation that may affect daily functioning. Strokes affecting the superior and inferior mesial cortices may result in apathy, lack of motivation, altered self-regulation, altered emotional processing, and disinhibition. Patients who experience a basal forebrain stroke may exhibit confabulation, reduced motivation, and delusions such as Capgras syndrome (the belief that a person or place has been replaced by an exact copy) and reduplicative paramnesia (the belief that a place has been either moved, duplicated, or exists in 2 places simultaneously). Strokes involving the orbital cortex can be associated with personality changes, impulsivity, poor social judgment, reduced empathy, altered self-regulation, lack of goal-directed behavior, and environmental dependency.
Some strokes may occur primarily in the subcortical white matter within the frontal lobes. Symptoms may be due to a single stroke with sudden onset, or due to repeated ischemic events that accumulate over time, as seen with microvascular disease. In the case of microvascular disease, the onset of symptoms may be insidious and the course progressive. Infarcts in the subcortical area can also cause personality changes (though typically more subtle when compared to orbitofrontal strokes), reduced emotions, poor empathy, and irritability.1 Patients may lack insight into some of or all these symptoms following a frontal lobe infarct, which makes it critical to gather collateral information from the patient’s friends or family.
Parietal lobe strokes
Symptomatology from parietal strokes depends on whether the stroke affects the dominant or nondominant hemisphere. Dominant parietal lesions cause language deficits, and psychiatric symptoms may be difficult to elucidate due to the patient’s inability to communicate.2 On the other hand, patients with nondominant parietal stroke may have neglect of, or inattention to, the opposite (typically left) side.3 This often manifests as a reluctance to use the affected limb or limbs, in some cases despite a lack of true weakness or motor dysfunction. In addition, patients may also have visual and/or tactile inattention towards the affected side, despite a lack of gross visual or sensory impairment.2 In rare cases, a patient’s stroke may be misdiagnosed as a functional disorder due to the perceived unwillingness to use a neurologically intact limb. In severe cases, patients may not recognize an affected extremity as their own. Patients are also frequently unaware of deficits affecting their nondominant side and may argue with those attempting to explain their deficit. Anosodiaphoria—an abnormal lack of concern regarding their deficits—may also be observed. Additionally, aprosodia, flat affect, and personality changes may result from strokes affecting the nondominant hemisphere, which can impact the patient’s relationships and social functioning.3
Occipital lobe strokes
While negative or loss-of-function symptomatology is one of the hallmarks of stroke, occipital lobe infarcts can pose an exception. Although vision loss is the most common symptom with occipital lobe strokes, some patients experience visual hallucinations that may occur acutely or subacutely. In the acute phase, patients may report hallucinations of varied description,4 including poorly formed areas of color, scotomas, metamorphopsia (visual distortion in which straight lines appear curved), more complex and formed hallucinations and/or palinoptic images (images or brief scenes that continue to be perceived after looking away). These hallucinations, often referred to as release phenomena or release hallucinations, are thought to result from disinhibition of the visual cortex, which then fires spontaneously.
Hallucinations are associated with either infarction or hemorrhage in the posterior cerebral artery territory. In some cases, the hallucinations may take on a formed, complex appearance, and Charles Bonnet syndrome (visual hallucinations in the setting of vision loss, with insight into the hallucinations) has been identified in a small portion of patients.5
Continue to: The duration of these...
The duration of these hallucinations varies. Some patients describe very short periods of the disturbance, lasting minutes to hours and corresponding with the onset of their stroke. Others experience prolonged hallucinations, which frequently evolve into formed, complex images, lasting from days to months.6 In the setting of cortical stroke, patients may be at risk for seizures, which could manifest as visual hallucinations. It is essential to ensure that epileptic causes of hallucinations have been ruled out, because seizures may require treatment and other precautions.
Other stroke locations
Strokes in other locations also can result in psychiatric or behavioral symptoms. Acute stroke in the subcortical midbrain or thalamus may result in peduncular hallucinosis, a syndrome of vivid visual hallucinations.7 The midbrain (most commonly the reticular formation) is usually affected; however, certain lesions of the thalamus may also cause peduncular hallucinosis. This phenomenon is theorized to be due to an increase in serotonin activity relative to acetylcholine and is often accompanied by drowsiness.
The subthalamic nucleus is most frequently associated with disordered movement such as hemiballismus, but also causes disturbances in mood and behavior, including hyperphagia and personality changes.8 Irritability, aggressiveness, disinhibition, anxiety, and obscene speech may also be seen with lesions of the subthalamic nucleus.
Finally, the caudate nucleus may cause alterations in executive functioning and behavior.9 A stroke in the dorsolateral caudate may cause abulia and psychic akinesia, decreased problem-solving ability, reduced abstract thinking, and/or diminished spontaneity, whereas an infarct in the ventromedial region of the nucleus may cause disinhibition, disorganization, impulsiveness, and, in severe cases, affective symptoms with psychosis.10 Strokes in any of these areas are at risk for being misdiagnosed because patients may not have a hemiparesis, and isolated positive or psychiatric symptoms may not be recognized as stroke.
Symptoms not related to stroke location
Delirium and psychosis
Following a stroke, a patient may exhibit neuropsychiatric symptoms that do not appear to relate directly to the anatomical structures affected by the infarct. In the acute phase, factors such as older age and medical complications (including infection, metabolic derangement, and lack of sleep due to frequent neurologic checks) create a high risk of delirium.11 Differentiating delirium from alterations in mental status due to seizure, cerebral edema, or other medical complications is essential, and delirium precautions should be exercised to the greatest extent possible. Other neuropsychiatric symptoms may manifest following hospitalization.
Continue to: Poststroke psychosis...
Poststroke psychosis often presents subacutely. Among these patients, the most common psychosis is delusion disorder, followed by schizophrenia-like psychosis and mood disorder with psychotic features.12 Some evidence suggests antipsychotics may be highly effective for many of these patients.12 Poststroke psychosis does appear to correlate somewhat with nondominant hemisphere lesions, including the frontal lobe, parietal lobe, temporal lobe, and/or caudate nucleus. Because high mortality and poor functional outcomes have been associated with poststroke psychosis, early intervention is essential.
Depression
Depression is a common problem following stroke, affecting approximately 35% of stroke patients.13 In addition to impairing quality of life, depression negatively impacts rehabilitation and increases caregiver burden. There is significant variability regarding risk factors that increases the likelihood of poststroke depression; however, psychiatric history, dysphagia, and poor social support consistently correlate with a higher risk.14,15 Characteristics of a patient’s stroke, such as lesion volume and the ability to perform activities of daily living, are also risk factors. Identifying depression among patients who recently had a stroke is sometimes difficult due to a plethora of confounding factors. Patients may not communicate well due to aphasia, while strokes in other locations may result in an altered affect. Depending on the stroke location, patients may also suffer anosognosia (a lack of awareness of their deficits), which may impair their ability to learn and use adaptive strategies and equipment. An additional confounder is the significant overlap between depressive symptoms and those seen in the setting of a major medical event or hospitalization (decreased appetite, fatigue, etc). The prevalence of depression peaks approximately 3 to 6 months after stroke, with symptoms lasting 9 to 12 months on average, although many patients experience symptoms significantly longer.14 Because symptoms can begin within hours to days following a stroke, it is essential that both hospital and outpatient clinicians assess for depression when indicated. Patients with poststroke depression should receive prompt treatment because appropriate treatment correlates with improved rehabilitation, and most patients respond well to antidepressants.16 Early treatment reduces mortality and improves compliance with secondary stroke prevention measures, including pharmacotherapy.17
Anxiety and posttraumatic stress
Anxiety and anxiety-related disorders are additional potential complications following stroke that significantly influence patient outcomes and well-being. The abrupt, unexpected onset of stroke is often frightening to patients and families. The potential for life-altering deficits as well as intense, often invasive, interactions with the health care system does little to assuage patients’ fear. Stroke patients must contend with a change in neurologic function while processing their difficult experiences, and may develop profound fear of a recurrent stroke. As many as 22% of patients have an anxiety disorder 3 months after they have a stroke.18 Phobic disorder is the most prevalent subtype, followed by generalized anxiety disorder. Younger age and previous anxiety or depression place patients at greater risk of developing poststroke anxiety. Patients suffering from poststroke anxiety have a reduced quality of life, are more dependent, and show restricted participation in rehabilitation, all of which culminate in poorer outcomes.
Many patients describe their experiences surrounding their stroke as traumatic, and posttraumatic stress disorder (PTSD) is increasingly acknowledged as a potential complication for patients with recent stroke.19 PTSD profoundly impacts patient quality of life. Interestingly, most patients who develop poststroke PTSD do not have a history of other psychiatric illness, and it is difficult to predict who may develop PTSD. Relatively little is known regarding optimal treatment strategies for poststroke PTSD, or the efficacy of pharmacotherapy and psychotherapeutic strategies to treat it.
Goals: Improve recovery and quality of life
Neuropsychiatric symptoms are common following a stroke and may manifest in a variety of ways. While some symptoms are a direct consequence of injury to a specific brain region, other symptoms may be a response to loss of independence, disability, experience with the medical system, or fear of recurrent stroke. The onset of psychiatric symptoms can be acute, beginning during hospitalization, or delayed. Understanding the association of psychiatric symptoms with the anatomical location of stroke may assist clinicians in identifying such symptoms. This knowledge informs conversations with patients and their caregivers, who may benefit from understanding that such symptoms are common after stroke. Furthermore, identifying psychiatric complications following stroke may affect rehabilitation. Additional investigation is necessary to find more effective treatment modalities and improve early intervention.
Continue to: Bottom Line
Bottom Line
Neuropsychiatric symptoms are frequently overlooked in patients with recent stroke. These symptoms include delirium, psychosis, depression, anxiety, and posttraumatic stress disorder, and can be the direct result of injury to neuroanatomical structures or a consequence of the patient’s experience. Prompt treatment can maximize stroke recovery and quality of life.
Related Resources
- Zhang S, Xu M, Liu ZJ, et al. Neuropsychiatric issues after stroke: clinical significance and therapeutic implications. World J Psychiatry. 2020;10(6):125-138. doi:10.5498/wjp. v10.i6.125
- Saha G, Chakraborty K, Pattojoshi A. Management of psychiatric disorders in patients with stroke and traumatic brain injury. Indian J Psychiatry. 2022;64(Suppl 2): S344-S354.
Many patients experience neuropsychiatric symptoms following stroke. There is tremendous variation in the type, severity, and timeline of these symptoms, which have the potential to significantly impact patients’ quality of life. Some symptoms occur as a direct result of ischemic injury to brain structures regulating behavior, executive function, perception, or affect. Other symptoms occur indirectly due to the patient’s often-difficult experiences with the health care system, disrupted routines, or altered poststroke functional abilities. Psychiatric symptoms are not as easily recognized as classic stroke symptoms (such as hemiparesis) and are frequently overlooked, especially in the acute phase. However, these symptoms can negatively influence patients’ interpersonal relationships, rehabilitation, and employment.
Patients and families may not realize certain symptoms are stroke-related and may not discuss them with their clinicians. It is important to ask about and recognize psychiatric symptoms in patients who have experienced a stroke so you can provide optimal education and treatment. In this article, we review the types of psychiatric symptoms associated with strokes in specific brain regions (Table1-10). We also describe symptoms that do not appear directly related to the anatomical structures affected by the infarct, including delirium, psychosis, depression, anxiety, and posttraumatic stress.
Symptoms associated with stroke in specific regions
Frontal lobe strokes
The frontal lobes are the largest lobes in the brain, and damage to areas within these lobes can cause behavioral and personality changes. Lesions in the lateral frontal cortex can cause aprosodia (difficulty expressing or comprehending variations in tone of voice), which can lead to communication errors. Lateral frontal cortex injury can cause executive dysfunction and a lack of empathy1 as well as trouble with attention, planning, and self-regulation that may affect daily functioning. Strokes affecting the superior and inferior mesial cortices may result in apathy, lack of motivation, altered self-regulation, altered emotional processing, and disinhibition. Patients who experience a basal forebrain stroke may exhibit confabulation, reduced motivation, and delusions such as Capgras syndrome (the belief that a person or place has been replaced by an exact copy) and reduplicative paramnesia (the belief that a place has been either moved, duplicated, or exists in 2 places simultaneously). Strokes involving the orbital cortex can be associated with personality changes, impulsivity, poor social judgment, reduced empathy, altered self-regulation, lack of goal-directed behavior, and environmental dependency.
Some strokes may occur primarily in the subcortical white matter within the frontal lobes. Symptoms may be due to a single stroke with sudden onset, or due to repeated ischemic events that accumulate over time, as seen with microvascular disease. In the case of microvascular disease, the onset of symptoms may be insidious and the course progressive. Infarcts in the subcortical area can also cause personality changes (though typically more subtle when compared to orbitofrontal strokes), reduced emotions, poor empathy, and irritability.1 Patients may lack insight into some of or all these symptoms following a frontal lobe infarct, which makes it critical to gather collateral information from the patient’s friends or family.
Parietal lobe strokes
Symptomatology from parietal strokes depends on whether the stroke affects the dominant or nondominant hemisphere. Dominant parietal lesions cause language deficits, and psychiatric symptoms may be difficult to elucidate due to the patient’s inability to communicate.2 On the other hand, patients with nondominant parietal stroke may have neglect of, or inattention to, the opposite (typically left) side.3 This often manifests as a reluctance to use the affected limb or limbs, in some cases despite a lack of true weakness or motor dysfunction. In addition, patients may also have visual and/or tactile inattention towards the affected side, despite a lack of gross visual or sensory impairment.2 In rare cases, a patient’s stroke may be misdiagnosed as a functional disorder due to the perceived unwillingness to use a neurologically intact limb. In severe cases, patients may not recognize an affected extremity as their own. Patients are also frequently unaware of deficits affecting their nondominant side and may argue with those attempting to explain their deficit. Anosodiaphoria—an abnormal lack of concern regarding their deficits—may also be observed. Additionally, aprosodia, flat affect, and personality changes may result from strokes affecting the nondominant hemisphere, which can impact the patient’s relationships and social functioning.3
Occipital lobe strokes
While negative or loss-of-function symptomatology is one of the hallmarks of stroke, occipital lobe infarcts can pose an exception. Although vision loss is the most common symptom with occipital lobe strokes, some patients experience visual hallucinations that may occur acutely or subacutely. In the acute phase, patients may report hallucinations of varied description,4 including poorly formed areas of color, scotomas, metamorphopsia (visual distortion in which straight lines appear curved), more complex and formed hallucinations and/or palinoptic images (images or brief scenes that continue to be perceived after looking away). These hallucinations, often referred to as release phenomena or release hallucinations, are thought to result from disinhibition of the visual cortex, which then fires spontaneously.
Hallucinations are associated with either infarction or hemorrhage in the posterior cerebral artery territory. In some cases, the hallucinations may take on a formed, complex appearance, and Charles Bonnet syndrome (visual hallucinations in the setting of vision loss, with insight into the hallucinations) has been identified in a small portion of patients.5
Continue to: The duration of these...
The duration of these hallucinations varies. Some patients describe very short periods of the disturbance, lasting minutes to hours and corresponding with the onset of their stroke. Others experience prolonged hallucinations, which frequently evolve into formed, complex images, lasting from days to months.6 In the setting of cortical stroke, patients may be at risk for seizures, which could manifest as visual hallucinations. It is essential to ensure that epileptic causes of hallucinations have been ruled out, because seizures may require treatment and other precautions.
Other stroke locations
Strokes in other locations also can result in psychiatric or behavioral symptoms. Acute stroke in the subcortical midbrain or thalamus may result in peduncular hallucinosis, a syndrome of vivid visual hallucinations.7 The midbrain (most commonly the reticular formation) is usually affected; however, certain lesions of the thalamus may also cause peduncular hallucinosis. This phenomenon is theorized to be due to an increase in serotonin activity relative to acetylcholine and is often accompanied by drowsiness.
The subthalamic nucleus is most frequently associated with disordered movement such as hemiballismus, but also causes disturbances in mood and behavior, including hyperphagia and personality changes.8 Irritability, aggressiveness, disinhibition, anxiety, and obscene speech may also be seen with lesions of the subthalamic nucleus.
Finally, the caudate nucleus may cause alterations in executive functioning and behavior.9 A stroke in the dorsolateral caudate may cause abulia and psychic akinesia, decreased problem-solving ability, reduced abstract thinking, and/or diminished spontaneity, whereas an infarct in the ventromedial region of the nucleus may cause disinhibition, disorganization, impulsiveness, and, in severe cases, affective symptoms with psychosis.10 Strokes in any of these areas are at risk for being misdiagnosed because patients may not have a hemiparesis, and isolated positive or psychiatric symptoms may not be recognized as stroke.
Symptoms not related to stroke location
Delirium and psychosis
Following a stroke, a patient may exhibit neuropsychiatric symptoms that do not appear to relate directly to the anatomical structures affected by the infarct. In the acute phase, factors such as older age and medical complications (including infection, metabolic derangement, and lack of sleep due to frequent neurologic checks) create a high risk of delirium.11 Differentiating delirium from alterations in mental status due to seizure, cerebral edema, or other medical complications is essential, and delirium precautions should be exercised to the greatest extent possible. Other neuropsychiatric symptoms may manifest following hospitalization.
Continue to: Poststroke psychosis...
Poststroke psychosis often presents subacutely. Among these patients, the most common psychosis is delusion disorder, followed by schizophrenia-like psychosis and mood disorder with psychotic features.12 Some evidence suggests antipsychotics may be highly effective for many of these patients.12 Poststroke psychosis does appear to correlate somewhat with nondominant hemisphere lesions, including the frontal lobe, parietal lobe, temporal lobe, and/or caudate nucleus. Because high mortality and poor functional outcomes have been associated with poststroke psychosis, early intervention is essential.
Depression
Depression is a common problem following stroke, affecting approximately 35% of stroke patients.13 In addition to impairing quality of life, depression negatively impacts rehabilitation and increases caregiver burden. There is significant variability regarding risk factors that increases the likelihood of poststroke depression; however, psychiatric history, dysphagia, and poor social support consistently correlate with a higher risk.14,15 Characteristics of a patient’s stroke, such as lesion volume and the ability to perform activities of daily living, are also risk factors. Identifying depression among patients who recently had a stroke is sometimes difficult due to a plethora of confounding factors. Patients may not communicate well due to aphasia, while strokes in other locations may result in an altered affect. Depending on the stroke location, patients may also suffer anosognosia (a lack of awareness of their deficits), which may impair their ability to learn and use adaptive strategies and equipment. An additional confounder is the significant overlap between depressive symptoms and those seen in the setting of a major medical event or hospitalization (decreased appetite, fatigue, etc). The prevalence of depression peaks approximately 3 to 6 months after stroke, with symptoms lasting 9 to 12 months on average, although many patients experience symptoms significantly longer.14 Because symptoms can begin within hours to days following a stroke, it is essential that both hospital and outpatient clinicians assess for depression when indicated. Patients with poststroke depression should receive prompt treatment because appropriate treatment correlates with improved rehabilitation, and most patients respond well to antidepressants.16 Early treatment reduces mortality and improves compliance with secondary stroke prevention measures, including pharmacotherapy.17
Anxiety and posttraumatic stress
Anxiety and anxiety-related disorders are additional potential complications following stroke that significantly influence patient outcomes and well-being. The abrupt, unexpected onset of stroke is often frightening to patients and families. The potential for life-altering deficits as well as intense, often invasive, interactions with the health care system does little to assuage patients’ fear. Stroke patients must contend with a change in neurologic function while processing their difficult experiences, and may develop profound fear of a recurrent stroke. As many as 22% of patients have an anxiety disorder 3 months after they have a stroke.18 Phobic disorder is the most prevalent subtype, followed by generalized anxiety disorder. Younger age and previous anxiety or depression place patients at greater risk of developing poststroke anxiety. Patients suffering from poststroke anxiety have a reduced quality of life, are more dependent, and show restricted participation in rehabilitation, all of which culminate in poorer outcomes.
Many patients describe their experiences surrounding their stroke as traumatic, and posttraumatic stress disorder (PTSD) is increasingly acknowledged as a potential complication for patients with recent stroke.19 PTSD profoundly impacts patient quality of life. Interestingly, most patients who develop poststroke PTSD do not have a history of other psychiatric illness, and it is difficult to predict who may develop PTSD. Relatively little is known regarding optimal treatment strategies for poststroke PTSD, or the efficacy of pharmacotherapy and psychotherapeutic strategies to treat it.
Goals: Improve recovery and quality of life
Neuropsychiatric symptoms are common following a stroke and may manifest in a variety of ways. While some symptoms are a direct consequence of injury to a specific brain region, other symptoms may be a response to loss of independence, disability, experience with the medical system, or fear of recurrent stroke. The onset of psychiatric symptoms can be acute, beginning during hospitalization, or delayed. Understanding the association of psychiatric symptoms with the anatomical location of stroke may assist clinicians in identifying such symptoms. This knowledge informs conversations with patients and their caregivers, who may benefit from understanding that such symptoms are common after stroke. Furthermore, identifying psychiatric complications following stroke may affect rehabilitation. Additional investigation is necessary to find more effective treatment modalities and improve early intervention.
Continue to: Bottom Line
Bottom Line
Neuropsychiatric symptoms are frequently overlooked in patients with recent stroke. These symptoms include delirium, psychosis, depression, anxiety, and posttraumatic stress disorder, and can be the direct result of injury to neuroanatomical structures or a consequence of the patient’s experience. Prompt treatment can maximize stroke recovery and quality of life.
Related Resources
- Zhang S, Xu M, Liu ZJ, et al. Neuropsychiatric issues after stroke: clinical significance and therapeutic implications. World J Psychiatry. 2020;10(6):125-138. doi:10.5498/wjp. v10.i6.125
- Saha G, Chakraborty K, Pattojoshi A. Management of psychiatric disorders in patients with stroke and traumatic brain injury. Indian J Psychiatry. 2022;64(Suppl 2): S344-S354.
1. Eslinger PJ, Reichwein RK. Frontal lobe stroke syndromes. In: Caplan LR, van Gijn J, eds. Stroke Syndromes. 3rd ed. Cambridge University Press; 2012:232-241.
2. Critchley M, Russell WR, Zangwill OL. Discussion on parietal lobe syndromes. Proc R Soc Med. 1951;44(4):337-346.
3. Hier DB, Mondlock J, Caplan LR. Behavioral abnormalities after right hemisphere stroke. Neurology. 1983;33(3):337-344.
4. Brust JC, Behrens MM. “Release hallucinations” as the major symptom of posterior cerebral artery occlusion: a report of 2 cases. Ann Neurol. 1977;2(5):432-436.
5. Kumral E, Uluakay A, Donmez A. Complex visual hallucinations following stroke: epileptic origin or a deafferentiation phenomenon? Austin J Cerebrovasc Dis & Stroke. 2014;1(1):1005.
6. Lee JS, Ko KH, Oh JH, et al. Charles Bonnet syndrome after occipital infarction. J Neurosonol Neuroimag. 2018;10(2):154-157.
7. Young JB. Peduncular hallucinosis. In: Aminoff MJ, Daroff RB, eds. Encyclopedia of the Neurological Sciences. 2nd ed. Elsevier; 2014:848.
8. Etemadifar M, Abtahi SH, Abtahi SM, et al. Hemiballismus, hyperphagia, and behavioral changes following subthalamic infarct. Case Rep Med. 2012;2012:768580. doi:10.1155/2012/768580
9. Kumral E, Evyapan D, Balkir K. Acute caudate vascular lesions. Stroke. 1999;30(1):100-108.
10. Wang PY. Neurobehavioral changes following caudate infarct: a case report with literature review. Zhonghua Yi Xue Za Zhi (Taipei). 1991;47(3):199-203.
11. Ahmed S, Leurent B, Sampson EL. Risk factors for incident delirium among older people in acute hospital medical units: a systematic review and meta-analysis. Age Ageing. 2014;43(3):326-33.
12. Stangeland H, Orgeta V, Bell V. Poststroke psychosis: a systematic review. J Neurol Neurosurg Psychiatry. 2018;89(8):879-885.
13. Lenzi GL, Altieri M, Maestrini I. Post-stroke depression. Rev Neurol (Paris). 2008;164(10):837-840.
14. Whyte EM, Mulsant BH. Post stroke depression: epidemiology, pathophysiology, and biological treatment. Biol Psychiatry. 2002;52(3):253-264.
15. Pritchard KT, Hreha KP, Hong I. Dysphagia associated with risk of depressive symptoms among stroke survivors after discharge from a cluster of inpatient rehabilitation facilities. Swallowing Rehabil. 2020;3(1):33-44.
16. Wiart L, Petit H, Joseph PA, et al. Fluoxetine in early poststroke depression: a double-blind placebo-controlled study. Stroke. 2000;31(8):1829-1832.
17. Jorge RE, Robinson RG, Arndt S, et al. Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry. 2003;160(10):1823-1829.
18. Chun HY, Whiteley WN, Dennis MS, et al. Anxiety after stroke: the importance of subtyping. Stroke. 2018;49(3):556-564.
19. Garton AL, Sisti JA, Gupta VP, et al. Poststroke post-traumatic stress disorder: a review. Stroke. 2017;48(2):507-512.
1. Eslinger PJ, Reichwein RK. Frontal lobe stroke syndromes. In: Caplan LR, van Gijn J, eds. Stroke Syndromes. 3rd ed. Cambridge University Press; 2012:232-241.
2. Critchley M, Russell WR, Zangwill OL. Discussion on parietal lobe syndromes. Proc R Soc Med. 1951;44(4):337-346.
3. Hier DB, Mondlock J, Caplan LR. Behavioral abnormalities after right hemisphere stroke. Neurology. 1983;33(3):337-344.
4. Brust JC, Behrens MM. “Release hallucinations” as the major symptom of posterior cerebral artery occlusion: a report of 2 cases. Ann Neurol. 1977;2(5):432-436.
5. Kumral E, Uluakay A, Donmez A. Complex visual hallucinations following stroke: epileptic origin or a deafferentiation phenomenon? Austin J Cerebrovasc Dis & Stroke. 2014;1(1):1005.
6. Lee JS, Ko KH, Oh JH, et al. Charles Bonnet syndrome after occipital infarction. J Neurosonol Neuroimag. 2018;10(2):154-157.
7. Young JB. Peduncular hallucinosis. In: Aminoff MJ, Daroff RB, eds. Encyclopedia of the Neurological Sciences. 2nd ed. Elsevier; 2014:848.
8. Etemadifar M, Abtahi SH, Abtahi SM, et al. Hemiballismus, hyperphagia, and behavioral changes following subthalamic infarct. Case Rep Med. 2012;2012:768580. doi:10.1155/2012/768580
9. Kumral E, Evyapan D, Balkir K. Acute caudate vascular lesions. Stroke. 1999;30(1):100-108.
10. Wang PY. Neurobehavioral changes following caudate infarct: a case report with literature review. Zhonghua Yi Xue Za Zhi (Taipei). 1991;47(3):199-203.
11. Ahmed S, Leurent B, Sampson EL. Risk factors for incident delirium among older people in acute hospital medical units: a systematic review and meta-analysis. Age Ageing. 2014;43(3):326-33.
12. Stangeland H, Orgeta V, Bell V. Poststroke psychosis: a systematic review. J Neurol Neurosurg Psychiatry. 2018;89(8):879-885.
13. Lenzi GL, Altieri M, Maestrini I. Post-stroke depression. Rev Neurol (Paris). 2008;164(10):837-840.
14. Whyte EM, Mulsant BH. Post stroke depression: epidemiology, pathophysiology, and biological treatment. Biol Psychiatry. 2002;52(3):253-264.
15. Pritchard KT, Hreha KP, Hong I. Dysphagia associated with risk of depressive symptoms among stroke survivors after discharge from a cluster of inpatient rehabilitation facilities. Swallowing Rehabil. 2020;3(1):33-44.
16. Wiart L, Petit H, Joseph PA, et al. Fluoxetine in early poststroke depression: a double-blind placebo-controlled study. Stroke. 2000;31(8):1829-1832.
17. Jorge RE, Robinson RG, Arndt S, et al. Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry. 2003;160(10):1823-1829.
18. Chun HY, Whiteley WN, Dennis MS, et al. Anxiety after stroke: the importance of subtyping. Stroke. 2018;49(3):556-564.
19. Garton AL, Sisti JA, Gupta VP, et al. Poststroke post-traumatic stress disorder: a review. Stroke. 2017;48(2):507-512.
Drug-induced progressive multifocal leukoencephalopathy: Rare but serious
Mr. P, age 67, presents to the clinic with vision changes and memory loss following a fall in his home due to limb weakness. Six years ago, his care team diagnosed him with rheumatoid arthritis (RA). Mr. P’s current medication regimen includes methotrexate 20 mg once weekly and etanercept 50 mg once weekly, and he has been stable on this plan for 3 years. Mr. P also was recently diagnosed with major depressive disorder (MDD), but has not yet started treatment. Following a complete workup, an MRI of Mr. P’s brain revealed white matter demyelination. Due to these findings, he is scheduled for a brain biopsy, which confirms a diagnosis of progressive multifocal leukoencephalopathy (PML).
PML is a demyelinating disease of the central nervous system caused by the John Cunningham virus (JCV), or JC polyomavirus, named for the first patient identified to have contracted the virus.1 Asymptomatic infection of JCV often occurs in childhood, and antibodies are found in ≤70% of healthy adults. In most individuals, JCV remains latent in the kidneys and lymphoid organs, but immunosuppression can cause it to reactivate.2
JCV infects oligodendrocytes, astrocytes, and neurons, which results in white matter demyelination. Due to this demyelination, individuals can experience visual field defects, speech disturbances, ataxia, paresthesia, and cognitive impairments.2 Limb weakness presents in 60% of patients with PML, visual disturbances in 20%, and gait disturbances in 65%.3 Progression of these symptoms can lead to a more severe clinical presentation, including focal seizures in ≤10% of patients, and the mortality rate is 30% to 50%.3 Patients with comorbid HIV have a mortality rate ≤90%.2
Currently, there are no biomarkers that can identify PML in its early stages. A PML diagnosis is typically based on the patient’s clinical presentation, radiological imaging, and detection of JCV DNA. A brain biopsy is the gold standard for PML diagnosis.1
Interestingly, data suggest that glial cells harboring JCV in the brain express receptors for serotonin and dopamine.4 Researchers pinpointed 5HT2A receptors as JCV entry points into cells, and theorized that medications competing for binding, such as certain psychotropic agents, might decrease JCV entry. Cells lacking the 5HT2A receptor have shown immunity to JCV infection and the ability of cells to be infected was restored through transfection of 5HT2A receptors.4
Immunosuppressant medications can cause PML
PML was initially seen in individuals with conditions that cause immunosuppression, such as malignancies and HIV. However, “drug-induced PML” refers to cases in which drug-induced immunosuppression creates an environment that allows JCV to reactivate and disseminate back into the CNS.4 It is important to emphasize that drug-induced PML is a very rare effect of certain immunosuppressant medications. Medications that can weaken the immune system include glucocorticoids, monoclonal antibodies, alkylating agents, purine analogues, antimetabolites, and immunosuppressants (Table).1
These medications are used to treat conditions such as multiple sclerosis, RA, psoriatic arthritis, and lupus. Although drug-induced PML can result from the use of any of these agents, the highest incidence (1%) is found with natalizumab. Rates of incidence with other agents are either unknown or as low as .002%.1 Evidence suggests that the risk for PML increases with the duration of therapy.5
Continue to: Management
Management: Stop the offending agent, restore immune function
Specific pharmacologic treatments for PML are lacking. Management of drug-induced PML starts with discontinuing the offending agent. Restoring immune function has been found to be the most effective approach to treat PML.3 Restoration is possible through interleukin-2 (IL-2), IL-7, and T-cell infusions. Other treatment options are theoretical and include the development of a JCV vaccine to stimulate host response, plasma exchange to remove the medication from the host, and antiviral therapy targeting JCV replication. Diclofenac, isotretinoin, and mefloquine can inhibit JCV replication.3
Based on the theory that JCV requires 5HT2A receptors for entry into cells, researchers have studied medications that block this receptor as a treatment for PML. The first-generation antipsychotic chlorpromazine did not show benefit when combined with cidofovir, a replication inhibitor.3 Antipsychotics agents such as ziprasidone and olanzapine have shown in vitro inhibition of JCV, while risperidone has mixed results, with 1 trial failing to find a difference on JCV in fetal glial cells.3 Second-generation antipsychotics may be the preferred option due to more potent antagonism of the 5HT2A receptors and fewer adverse effects compared to agents such as chlorpromazine.4 The antidepressant mirtazapine has shown to have promising results, with evidence indicating that earlier initiation is more beneficial.3 Overall, data involving the use of medications that act on the 5HT2A receptor are mixed. Recent data suggest that JCV might enter cells independent of 5HT2A receptors; however, more research in this area is needed.2
The best strategy for treating drug-induced PML has not yet been determined. While combination therapy is thought to be more successful than monotherapy, ultimately, it depends on the patient’s immune response. If a psychotropic medication is chosen as adjunct treatment for drug-induced PML, it is prudent to assess the patient’s entire clinical picture to determine the specific indication for therapy (ie, treating symptomatology or drug-induced PML).
CASE CONTINUED
Following diagnosis, Mr. P is provided supportive therapy, and his care team discontinues methotrexate and etanercept. Although data are mixed on the efficacy of medications that work on 5HT2A receptors, because Mr. P was recently diagnosed with MDD, he is started on mirtazapine 15 mg/d at night in an attempt to manage both MDD and PML. It is possible that his depressive symptoms developed as a result of drug-induced PML rather than major depressive disorder. Discontinuing methotrexate and etanercept stabilizes Mr. P’s PML symptoms but leads to an exacerbation of his RA symptoms. Mr. P is initiated on hyd
Related Resources
- Castle D, Robertson NP. Treatment of progressive multifocal leukoencephalopathy. J Neurol. 2019;266(10):2587-2589. doi:10.1007/s00415-019-09501-y
Drug Brand Names
Abatacept • Orencia
Adalimumab • Humira
Alemtuzumab • Campath
Azathioprine • Azasan, Imuran
Basiliximab • Simulect
Belimumab • Benlysta
Bevacizumab • Avastin
Brentuximab vedotin • Adcetris
Cetuximab • Erbitux
Chlorpromazine • Thorazine, Largactil
Cidofovir • Vistide
Cladribine • Mavenclad
Cyclophosphamide • Cytoxan
Cyclosporine • Gengraf, Neoral
Dacarbazine • DTIC-Dome
Diclofenac • Cambia, Zorvolex
Dimethyl fumarate • Tecfidera
Etanercept • Enbrel
Fingolimod • Gilenya
Fludarabine • Fludara
Hydroxychloroquine • Plaquenil
Ibritumomab tiuxetan • Zevalin
Infliximab • Avsola, Inflectra
Isotretinoin • Absorica, Claravis
Mefloquine • Lariam
Methotrexate • Rheumatrex, Trexall
Mirtazapine • Remeron
Mitoxantrone • Novantrone
Muromonab-CD3 • Orthoclone OKT3
Mycophenolate mofetil • CellCept
Natalizumab • Tysabri
Nelarabine • Arranon
Obinutuzumab • Gazyva
Olanzapine • Zyprexa
Risperidone • Risperdal
Tacrolimus • Prograf
Vincristine • Vincasar PFS
Ziprasidone • Geodon
1. Yukitake M. Drug-induced progressive multifocal leukoencephalopathy in multiple sclerosis: a comprehensive review. Clin Exp Neuroimmunol. 2018;9(1):37-47. doi:10.1111/cen3.12440
2. Alstadhaug KB, Myhr KM, Rinaldo CH. Progressive multifocal leukoencephalopathy. Tidsskr Nor Laegeforen. 2017;137(23-24):10.4045/tidsskr.16.1092. doi:10.4045/tidsskr.16.1092
3. Williamson EML, Berger JR. Diagnosis and treatment of progressive multifocal leukoencephalopathy associated with multiple sclerosis therapies. Neurotherapeutics. 2017;14(4):961-973. doi:10.1007/s13311-017-0570-7
4. Altschuler EL, Kast RE. The atypical antipsychotic agents ziprasidone, risperidone and olanzapine as treatment for and prophylaxis against progressive multifocal leukoencephalopathy. Med Hypotheses. 2005;65(3):585-586.
5. Vinhas de Souza M, Keller-Stanislawski B, Blake K, et al. Drug-induced PML: a global agenda for a global challenge. Clin Pharmacol Ther. 2012;91(4):747-750. doi:10.1038/clpt.2012.4
Mr. P, age 67, presents to the clinic with vision changes and memory loss following a fall in his home due to limb weakness. Six years ago, his care team diagnosed him with rheumatoid arthritis (RA). Mr. P’s current medication regimen includes methotrexate 20 mg once weekly and etanercept 50 mg once weekly, and he has been stable on this plan for 3 years. Mr. P also was recently diagnosed with major depressive disorder (MDD), but has not yet started treatment. Following a complete workup, an MRI of Mr. P’s brain revealed white matter demyelination. Due to these findings, he is scheduled for a brain biopsy, which confirms a diagnosis of progressive multifocal leukoencephalopathy (PML).
PML is a demyelinating disease of the central nervous system caused by the John Cunningham virus (JCV), or JC polyomavirus, named for the first patient identified to have contracted the virus.1 Asymptomatic infection of JCV often occurs in childhood, and antibodies are found in ≤70% of healthy adults. In most individuals, JCV remains latent in the kidneys and lymphoid organs, but immunosuppression can cause it to reactivate.2
JCV infects oligodendrocytes, astrocytes, and neurons, which results in white matter demyelination. Due to this demyelination, individuals can experience visual field defects, speech disturbances, ataxia, paresthesia, and cognitive impairments.2 Limb weakness presents in 60% of patients with PML, visual disturbances in 20%, and gait disturbances in 65%.3 Progression of these symptoms can lead to a more severe clinical presentation, including focal seizures in ≤10% of patients, and the mortality rate is 30% to 50%.3 Patients with comorbid HIV have a mortality rate ≤90%.2
Currently, there are no biomarkers that can identify PML in its early stages. A PML diagnosis is typically based on the patient’s clinical presentation, radiological imaging, and detection of JCV DNA. A brain biopsy is the gold standard for PML diagnosis.1
Interestingly, data suggest that glial cells harboring JCV in the brain express receptors for serotonin and dopamine.4 Researchers pinpointed 5HT2A receptors as JCV entry points into cells, and theorized that medications competing for binding, such as certain psychotropic agents, might decrease JCV entry. Cells lacking the 5HT2A receptor have shown immunity to JCV infection and the ability of cells to be infected was restored through transfection of 5HT2A receptors.4
Immunosuppressant medications can cause PML
PML was initially seen in individuals with conditions that cause immunosuppression, such as malignancies and HIV. However, “drug-induced PML” refers to cases in which drug-induced immunosuppression creates an environment that allows JCV to reactivate and disseminate back into the CNS.4 It is important to emphasize that drug-induced PML is a very rare effect of certain immunosuppressant medications. Medications that can weaken the immune system include glucocorticoids, monoclonal antibodies, alkylating agents, purine analogues, antimetabolites, and immunosuppressants (Table).1
These medications are used to treat conditions such as multiple sclerosis, RA, psoriatic arthritis, and lupus. Although drug-induced PML can result from the use of any of these agents, the highest incidence (1%) is found with natalizumab. Rates of incidence with other agents are either unknown or as low as .002%.1 Evidence suggests that the risk for PML increases with the duration of therapy.5
Continue to: Management
Management: Stop the offending agent, restore immune function
Specific pharmacologic treatments for PML are lacking. Management of drug-induced PML starts with discontinuing the offending agent. Restoring immune function has been found to be the most effective approach to treat PML.3 Restoration is possible through interleukin-2 (IL-2), IL-7, and T-cell infusions. Other treatment options are theoretical and include the development of a JCV vaccine to stimulate host response, plasma exchange to remove the medication from the host, and antiviral therapy targeting JCV replication. Diclofenac, isotretinoin, and mefloquine can inhibit JCV replication.3
Based on the theory that JCV requires 5HT2A receptors for entry into cells, researchers have studied medications that block this receptor as a treatment for PML. The first-generation antipsychotic chlorpromazine did not show benefit when combined with cidofovir, a replication inhibitor.3 Antipsychotics agents such as ziprasidone and olanzapine have shown in vitro inhibition of JCV, while risperidone has mixed results, with 1 trial failing to find a difference on JCV in fetal glial cells.3 Second-generation antipsychotics may be the preferred option due to more potent antagonism of the 5HT2A receptors and fewer adverse effects compared to agents such as chlorpromazine.4 The antidepressant mirtazapine has shown to have promising results, with evidence indicating that earlier initiation is more beneficial.3 Overall, data involving the use of medications that act on the 5HT2A receptor are mixed. Recent data suggest that JCV might enter cells independent of 5HT2A receptors; however, more research in this area is needed.2
The best strategy for treating drug-induced PML has not yet been determined. While combination therapy is thought to be more successful than monotherapy, ultimately, it depends on the patient’s immune response. If a psychotropic medication is chosen as adjunct treatment for drug-induced PML, it is prudent to assess the patient’s entire clinical picture to determine the specific indication for therapy (ie, treating symptomatology or drug-induced PML).
CASE CONTINUED
Following diagnosis, Mr. P is provided supportive therapy, and his care team discontinues methotrexate and etanercept. Although data are mixed on the efficacy of medications that work on 5HT2A receptors, because Mr. P was recently diagnosed with MDD, he is started on mirtazapine 15 mg/d at night in an attempt to manage both MDD and PML. It is possible that his depressive symptoms developed as a result of drug-induced PML rather than major depressive disorder. Discontinuing methotrexate and etanercept stabilizes Mr. P’s PML symptoms but leads to an exacerbation of his RA symptoms. Mr. P is initiated on hyd
Related Resources
- Castle D, Robertson NP. Treatment of progressive multifocal leukoencephalopathy. J Neurol. 2019;266(10):2587-2589. doi:10.1007/s00415-019-09501-y
Drug Brand Names
Abatacept • Orencia
Adalimumab • Humira
Alemtuzumab • Campath
Azathioprine • Azasan, Imuran
Basiliximab • Simulect
Belimumab • Benlysta
Bevacizumab • Avastin
Brentuximab vedotin • Adcetris
Cetuximab • Erbitux
Chlorpromazine • Thorazine, Largactil
Cidofovir • Vistide
Cladribine • Mavenclad
Cyclophosphamide • Cytoxan
Cyclosporine • Gengraf, Neoral
Dacarbazine • DTIC-Dome
Diclofenac • Cambia, Zorvolex
Dimethyl fumarate • Tecfidera
Etanercept • Enbrel
Fingolimod • Gilenya
Fludarabine • Fludara
Hydroxychloroquine • Plaquenil
Ibritumomab tiuxetan • Zevalin
Infliximab • Avsola, Inflectra
Isotretinoin • Absorica, Claravis
Mefloquine • Lariam
Methotrexate • Rheumatrex, Trexall
Mirtazapine • Remeron
Mitoxantrone • Novantrone
Muromonab-CD3 • Orthoclone OKT3
Mycophenolate mofetil • CellCept
Natalizumab • Tysabri
Nelarabine • Arranon
Obinutuzumab • Gazyva
Olanzapine • Zyprexa
Risperidone • Risperdal
Tacrolimus • Prograf
Vincristine • Vincasar PFS
Ziprasidone • Geodon
Mr. P, age 67, presents to the clinic with vision changes and memory loss following a fall in his home due to limb weakness. Six years ago, his care team diagnosed him with rheumatoid arthritis (RA). Mr. P’s current medication regimen includes methotrexate 20 mg once weekly and etanercept 50 mg once weekly, and he has been stable on this plan for 3 years. Mr. P also was recently diagnosed with major depressive disorder (MDD), but has not yet started treatment. Following a complete workup, an MRI of Mr. P’s brain revealed white matter demyelination. Due to these findings, he is scheduled for a brain biopsy, which confirms a diagnosis of progressive multifocal leukoencephalopathy (PML).
PML is a demyelinating disease of the central nervous system caused by the John Cunningham virus (JCV), or JC polyomavirus, named for the first patient identified to have contracted the virus.1 Asymptomatic infection of JCV often occurs in childhood, and antibodies are found in ≤70% of healthy adults. In most individuals, JCV remains latent in the kidneys and lymphoid organs, but immunosuppression can cause it to reactivate.2
JCV infects oligodendrocytes, astrocytes, and neurons, which results in white matter demyelination. Due to this demyelination, individuals can experience visual field defects, speech disturbances, ataxia, paresthesia, and cognitive impairments.2 Limb weakness presents in 60% of patients with PML, visual disturbances in 20%, and gait disturbances in 65%.3 Progression of these symptoms can lead to a more severe clinical presentation, including focal seizures in ≤10% of patients, and the mortality rate is 30% to 50%.3 Patients with comorbid HIV have a mortality rate ≤90%.2
Currently, there are no biomarkers that can identify PML in its early stages. A PML diagnosis is typically based on the patient’s clinical presentation, radiological imaging, and detection of JCV DNA. A brain biopsy is the gold standard for PML diagnosis.1
Interestingly, data suggest that glial cells harboring JCV in the brain express receptors for serotonin and dopamine.4 Researchers pinpointed 5HT2A receptors as JCV entry points into cells, and theorized that medications competing for binding, such as certain psychotropic agents, might decrease JCV entry. Cells lacking the 5HT2A receptor have shown immunity to JCV infection and the ability of cells to be infected was restored through transfection of 5HT2A receptors.4
Immunosuppressant medications can cause PML
PML was initially seen in individuals with conditions that cause immunosuppression, such as malignancies and HIV. However, “drug-induced PML” refers to cases in which drug-induced immunosuppression creates an environment that allows JCV to reactivate and disseminate back into the CNS.4 It is important to emphasize that drug-induced PML is a very rare effect of certain immunosuppressant medications. Medications that can weaken the immune system include glucocorticoids, monoclonal antibodies, alkylating agents, purine analogues, antimetabolites, and immunosuppressants (Table).1
These medications are used to treat conditions such as multiple sclerosis, RA, psoriatic arthritis, and lupus. Although drug-induced PML can result from the use of any of these agents, the highest incidence (1%) is found with natalizumab. Rates of incidence with other agents are either unknown or as low as .002%.1 Evidence suggests that the risk for PML increases with the duration of therapy.5
Continue to: Management
Management: Stop the offending agent, restore immune function
Specific pharmacologic treatments for PML are lacking. Management of drug-induced PML starts with discontinuing the offending agent. Restoring immune function has been found to be the most effective approach to treat PML.3 Restoration is possible through interleukin-2 (IL-2), IL-7, and T-cell infusions. Other treatment options are theoretical and include the development of a JCV vaccine to stimulate host response, plasma exchange to remove the medication from the host, and antiviral therapy targeting JCV replication. Diclofenac, isotretinoin, and mefloquine can inhibit JCV replication.3
Based on the theory that JCV requires 5HT2A receptors for entry into cells, researchers have studied medications that block this receptor as a treatment for PML. The first-generation antipsychotic chlorpromazine did not show benefit when combined with cidofovir, a replication inhibitor.3 Antipsychotics agents such as ziprasidone and olanzapine have shown in vitro inhibition of JCV, while risperidone has mixed results, with 1 trial failing to find a difference on JCV in fetal glial cells.3 Second-generation antipsychotics may be the preferred option due to more potent antagonism of the 5HT2A receptors and fewer adverse effects compared to agents such as chlorpromazine.4 The antidepressant mirtazapine has shown to have promising results, with evidence indicating that earlier initiation is more beneficial.3 Overall, data involving the use of medications that act on the 5HT2A receptor are mixed. Recent data suggest that JCV might enter cells independent of 5HT2A receptors; however, more research in this area is needed.2
The best strategy for treating drug-induced PML has not yet been determined. While combination therapy is thought to be more successful than monotherapy, ultimately, it depends on the patient’s immune response. If a psychotropic medication is chosen as adjunct treatment for drug-induced PML, it is prudent to assess the patient’s entire clinical picture to determine the specific indication for therapy (ie, treating symptomatology or drug-induced PML).
CASE CONTINUED
Following diagnosis, Mr. P is provided supportive therapy, and his care team discontinues methotrexate and etanercept. Although data are mixed on the efficacy of medications that work on 5HT2A receptors, because Mr. P was recently diagnosed with MDD, he is started on mirtazapine 15 mg/d at night in an attempt to manage both MDD and PML. It is possible that his depressive symptoms developed as a result of drug-induced PML rather than major depressive disorder. Discontinuing methotrexate and etanercept stabilizes Mr. P’s PML symptoms but leads to an exacerbation of his RA symptoms. Mr. P is initiated on hyd
Related Resources
- Castle D, Robertson NP. Treatment of progressive multifocal leukoencephalopathy. J Neurol. 2019;266(10):2587-2589. doi:10.1007/s00415-019-09501-y
Drug Brand Names
Abatacept • Orencia
Adalimumab • Humira
Alemtuzumab • Campath
Azathioprine • Azasan, Imuran
Basiliximab • Simulect
Belimumab • Benlysta
Bevacizumab • Avastin
Brentuximab vedotin • Adcetris
Cetuximab • Erbitux
Chlorpromazine • Thorazine, Largactil
Cidofovir • Vistide
Cladribine • Mavenclad
Cyclophosphamide • Cytoxan
Cyclosporine • Gengraf, Neoral
Dacarbazine • DTIC-Dome
Diclofenac • Cambia, Zorvolex
Dimethyl fumarate • Tecfidera
Etanercept • Enbrel
Fingolimod • Gilenya
Fludarabine • Fludara
Hydroxychloroquine • Plaquenil
Ibritumomab tiuxetan • Zevalin
Infliximab • Avsola, Inflectra
Isotretinoin • Absorica, Claravis
Mefloquine • Lariam
Methotrexate • Rheumatrex, Trexall
Mirtazapine • Remeron
Mitoxantrone • Novantrone
Muromonab-CD3 • Orthoclone OKT3
Mycophenolate mofetil • CellCept
Natalizumab • Tysabri
Nelarabine • Arranon
Obinutuzumab • Gazyva
Olanzapine • Zyprexa
Risperidone • Risperdal
Tacrolimus • Prograf
Vincristine • Vincasar PFS
Ziprasidone • Geodon
1. Yukitake M. Drug-induced progressive multifocal leukoencephalopathy in multiple sclerosis: a comprehensive review. Clin Exp Neuroimmunol. 2018;9(1):37-47. doi:10.1111/cen3.12440
2. Alstadhaug KB, Myhr KM, Rinaldo CH. Progressive multifocal leukoencephalopathy. Tidsskr Nor Laegeforen. 2017;137(23-24):10.4045/tidsskr.16.1092. doi:10.4045/tidsskr.16.1092
3. Williamson EML, Berger JR. Diagnosis and treatment of progressive multifocal leukoencephalopathy associated with multiple sclerosis therapies. Neurotherapeutics. 2017;14(4):961-973. doi:10.1007/s13311-017-0570-7
4. Altschuler EL, Kast RE. The atypical antipsychotic agents ziprasidone, risperidone and olanzapine as treatment for and prophylaxis against progressive multifocal leukoencephalopathy. Med Hypotheses. 2005;65(3):585-586.
5. Vinhas de Souza M, Keller-Stanislawski B, Blake K, et al. Drug-induced PML: a global agenda for a global challenge. Clin Pharmacol Ther. 2012;91(4):747-750. doi:10.1038/clpt.2012.4
1. Yukitake M. Drug-induced progressive multifocal leukoencephalopathy in multiple sclerosis: a comprehensive review. Clin Exp Neuroimmunol. 2018;9(1):37-47. doi:10.1111/cen3.12440
2. Alstadhaug KB, Myhr KM, Rinaldo CH. Progressive multifocal leukoencephalopathy. Tidsskr Nor Laegeforen. 2017;137(23-24):10.4045/tidsskr.16.1092. doi:10.4045/tidsskr.16.1092
3. Williamson EML, Berger JR. Diagnosis and treatment of progressive multifocal leukoencephalopathy associated with multiple sclerosis therapies. Neurotherapeutics. 2017;14(4):961-973. doi:10.1007/s13311-017-0570-7
4. Altschuler EL, Kast RE. The atypical antipsychotic agents ziprasidone, risperidone and olanzapine as treatment for and prophylaxis against progressive multifocal leukoencephalopathy. Med Hypotheses. 2005;65(3):585-586.
5. Vinhas de Souza M, Keller-Stanislawski B, Blake K, et al. Drug-induced PML: a global agenda for a global challenge. Clin Pharmacol Ther. 2012;91(4):747-750. doi:10.1038/clpt.2012.4
Inhaled, systemic steroids linked to changes in brain structure
New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.
Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.
Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.
The findings should encourage clinicians to consider whether doses they are prescribing are too high, said Dr. Meijer. He added that the negative effect of glucocorticoids on the brain was also found in those using inhalers, such as patients with asthma.
The findings were published online in the BMJ Open.
Serious side effects
Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.
However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.
About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.
Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.
The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.
The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).
Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.
The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).
In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
Imaging analyses
Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.
Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.
Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.
The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”
He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.
Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.
Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.
In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
Move away from ‘one dose for all’?
Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.
The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.
He added that longer use or higher doses may be necessary to also induce volumetric changes.
Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.
The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.
In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.
In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
Impressive, but several limitations
Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”
In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.
That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.
He noted that cognitive differences were also only observed with systemic corticosteroids.
Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.
However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.
Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.
No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.
A version of this article first appeared on Medscape.com.
New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.
Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.
Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.
The findings should encourage clinicians to consider whether doses they are prescribing are too high, said Dr. Meijer. He added that the negative effect of glucocorticoids on the brain was also found in those using inhalers, such as patients with asthma.
The findings were published online in the BMJ Open.
Serious side effects
Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.
However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.
About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.
Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.
The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.
The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).
Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.
The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).
In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
Imaging analyses
Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.
Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.
Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.
The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”
He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.
Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.
Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.
In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
Move away from ‘one dose for all’?
Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.
The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.
He added that longer use or higher doses may be necessary to also induce volumetric changes.
Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.
The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.
In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.
In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
Impressive, but several limitations
Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”
In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.
That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.
He noted that cognitive differences were also only observed with systemic corticosteroids.
Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.
However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.
Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.
No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.
A version of this article first appeared on Medscape.com.
New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.
Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.
Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.
The findings should encourage clinicians to consider whether doses they are prescribing are too high, said Dr. Meijer. He added that the negative effect of glucocorticoids on the brain was also found in those using inhalers, such as patients with asthma.
The findings were published online in the BMJ Open.
Serious side effects
Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.
However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.
About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.
Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.
The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.
The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).
Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.
The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).
In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
Imaging analyses
Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.
Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.
Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.
The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”
He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.
Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.
Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.
In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
Move away from ‘one dose for all’?
Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.
The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.
He added that longer use or higher doses may be necessary to also induce volumetric changes.
Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.
The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.
In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.
In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
Impressive, but several limitations
Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”
In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.
That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.
He noted that cognitive differences were also only observed with systemic corticosteroids.
Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.
However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.
Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.
No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.
A version of this article first appeared on Medscape.com.
FROM BMJ OPEN
AXIOMATIC-SSP: Cautious optimism on factor XI inhibitor in stroke
The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.
Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.
Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.
There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.
“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.
Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
New generation
Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.
This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.
“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”
Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.
The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.
Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.
The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.
They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.
The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).
However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).
The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.
Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
Incremental improvement
On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.
“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.
He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.
In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.
Both drugs are now believed to be going forward into phase 3 trials.
Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.
She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials
“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”
The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.
A version of this article first appeared on Medscape.com.
The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.
Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.
Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.
There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.
“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.
Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
New generation
Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.
This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.
“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”
Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.
The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.
Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.
The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.
They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.
The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).
However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).
The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.
Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
Incremental improvement
On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.
“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.
He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.
In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.
Both drugs are now believed to be going forward into phase 3 trials.
Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.
She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials
“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”
The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.
A version of this article first appeared on Medscape.com.
The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.
Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.
Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.
There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.
“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.
Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
New generation
Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.
This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.
“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”
Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.
The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.
Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.
The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.
They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.
The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).
However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).
The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.
Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
Incremental improvement
On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.
“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.
He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.
In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.
Both drugs are now believed to be going forward into phase 3 trials.
Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.
She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials
“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”
The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2022
Sacubitril/valsartan shows cognitive safety in heart failure: PERSPECTIVE
BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.
The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.
Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.
Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
Reassuring results, but cost still a drag on uptake
“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.
Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.
“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.
PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.
Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.
The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.
A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.
Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.
But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”
The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.
PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.
BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.
The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.
Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.
Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
Reassuring results, but cost still a drag on uptake
“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.
Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.
“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.
PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.
Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.
The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.
A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.
Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.
But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”
The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.
PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.
BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.
The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.
Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.
Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
Reassuring results, but cost still a drag on uptake
“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.
Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.
“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.
PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.
Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.
The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.
A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.
Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.
But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”
The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.
PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.
AT ESC CONGRESS 2022
Secondary CV prevention benefit from polypill promises global health benefit
Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.
“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.
By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).
AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
SECURE trial is latest test of polypill concept
A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.
The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.
The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.
Multiple polypill versions permit dose titration
The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.
The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).
When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).
In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.
The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.
Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.
“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.
One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.
Polypill benefit documented in all subgroups
While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.
“This really validates the importance of the study,” Dr. Fuster said.
In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.
Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.
“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”
Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.
Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.
“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.
By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).
AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
SECURE trial is latest test of polypill concept
A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.
The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.
The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.
Multiple polypill versions permit dose titration
The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.
The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).
When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).
In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.
The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.
Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.
“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.
One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.
Polypill benefit documented in all subgroups
While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.
“This really validates the importance of the study,” Dr. Fuster said.
In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.
Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.
“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”
Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.
Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.
“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.
By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).
AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
SECURE trial is latest test of polypill concept
A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.
The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.
The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.
Multiple polypill versions permit dose titration
The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.
The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).
When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).
In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.
The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.
Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.
“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.
One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.
Polypill benefit documented in all subgroups
While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.
“This really validates the importance of the study,” Dr. Fuster said.
In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.
Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.
“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”
Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.
FROM ESC CONGRESS 2022
Call for Neurology Papers
Federal Practitioner invites VA, DoD, and PHS health care professionals and researchers to contribute to a future special issue on neurology. Topics of interest include epilepsy, headache and migraine, COVID-19 and neurology, Alzheimer and dementia, MS, and other neurological disorders.
Interested authors should submit an abstract to [email protected] with the subject line “Neurology Special Issue” for consideration. Once the editorial team confirms the article is eligible for consideration, authors will be asked to submit their manuscript in full through Editorial Manager.
Federal Practitioner never charges authors or readers. All submissions undergo a double-blinded peer review before publication. Accepted manuscripts are always available for free online at www.mdedge.com/fedprac and on PubMed Central.
Federal Practitioner welcomes original research, commentaries, clinical reviews, program profiles, case reports, and other evidence-based articles. The updated and complete submission guidelines, including details about the style and format, can be found here:
Federal Practitioner invites VA, DoD, and PHS health care professionals and researchers to contribute to a future special issue on neurology. Topics of interest include epilepsy, headache and migraine, COVID-19 and neurology, Alzheimer and dementia, MS, and other neurological disorders.
Interested authors should submit an abstract to [email protected] with the subject line “Neurology Special Issue” for consideration. Once the editorial team confirms the article is eligible for consideration, authors will be asked to submit their manuscript in full through Editorial Manager.
Federal Practitioner never charges authors or readers. All submissions undergo a double-blinded peer review before publication. Accepted manuscripts are always available for free online at www.mdedge.com/fedprac and on PubMed Central.
Federal Practitioner welcomes original research, commentaries, clinical reviews, program profiles, case reports, and other evidence-based articles. The updated and complete submission guidelines, including details about the style and format, can be found here:
Federal Practitioner invites VA, DoD, and PHS health care professionals and researchers to contribute to a future special issue on neurology. Topics of interest include epilepsy, headache and migraine, COVID-19 and neurology, Alzheimer and dementia, MS, and other neurological disorders.
Interested authors should submit an abstract to [email protected] with the subject line “Neurology Special Issue” for consideration. Once the editorial team confirms the article is eligible for consideration, authors will be asked to submit their manuscript in full through Editorial Manager.
Federal Practitioner never charges authors or readers. All submissions undergo a double-blinded peer review before publication. Accepted manuscripts are always available for free online at www.mdedge.com/fedprac and on PubMed Central.
Federal Practitioner welcomes original research, commentaries, clinical reviews, program profiles, case reports, and other evidence-based articles. The updated and complete submission guidelines, including details about the style and format, can be found here:
Large genetic study links 72 genes to autism spectrum disorders
according to a study published in Nature Genetics. The findings, based on analysis of more than 150,000 people’s genetics, arose from a collaboration of five research groups whose work included comparisons of ASD cohorts with separate cohorts of individuals with developmental delay or schizophrenia.
“We know that many genes, when mutated, contribute to autism,” and this study brought together “multiple types of mutations in a wide array of samples to get a much richer sense of the genes and genetic architecture involved in autism and other neurodevelopmental conditions,” co–senior author Joseph D. Buxbaum, PhD, director of the Seaver Autism Center for Research and Treatment at Mount Sinai and a professor at the Icahn School of Medicine at Mount Sinai, both in New York, said in a prepared statement. “This is significant in that we now have more insights as to the biology of the brain changes that underlie autism and more potential targets for treatment.”
Glen Elliott, PhD, MD, a clinical professor of psychiatry at Stanford (Calif.) University who was not involved in the study, said the paper is important paper for informing clinicians of where the basic research is headed. “We’re still in for a long road” before it bears fruit in terms of therapeutics. The value of studies like these, that investigate which genes are most associated with ASD, is that they may lead toward understanding the pathways in the brain that give rise to certain symptoms of ASD, which can then become therapeutic targets, Dr. Elliott said.
Investigating large cohorts
The researchers analyzed genetic exome sequencing data from 33 ASD cohorts with a total of 63,237 people and then compared these data with another cohort of people with developmental delay and a cohort of people with schizophrenia. The combined ASD cohorts included 15,036 individuals with ASD, 28,522 parents, and 5,492 unaffected siblings. The remaining participants were 5,591 people with ASD and 8,597 matched controls from case control studies.
In the ASD cohorts, the researchers identified 72 genes that were associated with ASD. De novo variants were eight times more likely in cases (4%) than in controls (0.5%). Ten genes occurred at least twice in ASD cases but never occurred in unaffected siblings.
Then the researchers integrated these ASD genetic data with a cohort of 91,605 people that included 31,058 people with developmental delay and their parents. Substantial overlap with gene mutations existed between these two cohorts: 70.1% of the genes related to developmental delay appeared linked to risk for ASD, and 86.6% of genes associated with ASD risk also had associations with developmental delay. Overall, the researchers identified 373 genes strongly associated with ASD and/or developmental delay and 664 genes with a likely association.
“Isolating genes that exert a greater effect on ASD than they do on other developmental delays has remained challenging due to the frequent comorbidity of these phenotypes,” wrote lead author Jack M. Fu, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues. “Still, an estimated 13.4% of the transmission and de novo association–ASD genes show little evidence for association in the developmental delay cohort.”
ASD, developmental delay, and schizophrenia
When the researchers compared the cells where the genetic mutations occurred in fetal brains, they found that genes associated with developmental delay more often occurred in less differentiated cell types – less mature cells in the developmental process. Gene mutations associated with ASD, on the other hand, occurred in more mature cell types, particularly in maturing excitatory neurons and related cells.
”Our results are consistent with developmental delay-predominant genes being expressed earlier in development and in less differentiated cells than ASD-predominant genes,” they wrote.
The researchers also compared the specific gene mutations found in these two cohorts with a previously published set of 244 genes associated with schizophrenia. Of these, 234 genes are among those with a transmission and de novo association to ASD and/or developmental delay. Of the 72 genes linked to ASD, eight appear in the set of genes linked to schizophrenia, and 61 were associated with developmental delay, though these two subsets do not overlap each other much.
“The ASD-schizophrenia overlap was significantly enriched, while the developmental delay-schizophrenia overlap was not,” they reported. ”Together, these data suggest that one subset of ASD risk genes may overlap developmental delay while a different subset overlaps schizophrenia.”
Chasing therapy targets by backtracking through genes
The findings are a substantial step forward in understanding the potential genetic contribution to ASD, but they also highlight the challenges of eventually trying to use this information in a clinically meaningful way.
“Given the substantial overlap between the genes implicated in neurodevelopmental disorders writ large and those implicated directly in ASD, disentangling the relative impact of individual genes on neurodevelopment and phenotypic spectra is a daunting yet important challenge,” the researchers wrote. “To identify the key neurobiological features of ASD will likely require convergence of evidence from many ASD genes and studies.”
Dr. Elliott said the biggest takeaway from this study is a better understanding of how the paradigm has shifted away from finding “one gene” for autism or a cure based on genetics and more toward understanding the pathophysiology of symptoms that can point to therapies for better management of the condition.
“Basic researchers have completely changed the strategy for trying to understand the biology of major disorders,” including, in this case, autism, Dr. Elliott said. “The intent is to try to find the underlying systems [in the brain] by backtracking through genes. Meanwhile, given that scientists have made substantial progress in identifying genes that have specific effects on brain development, “the hope is that will mesh with this kind of research, to begin to identify systems that might ultimately be targets for treating.”
The end goal is to be able to offer targeted approaches, based on the pathways causing a symptom, which can be linked backward to a gene.
”So this is not going to offer an immediate cure – it’s probably not going to offer a cure at all – but it may actually lead to much more targeted medications than we currently have for specific types of symptoms within the autism spectrum,” Dr. Elliott said. “What they’re trying to do, ultimately, is to say, when this system is really badly affected because of a genetic abnormality, even though that genetic abnormality is very rare, it leads to these specific kinds of symptoms. If we can find out the neuroregulators underlying that change, then that would be the target, even if that gene were not present.”
The research was funded by the Simons Foundation for Autism Research Initiative, the SPARK project, the National Human Genome Research Institute Home, the National Institute of Mental Health, the National Institute of Child Health and Development, AMED, and the Beatrice and Samuel Seaver Foundation. Five authors reported financial disclosures linked to Desitin, Roche, BioMarin, BrigeBio Pharma, Illumina, Levo Therapeutics, and Microsoft.
according to a study published in Nature Genetics. The findings, based on analysis of more than 150,000 people’s genetics, arose from a collaboration of five research groups whose work included comparisons of ASD cohorts with separate cohorts of individuals with developmental delay or schizophrenia.
“We know that many genes, when mutated, contribute to autism,” and this study brought together “multiple types of mutations in a wide array of samples to get a much richer sense of the genes and genetic architecture involved in autism and other neurodevelopmental conditions,” co–senior author Joseph D. Buxbaum, PhD, director of the Seaver Autism Center for Research and Treatment at Mount Sinai and a professor at the Icahn School of Medicine at Mount Sinai, both in New York, said in a prepared statement. “This is significant in that we now have more insights as to the biology of the brain changes that underlie autism and more potential targets for treatment.”
Glen Elliott, PhD, MD, a clinical professor of psychiatry at Stanford (Calif.) University who was not involved in the study, said the paper is important paper for informing clinicians of where the basic research is headed. “We’re still in for a long road” before it bears fruit in terms of therapeutics. The value of studies like these, that investigate which genes are most associated with ASD, is that they may lead toward understanding the pathways in the brain that give rise to certain symptoms of ASD, which can then become therapeutic targets, Dr. Elliott said.
Investigating large cohorts
The researchers analyzed genetic exome sequencing data from 33 ASD cohorts with a total of 63,237 people and then compared these data with another cohort of people with developmental delay and a cohort of people with schizophrenia. The combined ASD cohorts included 15,036 individuals with ASD, 28,522 parents, and 5,492 unaffected siblings. The remaining participants were 5,591 people with ASD and 8,597 matched controls from case control studies.
In the ASD cohorts, the researchers identified 72 genes that were associated with ASD. De novo variants were eight times more likely in cases (4%) than in controls (0.5%). Ten genes occurred at least twice in ASD cases but never occurred in unaffected siblings.
Then the researchers integrated these ASD genetic data with a cohort of 91,605 people that included 31,058 people with developmental delay and their parents. Substantial overlap with gene mutations existed between these two cohorts: 70.1% of the genes related to developmental delay appeared linked to risk for ASD, and 86.6% of genes associated with ASD risk also had associations with developmental delay. Overall, the researchers identified 373 genes strongly associated with ASD and/or developmental delay and 664 genes with a likely association.
“Isolating genes that exert a greater effect on ASD than they do on other developmental delays has remained challenging due to the frequent comorbidity of these phenotypes,” wrote lead author Jack M. Fu, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues. “Still, an estimated 13.4% of the transmission and de novo association–ASD genes show little evidence for association in the developmental delay cohort.”
ASD, developmental delay, and schizophrenia
When the researchers compared the cells where the genetic mutations occurred in fetal brains, they found that genes associated with developmental delay more often occurred in less differentiated cell types – less mature cells in the developmental process. Gene mutations associated with ASD, on the other hand, occurred in more mature cell types, particularly in maturing excitatory neurons and related cells.
”Our results are consistent with developmental delay-predominant genes being expressed earlier in development and in less differentiated cells than ASD-predominant genes,” they wrote.
The researchers also compared the specific gene mutations found in these two cohorts with a previously published set of 244 genes associated with schizophrenia. Of these, 234 genes are among those with a transmission and de novo association to ASD and/or developmental delay. Of the 72 genes linked to ASD, eight appear in the set of genes linked to schizophrenia, and 61 were associated with developmental delay, though these two subsets do not overlap each other much.
“The ASD-schizophrenia overlap was significantly enriched, while the developmental delay-schizophrenia overlap was not,” they reported. ”Together, these data suggest that one subset of ASD risk genes may overlap developmental delay while a different subset overlaps schizophrenia.”
Chasing therapy targets by backtracking through genes
The findings are a substantial step forward in understanding the potential genetic contribution to ASD, but they also highlight the challenges of eventually trying to use this information in a clinically meaningful way.
“Given the substantial overlap between the genes implicated in neurodevelopmental disorders writ large and those implicated directly in ASD, disentangling the relative impact of individual genes on neurodevelopment and phenotypic spectra is a daunting yet important challenge,” the researchers wrote. “To identify the key neurobiological features of ASD will likely require convergence of evidence from many ASD genes and studies.”
Dr. Elliott said the biggest takeaway from this study is a better understanding of how the paradigm has shifted away from finding “one gene” for autism or a cure based on genetics and more toward understanding the pathophysiology of symptoms that can point to therapies for better management of the condition.
“Basic researchers have completely changed the strategy for trying to understand the biology of major disorders,” including, in this case, autism, Dr. Elliott said. “The intent is to try to find the underlying systems [in the brain] by backtracking through genes. Meanwhile, given that scientists have made substantial progress in identifying genes that have specific effects on brain development, “the hope is that will mesh with this kind of research, to begin to identify systems that might ultimately be targets for treating.”
The end goal is to be able to offer targeted approaches, based on the pathways causing a symptom, which can be linked backward to a gene.
”So this is not going to offer an immediate cure – it’s probably not going to offer a cure at all – but it may actually lead to much more targeted medications than we currently have for specific types of symptoms within the autism spectrum,” Dr. Elliott said. “What they’re trying to do, ultimately, is to say, when this system is really badly affected because of a genetic abnormality, even though that genetic abnormality is very rare, it leads to these specific kinds of symptoms. If we can find out the neuroregulators underlying that change, then that would be the target, even if that gene were not present.”
The research was funded by the Simons Foundation for Autism Research Initiative, the SPARK project, the National Human Genome Research Institute Home, the National Institute of Mental Health, the National Institute of Child Health and Development, AMED, and the Beatrice and Samuel Seaver Foundation. Five authors reported financial disclosures linked to Desitin, Roche, BioMarin, BrigeBio Pharma, Illumina, Levo Therapeutics, and Microsoft.
according to a study published in Nature Genetics. The findings, based on analysis of more than 150,000 people’s genetics, arose from a collaboration of five research groups whose work included comparisons of ASD cohorts with separate cohorts of individuals with developmental delay or schizophrenia.
“We know that many genes, when mutated, contribute to autism,” and this study brought together “multiple types of mutations in a wide array of samples to get a much richer sense of the genes and genetic architecture involved in autism and other neurodevelopmental conditions,” co–senior author Joseph D. Buxbaum, PhD, director of the Seaver Autism Center for Research and Treatment at Mount Sinai and a professor at the Icahn School of Medicine at Mount Sinai, both in New York, said in a prepared statement. “This is significant in that we now have more insights as to the biology of the brain changes that underlie autism and more potential targets for treatment.”
Glen Elliott, PhD, MD, a clinical professor of psychiatry at Stanford (Calif.) University who was not involved in the study, said the paper is important paper for informing clinicians of where the basic research is headed. “We’re still in for a long road” before it bears fruit in terms of therapeutics. The value of studies like these, that investigate which genes are most associated with ASD, is that they may lead toward understanding the pathways in the brain that give rise to certain symptoms of ASD, which can then become therapeutic targets, Dr. Elliott said.
Investigating large cohorts
The researchers analyzed genetic exome sequencing data from 33 ASD cohorts with a total of 63,237 people and then compared these data with another cohort of people with developmental delay and a cohort of people with schizophrenia. The combined ASD cohorts included 15,036 individuals with ASD, 28,522 parents, and 5,492 unaffected siblings. The remaining participants were 5,591 people with ASD and 8,597 matched controls from case control studies.
In the ASD cohorts, the researchers identified 72 genes that were associated with ASD. De novo variants were eight times more likely in cases (4%) than in controls (0.5%). Ten genes occurred at least twice in ASD cases but never occurred in unaffected siblings.
Then the researchers integrated these ASD genetic data with a cohort of 91,605 people that included 31,058 people with developmental delay and their parents. Substantial overlap with gene mutations existed between these two cohorts: 70.1% of the genes related to developmental delay appeared linked to risk for ASD, and 86.6% of genes associated with ASD risk also had associations with developmental delay. Overall, the researchers identified 373 genes strongly associated with ASD and/or developmental delay and 664 genes with a likely association.
“Isolating genes that exert a greater effect on ASD than they do on other developmental delays has remained challenging due to the frequent comorbidity of these phenotypes,” wrote lead author Jack M. Fu, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues. “Still, an estimated 13.4% of the transmission and de novo association–ASD genes show little evidence for association in the developmental delay cohort.”
ASD, developmental delay, and schizophrenia
When the researchers compared the cells where the genetic mutations occurred in fetal brains, they found that genes associated with developmental delay more often occurred in less differentiated cell types – less mature cells in the developmental process. Gene mutations associated with ASD, on the other hand, occurred in more mature cell types, particularly in maturing excitatory neurons and related cells.
”Our results are consistent with developmental delay-predominant genes being expressed earlier in development and in less differentiated cells than ASD-predominant genes,” they wrote.
The researchers also compared the specific gene mutations found in these two cohorts with a previously published set of 244 genes associated with schizophrenia. Of these, 234 genes are among those with a transmission and de novo association to ASD and/or developmental delay. Of the 72 genes linked to ASD, eight appear in the set of genes linked to schizophrenia, and 61 were associated with developmental delay, though these two subsets do not overlap each other much.
“The ASD-schizophrenia overlap was significantly enriched, while the developmental delay-schizophrenia overlap was not,” they reported. ”Together, these data suggest that one subset of ASD risk genes may overlap developmental delay while a different subset overlaps schizophrenia.”
Chasing therapy targets by backtracking through genes
The findings are a substantial step forward in understanding the potential genetic contribution to ASD, but they also highlight the challenges of eventually trying to use this information in a clinically meaningful way.
“Given the substantial overlap between the genes implicated in neurodevelopmental disorders writ large and those implicated directly in ASD, disentangling the relative impact of individual genes on neurodevelopment and phenotypic spectra is a daunting yet important challenge,” the researchers wrote. “To identify the key neurobiological features of ASD will likely require convergence of evidence from many ASD genes and studies.”
Dr. Elliott said the biggest takeaway from this study is a better understanding of how the paradigm has shifted away from finding “one gene” for autism or a cure based on genetics and more toward understanding the pathophysiology of symptoms that can point to therapies for better management of the condition.
“Basic researchers have completely changed the strategy for trying to understand the biology of major disorders,” including, in this case, autism, Dr. Elliott said. “The intent is to try to find the underlying systems [in the brain] by backtracking through genes. Meanwhile, given that scientists have made substantial progress in identifying genes that have specific effects on brain development, “the hope is that will mesh with this kind of research, to begin to identify systems that might ultimately be targets for treating.”
The end goal is to be able to offer targeted approaches, based on the pathways causing a symptom, which can be linked backward to a gene.
”So this is not going to offer an immediate cure – it’s probably not going to offer a cure at all – but it may actually lead to much more targeted medications than we currently have for specific types of symptoms within the autism spectrum,” Dr. Elliott said. “What they’re trying to do, ultimately, is to say, when this system is really badly affected because of a genetic abnormality, even though that genetic abnormality is very rare, it leads to these specific kinds of symptoms. If we can find out the neuroregulators underlying that change, then that would be the target, even if that gene were not present.”
The research was funded by the Simons Foundation for Autism Research Initiative, the SPARK project, the National Human Genome Research Institute Home, the National Institute of Mental Health, the National Institute of Child Health and Development, AMED, and the Beatrice and Samuel Seaver Foundation. Five authors reported financial disclosures linked to Desitin, Roche, BioMarin, BrigeBio Pharma, Illumina, Levo Therapeutics, and Microsoft.
FROM NATURE GENETICS