Neurology

Any amount of exercise in middle age is associated with better cognition in later life, new research suggests.

A prospective study of 1,400 participants showed that those who exercised to any extent in adulthood had significantly better cognitive scores later in life, compared with their peers who were physically inactive.

Maintaining an exercise routine throughout adulthood showed the strongest link to subsequent mental acuity.

Although these associations lessened when investigators controlled for childhood cognitive ability, socioeconomic background, and education, they remained statistically significant.

“Our findings support recommendations for greater participation in physical activity across adulthood,” lead investigator Sarah-Naomi James, PhD, research fellow at the Medical Research Council Unit for Lifelong Health and Ageing at the University College London, told this news organization.

“We provide evidence to encourage inactive adults to be active even to a small extent … at any point during adulthood,” which can improve cognition and memory later in life, Dr. James said.

The findings were published online in the Journal of Neurology, Neurosurgery & Psychiatry.
 

Exercise timing

Previous studies have established a link between fitness training and cognitive benefit later in life, but the researchers wanted to explore whether the timing or type of exercise influenced cognitive outcomes in later life.

The investigators asked more than 1,400 participants in the 1946 British birth cohort how much they had exercised at ages 36, 43, 60, and 69 years.

The questions changed slightly for each assessment period, but in general, participants were asked whether in the past month they had exercised or participated in such activities as badminton, swimming, fitness exercises, yoga, dancing, football, mountain climbing, jogging, or brisk walks for 30 minutes or more; and if so, how many times they participated per month.

Prior research showed that when the participants were aged 60 years, the most commonly reported activities were walking (71%), swimming (33%), floor exercises (24%), and cycling (15%).

When they turned 69, researchers tested participants’ cognitive performance using the Addenbrooke’s Cognitive Examination–III, which measures attention and orientation, verbal fluency, memory, language, and visuospatial function. In this study sample, 53% were women, and all were White.

Physical activity levels were classified as inactive, moderately active (one to four times per month), and most active (five or more times per month). In addition, they were summed across all five assessments to create a total score ranging from 0 (inactive at all ages) to 5 (active at all ages).

Overall, 11% of participants were physically inactive at all five time points; 17% were active at one time point; 20% were active at two and three time points; 17% were active at four time points; and 15% were active at all five time points.
 

‘Cradle to grave’ study?

Results showed that being physically active at all study time points was significantly associated with higher cognitive performance, verbal memory, and processing speed when participants were aged 69 (P < .01).

Those who exercised to any extent in adulthood – even just once a month during one of the time periods, fared better cognitively in later life, compared with physically inactive participants. (P < .01).

Study limitations cited include a lack of diversity among participants and a disproportionately high attrition rate among those who were socially disadvantaged.

“Our findings show that being active during every decade from their 30s on was associated with better cognition at around 70. Indeed, those who were active for longer had the highest cognitive function,” Dr. James said.

“However, it is also never too late to start. People in our study who only started being active in their 50s or 60s still had higher cognitive scores at age 70, compared to people of the same age who had never been active,” she added.

Dr. James intends to continue following the study sample to determine whether physical activity is linked to preserved cognitive aging “and buffers the effects of cognitive deterioration in the presence of disease markers that cause dementia, ultimately delaying dementia onset.

“We hope the cohort we study will be the first ‘cradle to grave’ study in the world, where we have followed people for their entire lives,” she said.
 

Encouraging finding

In a comment, Joel Hughes, PhD, professor of psychology and director of clinical training at Kent (Ohio) State University, said the study contributes to the idea that “accumulation of physical activity over one’s lifetime fits the data better than a ‘sensitive period’ – which suggests that it’s never too late to start exercising.”

Dr. Hughes, who was not involved in the research, noted that “exercise can improve cerebral blood flow and hemodynamic function, as well as greater activation of relevant brain regions such as the frontal lobes.”

While observing that the effects of exercise on cognition are likely complex from a mechanistic point of view, the finding that “exercise preserves or improves cognition later in life is encouraging,” he said.

The study received funding from the UK Medical Research Council and Alzheimer’s Research UK. The investigators and Dr. Hughes report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Any amount of exercise in middle age is associated with better cognition in later life, new research suggests.

A prospective study of 1,400 participants showed that those who exercised to any extent in adulthood had significantly better cognitive scores later in life, compared with their peers who were physically inactive.

Maintaining an exercise routine throughout adulthood showed the strongest link to subsequent mental acuity.

Although these associations lessened when investigators controlled for childhood cognitive ability, socioeconomic background, and education, they remained statistically significant.

“Our findings support recommendations for greater participation in physical activity across adulthood,” lead investigator Sarah-Naomi James, PhD, research fellow at the Medical Research Council Unit for Lifelong Health and Ageing at the University College London, told this news organization.

“We provide evidence to encourage inactive adults to be active even to a small extent … at any point during adulthood,” which can improve cognition and memory later in life, Dr. James said.

The findings were published online in the Journal of Neurology, Neurosurgery & Psychiatry.
 

Exercise timing

Previous studies have established a link between fitness training and cognitive benefit later in life, but the researchers wanted to explore whether the timing or type of exercise influenced cognitive outcomes in later life.

The investigators asked more than 1,400 participants in the 1946 British birth cohort how much they had exercised at ages 36, 43, 60, and 69 years.

The questions changed slightly for each assessment period, but in general, participants were asked whether in the past month they had exercised or participated in such activities as badminton, swimming, fitness exercises, yoga, dancing, football, mountain climbing, jogging, or brisk walks for 30 minutes or more; and if so, how many times they participated per month.

Prior research showed that when the participants were aged 60 years, the most commonly reported activities were walking (71%), swimming (33%), floor exercises (24%), and cycling (15%).

When they turned 69, researchers tested participants’ cognitive performance using the Addenbrooke’s Cognitive Examination–III, which measures attention and orientation, verbal fluency, memory, language, and visuospatial function. In this study sample, 53% were women, and all were White.

Physical activity levels were classified as inactive, moderately active (one to four times per month), and most active (five or more times per month). In addition, they were summed across all five assessments to create a total score ranging from 0 (inactive at all ages) to 5 (active at all ages).

Overall, 11% of participants were physically inactive at all five time points; 17% were active at one time point; 20% were active at two and three time points; 17% were active at four time points; and 15% were active at all five time points.
 

‘Cradle to grave’ study?

Results showed that being physically active at all study time points was significantly associated with higher cognitive performance, verbal memory, and processing speed when participants were aged 69 (P < .01).

Those who exercised to any extent in adulthood – even just once a month during one of the time periods, fared better cognitively in later life, compared with physically inactive participants. (P < .01).

Study limitations cited include a lack of diversity among participants and a disproportionately high attrition rate among those who were socially disadvantaged.

“Our findings show that being active during every decade from their 30s on was associated with better cognition at around 70. Indeed, those who were active for longer had the highest cognitive function,” Dr. James said.

“However, it is also never too late to start. People in our study who only started being active in their 50s or 60s still had higher cognitive scores at age 70, compared to people of the same age who had never been active,” she added.

Dr. James intends to continue following the study sample to determine whether physical activity is linked to preserved cognitive aging “and buffers the effects of cognitive deterioration in the presence of disease markers that cause dementia, ultimately delaying dementia onset.

“We hope the cohort we study will be the first ‘cradle to grave’ study in the world, where we have followed people for their entire lives,” she said.
 

Encouraging finding

In a comment, Joel Hughes, PhD, professor of psychology and director of clinical training at Kent (Ohio) State University, said the study contributes to the idea that “accumulation of physical activity over one’s lifetime fits the data better than a ‘sensitive period’ – which suggests that it’s never too late to start exercising.”

Dr. Hughes, who was not involved in the research, noted that “exercise can improve cerebral blood flow and hemodynamic function, as well as greater activation of relevant brain regions such as the frontal lobes.”

While observing that the effects of exercise on cognition are likely complex from a mechanistic point of view, the finding that “exercise preserves or improves cognition later in life is encouraging,” he said.

The study received funding from the UK Medical Research Council and Alzheimer’s Research UK. The investigators and Dr. Hughes report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Any amount of exercise in middle age is associated with better cognition in later life, new research suggests.

A prospective study of 1,400 participants showed that those who exercised to any extent in adulthood had significantly better cognitive scores later in life, compared with their peers who were physically inactive.

Maintaining an exercise routine throughout adulthood showed the strongest link to subsequent mental acuity.

Although these associations lessened when investigators controlled for childhood cognitive ability, socioeconomic background, and education, they remained statistically significant.

“Our findings support recommendations for greater participation in physical activity across adulthood,” lead investigator Sarah-Naomi James, PhD, research fellow at the Medical Research Council Unit for Lifelong Health and Ageing at the University College London, told this news organization.

“We provide evidence to encourage inactive adults to be active even to a small extent … at any point during adulthood,” which can improve cognition and memory later in life, Dr. James said.

The findings were published online in the Journal of Neurology, Neurosurgery & Psychiatry.
 

Exercise timing

Previous studies have established a link between fitness training and cognitive benefit later in life, but the researchers wanted to explore whether the timing or type of exercise influenced cognitive outcomes in later life.

The investigators asked more than 1,400 participants in the 1946 British birth cohort how much they had exercised at ages 36, 43, 60, and 69 years.

The questions changed slightly for each assessment period, but in general, participants were asked whether in the past month they had exercised or participated in such activities as badminton, swimming, fitness exercises, yoga, dancing, football, mountain climbing, jogging, or brisk walks for 30 minutes or more; and if so, how many times they participated per month.

Prior research showed that when the participants were aged 60 years, the most commonly reported activities were walking (71%), swimming (33%), floor exercises (24%), and cycling (15%).

When they turned 69, researchers tested participants’ cognitive performance using the Addenbrooke’s Cognitive Examination–III, which measures attention and orientation, verbal fluency, memory, language, and visuospatial function. In this study sample, 53% were women, and all were White.

Physical activity levels were classified as inactive, moderately active (one to four times per month), and most active (five or more times per month). In addition, they were summed across all five assessments to create a total score ranging from 0 (inactive at all ages) to 5 (active at all ages).

Overall, 11% of participants were physically inactive at all five time points; 17% were active at one time point; 20% were active at two and three time points; 17% were active at four time points; and 15% were active at all five time points.
 

‘Cradle to grave’ study?

Results showed that being physically active at all study time points was significantly associated with higher cognitive performance, verbal memory, and processing speed when participants were aged 69 (P < .01).

Those who exercised to any extent in adulthood – even just once a month during one of the time periods, fared better cognitively in later life, compared with physically inactive participants. (P < .01).

Study limitations cited include a lack of diversity among participants and a disproportionately high attrition rate among those who were socially disadvantaged.

“Our findings show that being active during every decade from their 30s on was associated with better cognition at around 70. Indeed, those who were active for longer had the highest cognitive function,” Dr. James said.

“However, it is also never too late to start. People in our study who only started being active in their 50s or 60s still had higher cognitive scores at age 70, compared to people of the same age who had never been active,” she added.

Dr. James intends to continue following the study sample to determine whether physical activity is linked to preserved cognitive aging “and buffers the effects of cognitive deterioration in the presence of disease markers that cause dementia, ultimately delaying dementia onset.

“We hope the cohort we study will be the first ‘cradle to grave’ study in the world, where we have followed people for their entire lives,” she said.
 

Encouraging finding

In a comment, Joel Hughes, PhD, professor of psychology and director of clinical training at Kent (Ohio) State University, said the study contributes to the idea that “accumulation of physical activity over one’s lifetime fits the data better than a ‘sensitive period’ – which suggests that it’s never too late to start exercising.”

Dr. Hughes, who was not involved in the research, noted that “exercise can improve cerebral blood flow and hemodynamic function, as well as greater activation of relevant brain regions such as the frontal lobes.”

While observing that the effects of exercise on cognition are likely complex from a mechanistic point of view, the finding that “exercise preserves or improves cognition later in life is encouraging,” he said.

The study received funding from the UK Medical Research Council and Alzheimer’s Research UK. The investigators and Dr. Hughes report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

SAN DIEGO – The prevalence of psychiatric morbidity is significantly higher among patients with multiple sclerosis (MS) versus controls in each of the 5 years prior to the onset of the disease, new research reveals. Results of a population-based study show the relative risk of psychiatric morbidity, including depression and anxiety, was up to 88% higher in patients with MS, compared with their counterparts without the disease.

These results are an incentive to “keep exploring” to get a “clearer picture” of the MS prodrome, said study investigator Anibal Chertcoff, MD, who is trained both as a neurologist and psychiatrist and is a postdoctoral fellow at the University of British Columbia, Vancouver.

With a better understanding of this phase, it might be possible to “push the limits to get an earlier diagnosis of MS,” said Dr. Chertcoff.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Psychiatric morbidity during the prodromal phase of MS

Psychiatric comorbidities are common in MS. Emerging research suggests psychiatric disorders may be present before disease onset.

Using administrative and clinical data, the investigators collected information on MS cases and healthy matched controls who had no demyelinating disease claims. They used a clinical cohort of patients attending an MS clinic and a much larger administrative cohort that used an algorithm to detect MS cases using diagnostic codes and prescription data for disease modifying therapies.

The administrative cohort consisted of 6,863 MS cases and 31,865 controls while the clinical cohort had 966 cases and 4,534 controls. The majority (73%) of cases and controls were female. The mean age at the first demyelinating claim was 44 years.

The study’s primary outcome was prevalence of psychiatric morbidity using diagnostic codes for depression, anxiety, bipolar disorder, and schizophrenia. In the 5 years pre-MS onset, 28% of MS cases and 14.9% of controls had psychiatric morbidity.

The researchers plotted psychiatric morbidity in both MS cases and controls over time on a graph. “In terms of the prevalence of psychiatric morbidity, in each year the difference between the groups, at least visually, seems to increase with time as it gets closer to MS onset,” said Dr. Chertcoff.

The analysis showed the relative risk of psychiatric morbidity over the 5 years before MS onset was 1.88 (95% confidence interval, 1.80-1.97) in the administrative cohort, and 1.57 (95% CI, 1.36-1.80) in the clinical cohort.

Secondary analyses showed individuals with MS had more yearly physician visits, visits to psychiatrists, psychiatric hospital admissions, and prescription fills for psychiatric medication, compared with controls. This, said Dr. Chertcoff, illustrates the burden psychiatric morbidity during the prodromal phase of MS places on health care resources.

It’s possible that low-grade inflammation, which is linked to MS, is also pushing these psychiatric phenomena, said Dr. Chertcoff. He noted that the prevalence of depression is significantly higher not only in MS, but in a wide range of other inflammatory conditions.

In addition to psychiatric complaints, MS patients experience other symptoms, including  pain, sleep disturbances, fatigue, and gastrointestinal issues during the MS prodrome, said Dr. Chertcoff.

Patients with MS are often seeing other physicians – including psychiatrists during the prodromal phase of the disease. Neurologists, Dr. Chertcoff said, could perhaps “raise awareness” among these other specialists about the prevalence of psychiatric morbidities during this phase.

He hopes experts in the field will consider developing research criteria for the MS prodrome similar to what has been done in Parkinson’s disease.
 

When does MS start?

Commenting on the research findings, Mark Freedman, MD, professor of medicine (Neurology), University of Ottawa, and director of the multiple sclerosis research unit, Ottawa Hospital-General Campus, said the study illustrates the increased research attention the interplay between MS and psychiatric disorders is getting.

He recalled “one of the most compelling” recent studies that looked at a large group of children with MS and showed their grades started falling more than 5 years before developing MS symptoms. “You could see their grades going down year by year by year, so an indicator that a young brain, which should be like a sponge and improving, was actually faltering well before the symptoms.”

Results from this new study continue to beg the question of when MS actually starts, said Dr. Freedman.

The study received funding from the U.S. National MS Society, the MS Society of Canada, and the Michael Smith Foundation. Dr. Chertcoff and Dr. Freedman reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

SAN DIEGO – The prevalence of psychiatric morbidity is significantly higher among patients with multiple sclerosis (MS) versus controls in each of the 5 years prior to the onset of the disease, new research reveals. Results of a population-based study show the relative risk of psychiatric morbidity, including depression and anxiety, was up to 88% higher in patients with MS, compared with their counterparts without the disease.

These results are an incentive to “keep exploring” to get a “clearer picture” of the MS prodrome, said study investigator Anibal Chertcoff, MD, who is trained both as a neurologist and psychiatrist and is a postdoctoral fellow at the University of British Columbia, Vancouver.

With a better understanding of this phase, it might be possible to “push the limits to get an earlier diagnosis of MS,” said Dr. Chertcoff.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Psychiatric morbidity during the prodromal phase of MS

Psychiatric comorbidities are common in MS. Emerging research suggests psychiatric disorders may be present before disease onset.

Using administrative and clinical data, the investigators collected information on MS cases and healthy matched controls who had no demyelinating disease claims. They used a clinical cohort of patients attending an MS clinic and a much larger administrative cohort that used an algorithm to detect MS cases using diagnostic codes and prescription data for disease modifying therapies.

The administrative cohort consisted of 6,863 MS cases and 31,865 controls while the clinical cohort had 966 cases and 4,534 controls. The majority (73%) of cases and controls were female. The mean age at the first demyelinating claim was 44 years.

The study’s primary outcome was prevalence of psychiatric morbidity using diagnostic codes for depression, anxiety, bipolar disorder, and schizophrenia. In the 5 years pre-MS onset, 28% of MS cases and 14.9% of controls had psychiatric morbidity.

The researchers plotted psychiatric morbidity in both MS cases and controls over time on a graph. “In terms of the prevalence of psychiatric morbidity, in each year the difference between the groups, at least visually, seems to increase with time as it gets closer to MS onset,” said Dr. Chertcoff.

The analysis showed the relative risk of psychiatric morbidity over the 5 years before MS onset was 1.88 (95% confidence interval, 1.80-1.97) in the administrative cohort, and 1.57 (95% CI, 1.36-1.80) in the clinical cohort.

Secondary analyses showed individuals with MS had more yearly physician visits, visits to psychiatrists, psychiatric hospital admissions, and prescription fills for psychiatric medication, compared with controls. This, said Dr. Chertcoff, illustrates the burden psychiatric morbidity during the prodromal phase of MS places on health care resources.

It’s possible that low-grade inflammation, which is linked to MS, is also pushing these psychiatric phenomena, said Dr. Chertcoff. He noted that the prevalence of depression is significantly higher not only in MS, but in a wide range of other inflammatory conditions.

In addition to psychiatric complaints, MS patients experience other symptoms, including  pain, sleep disturbances, fatigue, and gastrointestinal issues during the MS prodrome, said Dr. Chertcoff.

Patients with MS are often seeing other physicians – including psychiatrists during the prodromal phase of the disease. Neurologists, Dr. Chertcoff said, could perhaps “raise awareness” among these other specialists about the prevalence of psychiatric morbidities during this phase.

He hopes experts in the field will consider developing research criteria for the MS prodrome similar to what has been done in Parkinson’s disease.
 

When does MS start?

Commenting on the research findings, Mark Freedman, MD, professor of medicine (Neurology), University of Ottawa, and director of the multiple sclerosis research unit, Ottawa Hospital-General Campus, said the study illustrates the increased research attention the interplay between MS and psychiatric disorders is getting.

He recalled “one of the most compelling” recent studies that looked at a large group of children with MS and showed their grades started falling more than 5 years before developing MS symptoms. “You could see their grades going down year by year by year, so an indicator that a young brain, which should be like a sponge and improving, was actually faltering well before the symptoms.”

Results from this new study continue to beg the question of when MS actually starts, said Dr. Freedman.

The study received funding from the U.S. National MS Society, the MS Society of Canada, and the Michael Smith Foundation. Dr. Chertcoff and Dr. Freedman reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

SAN DIEGO – The prevalence of psychiatric morbidity is significantly higher among patients with multiple sclerosis (MS) versus controls in each of the 5 years prior to the onset of the disease, new research reveals. Results of a population-based study show the relative risk of psychiatric morbidity, including depression and anxiety, was up to 88% higher in patients with MS, compared with their counterparts without the disease.

These results are an incentive to “keep exploring” to get a “clearer picture” of the MS prodrome, said study investigator Anibal Chertcoff, MD, who is trained both as a neurologist and psychiatrist and is a postdoctoral fellow at the University of British Columbia, Vancouver.

With a better understanding of this phase, it might be possible to “push the limits to get an earlier diagnosis of MS,” said Dr. Chertcoff.

The findings were presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Psychiatric morbidity during the prodromal phase of MS

Psychiatric comorbidities are common in MS. Emerging research suggests psychiatric disorders may be present before disease onset.

Using administrative and clinical data, the investigators collected information on MS cases and healthy matched controls who had no demyelinating disease claims. They used a clinical cohort of patients attending an MS clinic and a much larger administrative cohort that used an algorithm to detect MS cases using diagnostic codes and prescription data for disease modifying therapies.

The administrative cohort consisted of 6,863 MS cases and 31,865 controls while the clinical cohort had 966 cases and 4,534 controls. The majority (73%) of cases and controls were female. The mean age at the first demyelinating claim was 44 years.

The study’s primary outcome was prevalence of psychiatric morbidity using diagnostic codes for depression, anxiety, bipolar disorder, and schizophrenia. In the 5 years pre-MS onset, 28% of MS cases and 14.9% of controls had psychiatric morbidity.

The researchers plotted psychiatric morbidity in both MS cases and controls over time on a graph. “In terms of the prevalence of psychiatric morbidity, in each year the difference between the groups, at least visually, seems to increase with time as it gets closer to MS onset,” said Dr. Chertcoff.

The analysis showed the relative risk of psychiatric morbidity over the 5 years before MS onset was 1.88 (95% confidence interval, 1.80-1.97) in the administrative cohort, and 1.57 (95% CI, 1.36-1.80) in the clinical cohort.

Secondary analyses showed individuals with MS had more yearly physician visits, visits to psychiatrists, psychiatric hospital admissions, and prescription fills for psychiatric medication, compared with controls. This, said Dr. Chertcoff, illustrates the burden psychiatric morbidity during the prodromal phase of MS places on health care resources.

It’s possible that low-grade inflammation, which is linked to MS, is also pushing these psychiatric phenomena, said Dr. Chertcoff. He noted that the prevalence of depression is significantly higher not only in MS, but in a wide range of other inflammatory conditions.

In addition to psychiatric complaints, MS patients experience other symptoms, including  pain, sleep disturbances, fatigue, and gastrointestinal issues during the MS prodrome, said Dr. Chertcoff.

Patients with MS are often seeing other physicians – including psychiatrists during the prodromal phase of the disease. Neurologists, Dr. Chertcoff said, could perhaps “raise awareness” among these other specialists about the prevalence of psychiatric morbidities during this phase.

He hopes experts in the field will consider developing research criteria for the MS prodrome similar to what has been done in Parkinson’s disease.
 

When does MS start?

Commenting on the research findings, Mark Freedman, MD, professor of medicine (Neurology), University of Ottawa, and director of the multiple sclerosis research unit, Ottawa Hospital-General Campus, said the study illustrates the increased research attention the interplay between MS and psychiatric disorders is getting.

He recalled “one of the most compelling” recent studies that looked at a large group of children with MS and showed their grades started falling more than 5 years before developing MS symptoms. “You could see their grades going down year by year by year, so an indicator that a young brain, which should be like a sponge and improving, was actually faltering well before the symptoms.”

Results from this new study continue to beg the question of when MS actually starts, said Dr. Freedman.

The study received funding from the U.S. National MS Society, the MS Society of Canada, and the Michael Smith Foundation. Dr. Chertcoff and Dr. Freedman reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Ayahuasca is a psychoactive beverage that has long been used by indigenous people in South America in religious ceremonies and tribal rituals. In recent years, the beverage has emerged as a strong candidate for implementation into psychiatric care, particularly for patients with treatment-resistant depression.

Studies have shown that taking ayahuasca is associated with an improvement of depressive symptoms. In a study published in Frontiers in Psychiatry, a team of researchers from Brazil’s Federal University of Rio Grande do Norte (UFRN) describe an experimental ayahuasca session. They found that specific emotional and physiologic parameters were critical moderators of improvement in major depression biomarkers, mainly serum brain-derived neurotrophic factor (BDNF) and serum cortisol (SC), 2 days after ayahuasca intake.

Nicole Leite Galvão-Coelho, PhD, professor of physiology and behavior at UFRN, is one of the authors of that study. She is also a researcher at the NICM Health Research Institute at Western Sydney University. Dr. Galvão-Coelho spoke with this news organization about her team’s work.

A total of 72 people volunteered to participate in the study. There were 28 patients, all of whom were experiencing a moderate to severe depressive episode at screening. In addition, they had been diagnosed with treatment-resistant depression and had not achieved remission after at least two treatments with antidepressant medications of different classes. These patients had been experiencing depression for about 10.71 ± 9.72 years. The other 44 volunteers were healthy control participants. All the participants – both in the patient group and the control group – were naive to any classic serotonergic psychedelic such as ayahuasca.

In each group, half received ayahuasca, and the other half received a placebo. The dosing session was performed at UFRN’s Onofre Lopes University Hospital and lasted about 8 hours.

All volunteers underwent a full clinical mental health evaluation and medical history. Blood and saliva samples were collected at baseline, approximately 4 hours before the dosing session, and 2 days after the dosing session. During the dosing session, saliva samples were collected at 1 hour 40 minutes, 2 hours 40 minutes, and 4 hours after ayahuasca intake.

The study showed that some acute measures assessed during ayahuasca dosing moderated the improvements in major depressive disorder (MDD) biomarkers 2 days after the session in patients with treatment-resistant depression. Larger acute decreases of depressive symptoms moderated higher levels of SC in those patients, while lower acute changes in SC levels were related to higher BDNF levels in patients with a larger clinical response.

The UFRN research team has been investigating the potential antidepressant effects of ayahuasca for approximately 12 years. According to Dr. Galvão-Coelho, the work reported in the most recent article – one in a series of articles that they wrote – provides a step forward as a pioneering psychedelic field study assessing the biological changes of MDD molecular biomarkers. “There have indeed been observational studies and open-label clinical studies. We were the first team, though, to conduct placebo-controlled clinical studies with ayahuasca in patients with treatment-resistant depression,” she explained. She noted that the work was carried out in partnership with Dráulio Barros de Araújo, PhD, a professor at UFRN’s Brain Institute, as well as with a multidisciplinary team of researchers in Brazil and Australia.

Dr. Galvão-Coelho said that in an earlier study, the UFRN researchers observed that a single dose of ayahuasca led to long-lasting behavioral and physiologic improvements in an animal (marmoset) model. In another study, there was improvement in depression severity for patients with treatment-resistant depression 7 days after taking ayahuasca.

As for biomarkers, Dr. Galvão-Coelho said that there is a long history of research on cortisol (the “stress hormone”) with respect to patients with depressive symptoms, given the link between chronic stress and depressive disorders. “In our patients with treatment-resistant depression, we found that before being dosed with ayahuasca, they presented hypocortisolemia,” she said. She noted that low levels of cortisol are as harmful to one’s health as high levels. According to her, the goal should be to sustain moderate levels. “In other studies, we’ve shown that patients with more recent, less chronic depression have high cortisol levels, but after a little while, the [adrenal] glands get overworked, which seems to lead to a situation where they’re not producing all those important hormones. That’s why chronic conditions of depression are marked by low levels of cortisol. But,” she pointed out, “after patients with treatment-resistant depression take ayahuasca, we no longer see hypocortisolemia.”

Another biomarker analyzed by the research team, the protein BDNF, has the capacity to induce neuroplasticity. Indeed, Dr. Galvão-Coelho mentioned a theory that antidepressant drugs work when they increase levels of this protein, which would stimulate new connections in the brain.

Because several earlier studies indicated that other psychedelic substances would promote an increase in BDNF, the UFRN researchers decided to explore the potential effects of ayahuasca on this biomarker. “We observed that there was actually an increase in serum BDNF, and the patients who showed the greatest increase [of this marker] had a more significant reduction in depressive symptoms,” Dr. Galvão-Coelho explained.

Considering all the previous findings, the team wondered whether acute parameters recorded during an ayahuasca dosing session could in some way modulate the responses of certain key MDD molecular biomarkers. They then conducted their study that was published last December.

Dr. Galvão-Coelho said that the results of that study show that acute emotional and physiologic effects of ayahuasca seem to be relevant to an improvement of key MDD molecular biomarkers (namely, SC and BDNF). She also noted that the results revealed that larger reductions of depressive symptoms during the dosing session significantly moderated higher levels of SC in patients 2 days after ayahuasca intake. In the case of BDNF, the positive correlation between clinical response and day-2 BDNF levels only occurred for patients who experienced small increases of cortisol during the experimental session. These were individuals who did not have such an intense response to stress and who felt more at ease during the session.

The findings showed which factors that arise during the psychedelic state induced by ayahuasca modulate biological response associated with the antidepressant action of these substances in patients with major depression. “We realized, for example, that to bring about a sense of comfort and trust, to get a good acute response, the dosing session had to be extremely well thought out. That seemed to be relevant to the results on the other days,” Dr. Galvão-Coelho explained.

For her, there was another takeaway from the research: New antidepressant treatments should be complemented by a more comprehensive view of the case at hand. “We have to think about the patient’s overall improvement – including, therefore, the improvement of biomarkers – and not focus solely on the clinical symptoms.”

This article was translated from the Medscape Portuguese Edition.

A version of this article first appeared on Medscape.com.

Ayahuasca is a psychoactive beverage that has long been used by indigenous people in South America in religious ceremonies and tribal rituals. In recent years, the beverage has emerged as a strong candidate for implementation into psychiatric care, particularly for patients with treatment-resistant depression.

Studies have shown that taking ayahuasca is associated with an improvement of depressive symptoms. In a study published in Frontiers in Psychiatry, a team of researchers from Brazil’s Federal University of Rio Grande do Norte (UFRN) describe an experimental ayahuasca session. They found that specific emotional and physiologic parameters were critical moderators of improvement in major depression biomarkers, mainly serum brain-derived neurotrophic factor (BDNF) and serum cortisol (SC), 2 days after ayahuasca intake.

Nicole Leite Galvão-Coelho, PhD, professor of physiology and behavior at UFRN, is one of the authors of that study. She is also a researcher at the NICM Health Research Institute at Western Sydney University. Dr. Galvão-Coelho spoke with this news organization about her team’s work.

A total of 72 people volunteered to participate in the study. There were 28 patients, all of whom were experiencing a moderate to severe depressive episode at screening. In addition, they had been diagnosed with treatment-resistant depression and had not achieved remission after at least two treatments with antidepressant medications of different classes. These patients had been experiencing depression for about 10.71 ± 9.72 years. The other 44 volunteers were healthy control participants. All the participants – both in the patient group and the control group – were naive to any classic serotonergic psychedelic such as ayahuasca.

In each group, half received ayahuasca, and the other half received a placebo. The dosing session was performed at UFRN’s Onofre Lopes University Hospital and lasted about 8 hours.

All volunteers underwent a full clinical mental health evaluation and medical history. Blood and saliva samples were collected at baseline, approximately 4 hours before the dosing session, and 2 days after the dosing session. During the dosing session, saliva samples were collected at 1 hour 40 minutes, 2 hours 40 minutes, and 4 hours after ayahuasca intake.

The study showed that some acute measures assessed during ayahuasca dosing moderated the improvements in major depressive disorder (MDD) biomarkers 2 days after the session in patients with treatment-resistant depression. Larger acute decreases of depressive symptoms moderated higher levels of SC in those patients, while lower acute changes in SC levels were related to higher BDNF levels in patients with a larger clinical response.

The UFRN research team has been investigating the potential antidepressant effects of ayahuasca for approximately 12 years. According to Dr. Galvão-Coelho, the work reported in the most recent article – one in a series of articles that they wrote – provides a step forward as a pioneering psychedelic field study assessing the biological changes of MDD molecular biomarkers. “There have indeed been observational studies and open-label clinical studies. We were the first team, though, to conduct placebo-controlled clinical studies with ayahuasca in patients with treatment-resistant depression,” she explained. She noted that the work was carried out in partnership with Dráulio Barros de Araújo, PhD, a professor at UFRN’s Brain Institute, as well as with a multidisciplinary team of researchers in Brazil and Australia.

Dr. Galvão-Coelho said that in an earlier study, the UFRN researchers observed that a single dose of ayahuasca led to long-lasting behavioral and physiologic improvements in an animal (marmoset) model. In another study, there was improvement in depression severity for patients with treatment-resistant depression 7 days after taking ayahuasca.

As for biomarkers, Dr. Galvão-Coelho said that there is a long history of research on cortisol (the “stress hormone”) with respect to patients with depressive symptoms, given the link between chronic stress and depressive disorders. “In our patients with treatment-resistant depression, we found that before being dosed with ayahuasca, they presented hypocortisolemia,” she said. She noted that low levels of cortisol are as harmful to one’s health as high levels. According to her, the goal should be to sustain moderate levels. “In other studies, we’ve shown that patients with more recent, less chronic depression have high cortisol levels, but after a little while, the [adrenal] glands get overworked, which seems to lead to a situation where they’re not producing all those important hormones. That’s why chronic conditions of depression are marked by low levels of cortisol. But,” she pointed out, “after patients with treatment-resistant depression take ayahuasca, we no longer see hypocortisolemia.”

Another biomarker analyzed by the research team, the protein BDNF, has the capacity to induce neuroplasticity. Indeed, Dr. Galvão-Coelho mentioned a theory that antidepressant drugs work when they increase levels of this protein, which would stimulate new connections in the brain.

Because several earlier studies indicated that other psychedelic substances would promote an increase in BDNF, the UFRN researchers decided to explore the potential effects of ayahuasca on this biomarker. “We observed that there was actually an increase in serum BDNF, and the patients who showed the greatest increase [of this marker] had a more significant reduction in depressive symptoms,” Dr. Galvão-Coelho explained.

Considering all the previous findings, the team wondered whether acute parameters recorded during an ayahuasca dosing session could in some way modulate the responses of certain key MDD molecular biomarkers. They then conducted their study that was published last December.

Dr. Galvão-Coelho said that the results of that study show that acute emotional and physiologic effects of ayahuasca seem to be relevant to an improvement of key MDD molecular biomarkers (namely, SC and BDNF). She also noted that the results revealed that larger reductions of depressive symptoms during the dosing session significantly moderated higher levels of SC in patients 2 days after ayahuasca intake. In the case of BDNF, the positive correlation between clinical response and day-2 BDNF levels only occurred for patients who experienced small increases of cortisol during the experimental session. These were individuals who did not have such an intense response to stress and who felt more at ease during the session.

The findings showed which factors that arise during the psychedelic state induced by ayahuasca modulate biological response associated with the antidepressant action of these substances in patients with major depression. “We realized, for example, that to bring about a sense of comfort and trust, to get a good acute response, the dosing session had to be extremely well thought out. That seemed to be relevant to the results on the other days,” Dr. Galvão-Coelho explained.

For her, there was another takeaway from the research: New antidepressant treatments should be complemented by a more comprehensive view of the case at hand. “We have to think about the patient’s overall improvement – including, therefore, the improvement of biomarkers – and not focus solely on the clinical symptoms.”

This article was translated from the Medscape Portuguese Edition.

A version of this article first appeared on Medscape.com.

Ayahuasca is a psychoactive beverage that has long been used by indigenous people in South America in religious ceremonies and tribal rituals. In recent years, the beverage has emerged as a strong candidate for implementation into psychiatric care, particularly for patients with treatment-resistant depression.

Studies have shown that taking ayahuasca is associated with an improvement of depressive symptoms. In a study published in Frontiers in Psychiatry, a team of researchers from Brazil’s Federal University of Rio Grande do Norte (UFRN) describe an experimental ayahuasca session. They found that specific emotional and physiologic parameters were critical moderators of improvement in major depression biomarkers, mainly serum brain-derived neurotrophic factor (BDNF) and serum cortisol (SC), 2 days after ayahuasca intake.

Nicole Leite Galvão-Coelho, PhD, professor of physiology and behavior at UFRN, is one of the authors of that study. She is also a researcher at the NICM Health Research Institute at Western Sydney University. Dr. Galvão-Coelho spoke with this news organization about her team’s work.

A total of 72 people volunteered to participate in the study. There were 28 patients, all of whom were experiencing a moderate to severe depressive episode at screening. In addition, they had been diagnosed with treatment-resistant depression and had not achieved remission after at least two treatments with antidepressant medications of different classes. These patients had been experiencing depression for about 10.71 ± 9.72 years. The other 44 volunteers were healthy control participants. All the participants – both in the patient group and the control group – were naive to any classic serotonergic psychedelic such as ayahuasca.

In each group, half received ayahuasca, and the other half received a placebo. The dosing session was performed at UFRN’s Onofre Lopes University Hospital and lasted about 8 hours.

All volunteers underwent a full clinical mental health evaluation and medical history. Blood and saliva samples were collected at baseline, approximately 4 hours before the dosing session, and 2 days after the dosing session. During the dosing session, saliva samples were collected at 1 hour 40 minutes, 2 hours 40 minutes, and 4 hours after ayahuasca intake.

The study showed that some acute measures assessed during ayahuasca dosing moderated the improvements in major depressive disorder (MDD) biomarkers 2 days after the session in patients with treatment-resistant depression. Larger acute decreases of depressive symptoms moderated higher levels of SC in those patients, while lower acute changes in SC levels were related to higher BDNF levels in patients with a larger clinical response.

The UFRN research team has been investigating the potential antidepressant effects of ayahuasca for approximately 12 years. According to Dr. Galvão-Coelho, the work reported in the most recent article – one in a series of articles that they wrote – provides a step forward as a pioneering psychedelic field study assessing the biological changes of MDD molecular biomarkers. “There have indeed been observational studies and open-label clinical studies. We were the first team, though, to conduct placebo-controlled clinical studies with ayahuasca in patients with treatment-resistant depression,” she explained. She noted that the work was carried out in partnership with Dráulio Barros de Araújo, PhD, a professor at UFRN’s Brain Institute, as well as with a multidisciplinary team of researchers in Brazil and Australia.

Dr. Galvão-Coelho said that in an earlier study, the UFRN researchers observed that a single dose of ayahuasca led to long-lasting behavioral and physiologic improvements in an animal (marmoset) model. In another study, there was improvement in depression severity for patients with treatment-resistant depression 7 days after taking ayahuasca.

As for biomarkers, Dr. Galvão-Coelho said that there is a long history of research on cortisol (the “stress hormone”) with respect to patients with depressive symptoms, given the link between chronic stress and depressive disorders. “In our patients with treatment-resistant depression, we found that before being dosed with ayahuasca, they presented hypocortisolemia,” she said. She noted that low levels of cortisol are as harmful to one’s health as high levels. According to her, the goal should be to sustain moderate levels. “In other studies, we’ve shown that patients with more recent, less chronic depression have high cortisol levels, but after a little while, the [adrenal] glands get overworked, which seems to lead to a situation where they’re not producing all those important hormones. That’s why chronic conditions of depression are marked by low levels of cortisol. But,” she pointed out, “after patients with treatment-resistant depression take ayahuasca, we no longer see hypocortisolemia.”

Another biomarker analyzed by the research team, the protein BDNF, has the capacity to induce neuroplasticity. Indeed, Dr. Galvão-Coelho mentioned a theory that antidepressant drugs work when they increase levels of this protein, which would stimulate new connections in the brain.

Because several earlier studies indicated that other psychedelic substances would promote an increase in BDNF, the UFRN researchers decided to explore the potential effects of ayahuasca on this biomarker. “We observed that there was actually an increase in serum BDNF, and the patients who showed the greatest increase [of this marker] had a more significant reduction in depressive symptoms,” Dr. Galvão-Coelho explained.

Considering all the previous findings, the team wondered whether acute parameters recorded during an ayahuasca dosing session could in some way modulate the responses of certain key MDD molecular biomarkers. They then conducted their study that was published last December.

Dr. Galvão-Coelho said that the results of that study show that acute emotional and physiologic effects of ayahuasca seem to be relevant to an improvement of key MDD molecular biomarkers (namely, SC and BDNF). She also noted that the results revealed that larger reductions of depressive symptoms during the dosing session significantly moderated higher levels of SC in patients 2 days after ayahuasca intake. In the case of BDNF, the positive correlation between clinical response and day-2 BDNF levels only occurred for patients who experienced small increases of cortisol during the experimental session. These were individuals who did not have such an intense response to stress and who felt more at ease during the session.

The findings showed which factors that arise during the psychedelic state induced by ayahuasca modulate biological response associated with the antidepressant action of these substances in patients with major depression. “We realized, for example, that to bring about a sense of comfort and trust, to get a good acute response, the dosing session had to be extremely well thought out. That seemed to be relevant to the results on the other days,” Dr. Galvão-Coelho explained.

For her, there was another takeaway from the research: New antidepressant treatments should be complemented by a more comprehensive view of the case at hand. “We have to think about the patient’s overall improvement – including, therefore, the improvement of biomarkers – and not focus solely on the clinical symptoms.”

This article was translated from the Medscape Portuguese Edition.

A version of this article first appeared on Medscape.com.

A visual hallucination is a visual percept experienced when awake that is not elicited by an external stimulus. Historically, hallucinations have been synonymous with psychiatric disease, most notably schizophrenia; however, over recent decades, hallucinations have been categorized based on their underlying etiology as psychodynamic (primary psychiatric), psychophysiologic (primary neurologic/structural), and psychobiochemical (neurotransmitter dysfunction).¹ Presently, visual hallucinations are known to be caused by a wide variety of primary psychiatric, neurologic, ophthalmologic, and chemically-mediated conditions. Despite these causes, clinically differentiating the characteristics and qualities of visual hallucinations is often a lesser-known skillset among clinicians. The utility of this skillset is important for the clinician’s ability to differentiate the expected and unexpected characteristics of visual hallucinations in patients with both known and unknown neuropsychiatric conditions.

Though many primary psychiatric and neurologic conditions have been associated with and/or known to cause visual hallucinations, this review focuses on the following grouped causes:

• Primary psychiatric causes: psychiatric disorders with psychotic features and delirium; and
• Primary neurologic causes: neurodegenerative disease/dementias, seizure disorders, migraine disorders, vision loss, peduncular hallucinosis, and hypnagogic/hypnopompic phenomena.

Because the accepted definition of visual hallucinations excludes visual percepts elicited by external stimuli, drug-induced hallucinations would not qualify for either of these categories. Additionally, most studies reporting on the effects of drug-induced hallucinations did not control for underlying comorbid psychiatric conditions, dementia, or delirium, and thus the results cannot be attributed to the drug alone, nor is it possible to identify reliable trends in the properties of the hallucinations.² The goals of this review are to characterize visual hallucinations experienced as a result of primary psychiatric and primary neurologic conditions and describe key grouping and differentiating features to help guide the diagnosis.

Visual hallucinations in the general population

A review of 6 studies (N = 42,519) reported that the prevalence of visual hallucinations in the general population is 7.3%.³ The prevalence decreases to 6% when visual hallucinations arising from physical illness or drug/chemical consumption are excluded. The prevalence of visual hallucinations in the general population has been associated with comorbid anxiety, stress, bereavement, and psychotic pathology.^4,5 Regarding the age of occurrence of visual hallucinations in the general population, there appears to be a bimodal distribution.³ One peak appears in later adolescence and early adulthood, which corresponds with higher rates of psychosis, and another peak occurs late in life, which corresponds to a higher prevalence of neurodegenerative conditions and visual impairment.

Primary psychiatric causes

Most studies of visual hallucinations in primary psychiatric conditions have specifically evaluated patients with schizophrenia and mood disorders with psychotic features.^6,7 In a review of 29 studies (N = 5,873) that specifically examined visual hallucinations in individuals diagnosed with schizophrenia, Waters et al³ found a wide range of reported prevalence (4% to 65%) and a weighted mean prevalence of 27%. In contrast, the prevalence of auditory hallucinations in these participants ranged from 25% to 86%, with a weighted mean of 59%.³

Hallucinations are a known but less common symptom of mood disorders that present with psychotic features.⁸ Waters et al³ also examined the prevalence of visual and auditory hallucinations in mood disorders (including mania, bipolar disorder, and depression) reported in 12 studies (N = 2,892).³ They found the prevalence of visual hallucinations in patients with mood disorders ranged from 6% to 27%, with a weighted mean of 15%, compared to the weighted mean of 28% who experienced auditory hallucinations. Visual hallucinations in primary psychiatric conditions are associated with more severe disease, longer hospitalizations, and poorer prognoses.^9-11

Visual hallucinations of psychosis

In patients with psychotic symptoms, the characteristics of the visually hallucinated entity as well as the cognitive and emotional perception of the hallucinations are notably different than in patients with other, nonpsychiatric causes of visual hallucations.³

Continue to: Content and perceived physical properties

Content and perceived physical properties. Hallucinated entities are most often perceived as solid, 3-dimensional, well-detailed, life-sized people, animals, and objects (often fire) or events existing in the real world.³ The entity is almost always perceived as real, with accurate form and color, fine edges, and shadow; is often out of reach of the perceiver; and can be stationary or moving within the physical properties of the external environment.³

Timing and triggers. The temporal properties vary widely. Hallucinations can last from seconds to minutes and occur at any time of day, though by definition, they must occur while the individual is awake.³ Visual hallucinations in psychosis are more common during times of acute stress, strong emotions, and tiredness.³

Patient reaction and belief. Because of realistic qualities of the visual hallucination and the perception that it is real, patients commonly attempt to participate in some activity in relation to the hallucination, such as moving away from or attempting to interact with it.³ Additionally, patients usually perceive the hallucinated entity as uncontrollable, and are surprised when the entity appears or disappears. Though the content of the hallucination is usually impersonal, the meaning the patient attributes to the presence of the hallucinated entity is usually perceived as very personal and often requiring action. The hallucination may represent a harbinger, sign, or omen, and is often interpreted religiously or spiritually and accompanied by comorbid delusions.³

Visual hallucinations of delirium

Delirium is a syndrome of altered mentation—most notably consciousness, attention, and orientation—that occurs as a result of ≥1 metabolic, infectious, drug-induced, or other medical conditions and often manifests as an acute secondary psychotic illness.¹² Multiple patient and environmental characteristics have been identified as risk factors for developing delirium, including multiple and/or severe medical illnesses, preexisting dementia, depression, advanced age, polypharmacy, having an indwelling urinary catheter, impaired sight or hearing, and low albumin levels.^13-15 The development of delirium is significantly and positively associated with regular alcohol use, benzodiazepine withdrawal, and angiotensin receptor blocker and dopamine receptor agonist usage.¹⁵ Approximately 40% of patients with delirium have symptoms of psychosis, and in contrast to the hallucinations experienced by patients with schizophrenia, visual hallucinations are the most common type of hallucinations seen in delirium (27%).¹³ In a 2021 review that included 602 patients with delirium, Tachibana et al¹⁵ found that approximately 26% experienced hallucinations, 92% of which were visual hallucinations.

Content, perceived physical properties, and reaction. Because of the limited attention and cognitive function of patients with delirium, less is known about the content of their visual hallucinations. However, much like those with primary psychotic symptoms, patients with delirium often report seeing complex, normal-sized, concrete entities, most commonly people. Tachibana et al¹⁵ found that the hallucinated person is more often a stranger than a familiar person, but (rarely) may be an ethereal being such as a devil or ghost. The next most common visually hallucinated entities were creatures, most frequently insects and animals. Other common hallucinations were visions of events or objects, such as fires, falling ceilings, or water. Similar to those with primary psychotic illness such as schizophrenia, patients with delirium often experience emotional distress, anxiety, fear, and confusion in response to the hallucinated person, object, and/or event.¹⁵

Continue to: Primary neurologic causes

 

 

Primary neurologic causes

Visual hallucinations in neurodegenerative diseases

Patients with neurodegenerative diseases such as Parkinson disease (PD), dementia with Lewy bodies (DLB), or Creutzfeldt-Jakob disease (CJD) commonly experience hallucinations as a feature of their condition. However, the true cause of these hallucinations often cannot be directly attributed to any specific pathophysiology because these patients often have multiple coexisting risk factors, such as advanced age, major depressive disorder, use of neuroactive medications, and co-occurring somatic illness. Though the prevalence of visual hallucinations varies widely between studies, with 15% to 40% reported in patients with PD, the prevalence roughly doubles in patients with PD-associated dementia (30% to 60%), and is reported by 60% to 90% of those with DLB.^16-18 Hallucinations are generally thought to be less common in Alzheimer disease; such patients most commonly experience visual hallucinations, although the reported prevalence ranges widely (4% to 59%).^19,20 Notably, similarly to hallucinations experienced in patients with delirium, and in contrast to those with psychosis, visual hallucinations are more common than auditory hallucinations in neurodegenerative diseases.²⁰ Hallucinations are not common in individuals with CJD but are a key defining feature of the Heidenhain variant of CJD, which makes up approximately 5% of cases.²¹

Content, perceived physical properties, and reaction. Similar to the visual hallucinations experienced by patients with psychosis or delirium, those experienced in patients with PD, DLB, or CJD are often complex, most commonly of people, followed by animals and objects. The presence of “passage hallucinations”—in which a person or animal is seen in a patient’s peripheral vision, but passes out of their visual field before the entity can be directly visualized—is common.²⁰ Those with PD also commonly have visual hallucinations in which the form of an object appears distorted (dysmorphopsia) or the color of an object appears distorted (metachromatopsia), though these would better be classified as illusions because a real object is being perceived with distortion.²²

Hallucinations are more common in the evening and at night. “Presence hallucinations” are a common type of hallucination that cannot be directly related to a specific sensory modality such as vision, though they are commonly described by patients with PD as a seen or perceived image (usually a person) that is not directly in the individual’s visual field.¹⁷ These presence hallucinations are often described as being behind the patient or in a visualized scene of what was about to happen. Before developing the dementia and myoclonus also seen in sporadic CJD, patients with the Heidenhain variant of CJD describe illusions such as metachromatopsia, dysmorphia, and micropsia that eventually develop into frank visual hallucinations, which have been poorly reported in medical literature.^22,23 There are no generalizable trends in the temporal nature of visual hallucinations in patients with neuro­degenerative diseases. In most cases of visual hallucinations in patients with PD and dementia, insight relating to the perception varies widely based on the patient’s cognitive status. Subsequently, patients’ reactions to the hallucinations also vary widely.

Visual hallucinations in epileptic seizures

Occipital lobe epilepsies represent 1% to 4.6% of all epilepsies; however, these represent 20% to 30% of benign childhood partial epilepsies.^24,25 These are commonly associated with various types of visual hallucinations depending upon the location of the seizure onset within the occipital lobe. These are referred to as visual auras.²⁶ Visual auras are classified into simple visual hallucinations, complex visual hallucinations, visual illusions, and ictal amaurosis (hemifield blindness or complete blindness).

Content, perceived physical properties, and reaction. Simple visual hallucinations are often described as brief, stereotypical flashing lights of various shapes and colors. These images may flicker, change shape, or take on a geometric or irregular pattern. Appearances can be repetitive and stereotyped, are often reported as moving horizontally from the periphery to the center of the visual field, and can spread to the entire visual field. Most often, these hallucinations occur for 5 to 30 seconds, and have no discernible provoking factors. Complex visual hallucinations consist of formed images of animals, people, or elaborate scenes. These are believed to reflect activation of a larger area of cortex in the temporo-parieto-occipital region, which is the visual association cortex. Very rarely, occipital lobe seizures can manifest with ictal amaurosis.²⁴

Continue to: Simple visual auras...

Simple visual auras have a very high localizing value to the occipital lobe. The primary visual cortex (Brodmann area 17) is situated in the banks of calcarine fissure and activation of this region produces these simple hallucinations. If the hallucinations are consistently lateralized, the seizures are very likely to be coming from the contralateral occipital lobe.

Visual hallucinations in brain tumors

In general, a tumor anywhere along the optic path can produce visual hallucinations; however, the exact causal mechanism of the hallucinations is unknown. Moreover, tumors in different locations—namely the occipital lobes, temporal lobes, and frontal lobes—appear to produce visual hallucinations with substantially different characteristics.^27-29 Further complicating the search for the mechanism of these hallucinations is the fact that tumors are epileptogenic. In addition, 36% to 48% of patients with brain tumors have mood symptoms (depression/mania), and 22% to 24% have psychotic symptoms (delusions/hallucinations); these symptoms are considerably location-dependent.^30-32

Content and associated signs/symptoms. There are some grouped symptoms and/or hallucination characteristics associated with cerebral tumors in different lobes of the brain, though these symptoms are not specific. The visual hallucinations associated with brain tumors are typically confined to the field of vision that corresponds to the location of the tumor. Additionally, many such patients have a baseline visual field defect to some extent due to the tumor location.

In patients with occipital lobe tumors, visual hallucinations closely resemble those experienced in occipital lobe seizures, specifically bright flashes of light in colorful simple and complex shapes. Interestingly, those with occipital lobe tumors report xanthopsia, a form of chromatopsia in which objects in their field of view appear abnormally colored a yellowish shade.^26,27

In patients with temporal lobe tumors, more complex visual hallucinations of people, objects, and events occurring around them are often accompanied by auditory hallucinations, olfactory hallucinations, and/or anosmia.²⁸In those with frontal lobe tumors, similar complex visual hallucinations of people, objects, and events are seen, and olfactory hallucinations and/or anosmia are often experienced. However, these patients often have a lower likelihood of experiencing auditory hallucinations, and a higher likelihood of developing personality changes and depression than other psychotic symptoms. The visual hallucinations experienced in those with frontal lobe tumors are more likely to have violent content.²⁹

Continue to: Visual hallucinations in migraine with aura

Visual hallucinations in migraine with aura

The estimated prevalence of migraine in the general population is 15% to 29%; 31% of those with migraine experience auras.^33-35 Approximately 99% of those with migraine auras experience some type of associated visual phenomena.^33,36 The pathophysiology of migraine is believed to be related to spreading cortical depression, in which a slowly propagating wave of neuroelectric depolarization travels over the cortex, followed by a depression of normal brain activity. Visual aura is thought to occur due to the resulting changes in cortical activity in the visual cortex; however, the exact electro­physiology of visual migraine aura is not entirely known.^37,38 Though most patients with visual migraine aura experience simple visual hallucinations, complex hallucinations have been reported in the (very rare) cases of migraine coma and familial hemiplegic migraine.³⁹

Content and associated signs/symptoms. The most common hallucinated entities reported by patients with migraine with aura are zigzag, flashing/sparkling, black and white curved figure(s) in the center of the visual field, commonly called a scintillating phosphene or scintillating scotoma.³⁶ The perceived entity is often singular and gradually moves from the center to the periphery of the visual field. These visual hallucinations appear in front of all other objects in the visual field and do not interact with the environment or observer, or resemble or morph into any real-world objects, though they may change in contour, size, and color. The scintillating nature of the hallucination often resolves within minutes, usually leaving a scotoma, or area of vision loss, in the area, with resolution back to baseline vision within 1 hour. The straight, zigzag, and usually black-and-white nature of the scintillating phosphenes of migraine are in notable contrast to the colorful, often circular visual hallucinations experienced in patients with occipital lobe seizures.²⁵

Visual hallucinations in peduncular hallucinosis

Peduncular hallucinosis is a syndrome of predominantly dreamlike visual hallucinations that occurs in the setting of lesions in the midbrain and/or thalamus.⁴⁰ A recent review of the lesion etiology found that approximately 63% are caused by focal infarction and approximately 15% are caused by mass lesions; subarachnoid hemorrhage, intracerebral hemorrhage, and demyelination cause approximately 5% of cases each.⁴⁰ Additionally, a review of the affected brainstem anatomy showed almost all lesions were found in the paramedian reticular formations of the midbrain and pons, with the vast majority of lesions affecting or adjacent to the oculomotor and raphe nuclei of the midbrain.³⁹ Due to the commonly involved visual pathway, some researchers have suggested these hallucinations may be the result of a release phenomenon.³⁹

Content and associated signs/symptoms. The visual hallucinations of peduncular hallucinosis usually start 1 to 5 days after the causal lesion forms, last several minutes to hours, and most stop after 1 to 3 weeks; however, cases of hallucinations lasting for years have been reported. These hallucinations have a diurnal pattern of usually appearing while the patient is resting in the evening and/or preparing for sleep. The characteristics of visual hallucinations vary widely from simple distortions in how real objects appear to colorful and vivid hallucinated events and people who can interact with the observer. The content of the visual hallucinations often changes in nature during the hallucination, or from one hallucination to the next. The hallucinated entities can be worldly or extraterrestrial. Once these patients fall asleep, they often have equally vivid and unusual dreams, with content similar to their visual hallucinations. Due to the anatomical involvement of the nigrostriatal pathway and oculomotor nuclei, co-occurring parkinsonism, ataxia, and oculomotor nerve palsy are common and can be a key clinical feature in establishing the diagnosis. Though patients with peduncular hallucinations commonly fear their hallucinations, they often eventually gain insight, which eases their anxiety.³⁹

Other causes

Visual hallucinations in visual impairment

Visual hallucinations are a diagnostic requirement for Charles Bonnet syndrome, in which individuals with vision loss experience visual hallucinations in the corresponding field of vision loss.⁴¹ A lesion at any point in the visual pathway that produces visual loss can lead to Charles Bonnet syndrome; however, age-related macular degeneration is the most common cause.⁴² The hallucinations of Charles Bonnet syndrome are believed to be a release phenomenon, given the defective visual pathway and resultant dysfunction in visual processing. The prevalence of Charles Bonnet syndrome ranges widely by study. Larger studies report a prevalence of 11% to 27% in patients with age-related macular degeneration, depending on the severity of vision loss.^43,44 Because there are many causes of Charles Bonnet syndrome, and because a recent study found that only 15% of patients with this syndrome told their eye care clinician and that 21% had not reported their hallucinatory symptoms to anyone, the true prevalence is unknown.⁴² Though the onset of visual hallucinations correlates with the onset of vision loss, there appears to be no association between the nature or complexity of the hallucinations and the severity or progression of the patient’s vision loss.⁴⁵ Some studies have reported either the onset of or a higher frequency of visual hallucinations at a time of visual recovery (for example, treatment or exudative age-related macular degeneration), which suggests that hallucinations may be triggered by fluctuations in visual acuity.^46,47 Additional risk factors for experiencing visual hallucinations in the setting of visual pathway deficit include a history of stroke, social isolation, poor cognitive function, poor lighting, and age ≥65.

Continue to: Content and associated signs/symptoms

Content and associated signs/symptoms. The visual hallucinations of patients with Charles Bonnet syndrome appear almost exclusively in the defective visual field. Images tend to be complex, colored, with moving parts, and appear in front of the patient. The hallucinations are usually of familiar or normal-appearing people or mundane objects, and as such, the patient often does not realize the hallucinated entity is not real. In patients without comorbid psychiatric disease, visual hallucinations are not accompanied by any other types of hallucinations. The most commonly hallucinated entities are people, followed by simple visual hallucinations of geometric patterns, and then by faces (natural or cartoon-like) and inanimate objects. Hallucinations most commonly occur daily or weekly, and upon waking. These hallucinations most often last several minutes, though they can last just a few seconds or for hours. Hallucinations are usually emotionally neutral, but most patients report feeling confused by their appearance and having a fear of underlying psychiatric disease. They often gain insight to the unreal nature of the hallucinations after counseling.⁴⁸

Visual hallucinations at the sleep/wake interface

Hypnagogic and hypnopompic hallucinations are fleeting perceptual experiences that occur while an individual is falling asleep or waking, respectively.⁴⁹ Because by definition visual hallucinations occur while the individual is fully awake, categorizing hallucination-like experiences such as hypnagogia and hypnopompia is difficult, especially since these are similar to other states in which alterations in perception are expected (namely a dream state). They are commonly associated with sleep disorders such as narcolepsy, cataplexy, and sleep paralysis.^50,51 In a study of 13,057 individuals in the general population, Ohayon et al⁴ found the overall prevalence of hypnagogic or hypnopompic hallucinations was 24.8% (5.3% visual) and 6.6% (1.5% visual), respectively. Approximately one-third of participants reported having experienced ≥1 hallucinatory experience in their lifetime, regardless of being asleep or awake.⁴ There was a higher prevalence of hypnagogic/hypnopompic experiences among those who also reported daytime hallucinations or other psychotic features.

Content and associated signs/symptoms. Unfortunately, because of the frequent co-occurrence of sleep disorders and psychiatric conditions, as well as the general paucity of research, it is difficult to characterize the visual phenomenology of hypnagogic/hypnopompic hallucinations. Some evidence suggests the nature of the perception of the objects hallucinated is substantially impacted by the presence of preexisting psychotic symptoms. Insight into the reality of these hallucinations also depends upon the presence of comorbid psychiatric disease. Hypnagogic/hypnopompic hallucinations are often described as complex, colorful, vivid, and dream-like, as if the patient was in a “half sleep” state.⁵² They are usually described as highly detailed events involving people and/or animals, though they may be grotesque in nature. Perceived entities are often described as undergoing a transformation or being mobile in their environment. Rarely do these perceptions invoke emotion or change the patient’s beliefs. Hypnagogia/hypnopompia also often have an auditory or haptic component to them. Visual phenomena can either appear to take place within an alternative background environment or appear superimposed on the patient’s actual physical environment.

How to determine the cause

In many of the studies cited in this review, the participants had a considerable amount of psychiatric comorbidity, which makes it difficult to discriminate between pure neurologic and pure psychiatric causes of hallucinations. Though the visual content of the hallucinations (people, objects, shapes, lights) can help clinicians broadly differentiate causes, many other characteristics of both the hallucinations and the patient can help determine the cause (Table^{3,4,12-39,41-52}). The most useful characteristics for discerning the etiology of an individual’s visual hallucinations are the patient’s age, the visual field in which the hallucination occurs, and the complexity/simplicity of the hallucination.

Patient age. Hallucinations associated with primary psychosis decrease with age. The average age of onset of migraine with aura is 21. Occipital lobe seizures occur in early childhood to age 40, but most commonly occur in the second decade.^32,36 No trend in age can be reliably determined in individuals who experience hypnagogia/hypnopompia. In contrast, other potential causes of visual hallucinations, such as delirium, neurodegenerative disease, eye disease, and peduncular hallucinosis, are more commonly associated with advanced age.

Continue to: The visual field(s)

The visual field(s) in which the hallucination occurs can help differentiate possible causes in patients with seizure, brain tumor, migraine, or visual impairment. In patients with psychosis, delirium, peduncular hallucinosis, or hypnagogia/hypnopompia, hallucinations can occur in any visual field. Those with neurodegenerative disease, particularly PD, commonly describe seeing so-called passage hallucinations and presence hallucinations, which occur outside of the patient’s direct vision. Visual hallucinations associated with seizure are often unilateral (homonymous left or right hemifield), and contralateral to the affected neurologic structures in the visual neural pathway; they start in the left or right peripheral vision and gradually move to the central visual field. In hallucinations experienced by patients with brain tumors, the hallucinated entities typically appear on the visual field contralateral to the underlying tumor. Visual hallucinations seen in migraine often include a figure that moves from central vision to more lateral in the visual field. The visual hallucinations seen in eye disease (namely Charles Bonnet syndrome) are almost exclusively perceived in the visual fields affected by decreased visual acuity, though non-side-locked visual hallucinations are common in patients with age-related macular degeneration.

Content and complexity. The visual hallucinations perceived in those with psychosis, delirium, neurodegenerative disease, and sleep disorders are generally complex. These hallucinations tend to be of people, animals, scenes, or faces and include color and associated sound, with moving parts and interactivity with either the patient or the environment. These are in contrast to the simple visual hallucinations of visual cortex seizures, brain tumors, and migraine aura, which are often reported as brightly colored or black/white lights, flashes, and shapes, with or without associated auditory, olfactory, or somatic sensation. Furthermore, hallucinations due to seizure and brain tumor (also likely due to seizure) are often of brightly colored shapes and lights with curved edges, while patients with migraine more commonly report singular sparkling black/white objects with straight lines.

Bottom Line

Though there are no features known to be specific to only 1 cause of visual hallucinations, some characteristics of both the patient and the hallucinations can help direct the diagnostic differential. The most useful characteristics are the patient’s age, the visual field in which the hallucination occurs, and the complexity/ simplicity of the hallucination.

Related Resources

• Wang J, Patel D, Francois D. Elaborate hallucinations, but is it a psychotic disorder? Current Psychiatry. 2021;20(2):46-50. doi:10.12788/cp.0091
• O’Brien J, Taylor JP, Ballard C, et al. Visual hallucinations in neurological and ophthalmological disease: pathophysiology and management. J Neurol Neurosurg Psychiatry. 2020; 91(5):512-519. doi:10.1136/jnnp-2019-322702

A visual hallucination is a visual percept experienced when awake that is not elicited by an external stimulus. Historically, hallucinations have been synonymous with psychiatric disease, most notably schizophrenia; however, over recent decades, hallucinations have been categorized based on their underlying etiology as psychodynamic (primary psychiatric), psychophysiologic (primary neurologic/structural), and psychobiochemical (neurotransmitter dysfunction).¹ Presently, visual hallucinations are known to be caused by a wide variety of primary psychiatric, neurologic, ophthalmologic, and chemically-mediated conditions. Despite these causes, clinically differentiating the characteristics and qualities of visual hallucinations is often a lesser-known skillset among clinicians. The utility of this skillset is important for the clinician’s ability to differentiate the expected and unexpected characteristics of visual hallucinations in patients with both known and unknown neuropsychiatric conditions.

Though many primary psychiatric and neurologic conditions have been associated with and/or known to cause visual hallucinations, this review focuses on the following grouped causes:

• Primary psychiatric causes: psychiatric disorders with psychotic features and delirium; and
• Primary neurologic causes: neurodegenerative disease/dementias, seizure disorders, migraine disorders, vision loss, peduncular hallucinosis, and hypnagogic/hypnopompic phenomena.

Because the accepted definition of visual hallucinations excludes visual percepts elicited by external stimuli, drug-induced hallucinations would not qualify for either of these categories. Additionally, most studies reporting on the effects of drug-induced hallucinations did not control for underlying comorbid psychiatric conditions, dementia, or delirium, and thus the results cannot be attributed to the drug alone, nor is it possible to identify reliable trends in the properties of the hallucinations.² The goals of this review are to characterize visual hallucinations experienced as a result of primary psychiatric and primary neurologic conditions and describe key grouping and differentiating features to help guide the diagnosis.

Visual hallucinations in the general population

A review of 6 studies (N = 42,519) reported that the prevalence of visual hallucinations in the general population is 7.3%.³ The prevalence decreases to 6% when visual hallucinations arising from physical illness or drug/chemical consumption are excluded. The prevalence of visual hallucinations in the general population has been associated with comorbid anxiety, stress, bereavement, and psychotic pathology.^4,5 Regarding the age of occurrence of visual hallucinations in the general population, there appears to be a bimodal distribution.³ One peak appears in later adolescence and early adulthood, which corresponds with higher rates of psychosis, and another peak occurs late in life, which corresponds to a higher prevalence of neurodegenerative conditions and visual impairment.

Primary psychiatric causes

Most studies of visual hallucinations in primary psychiatric conditions have specifically evaluated patients with schizophrenia and mood disorders with psychotic features.^6,7 In a review of 29 studies (N = 5,873) that specifically examined visual hallucinations in individuals diagnosed with schizophrenia, Waters et al³ found a wide range of reported prevalence (4% to 65%) and a weighted mean prevalence of 27%. In contrast, the prevalence of auditory hallucinations in these participants ranged from 25% to 86%, with a weighted mean of 59%.³

Hallucinations are a known but less common symptom of mood disorders that present with psychotic features.⁸ Waters et al³ also examined the prevalence of visual and auditory hallucinations in mood disorders (including mania, bipolar disorder, and depression) reported in 12 studies (N = 2,892).³ They found the prevalence of visual hallucinations in patients with mood disorders ranged from 6% to 27%, with a weighted mean of 15%, compared to the weighted mean of 28% who experienced auditory hallucinations. Visual hallucinations in primary psychiatric conditions are associated with more severe disease, longer hospitalizations, and poorer prognoses.^9-11

Visual hallucinations of psychosis

In patients with psychotic symptoms, the characteristics of the visually hallucinated entity as well as the cognitive and emotional perception of the hallucinations are notably different than in patients with other, nonpsychiatric causes of visual hallucations.³

Continue to: Content and perceived physical properties

Content and perceived physical properties. Hallucinated entities are most often perceived as solid, 3-dimensional, well-detailed, life-sized people, animals, and objects (often fire) or events existing in the real world.³ The entity is almost always perceived as real, with accurate form and color, fine edges, and shadow; is often out of reach of the perceiver; and can be stationary or moving within the physical properties of the external environment.³

Timing and triggers. The temporal properties vary widely. Hallucinations can last from seconds to minutes and occur at any time of day, though by definition, they must occur while the individual is awake.³ Visual hallucinations in psychosis are more common during times of acute stress, strong emotions, and tiredness.³

Patient reaction and belief. Because of realistic qualities of the visual hallucination and the perception that it is real, patients commonly attempt to participate in some activity in relation to the hallucination, such as moving away from or attempting to interact with it.³ Additionally, patients usually perceive the hallucinated entity as uncontrollable, and are surprised when the entity appears or disappears. Though the content of the hallucination is usually impersonal, the meaning the patient attributes to the presence of the hallucinated entity is usually perceived as very personal and often requiring action. The hallucination may represent a harbinger, sign, or omen, and is often interpreted religiously or spiritually and accompanied by comorbid delusions.³

Visual hallucinations of delirium

Delirium is a syndrome of altered mentation—most notably consciousness, attention, and orientation—that occurs as a result of ≥1 metabolic, infectious, drug-induced, or other medical conditions and often manifests as an acute secondary psychotic illness.¹² Multiple patient and environmental characteristics have been identified as risk factors for developing delirium, including multiple and/or severe medical illnesses, preexisting dementia, depression, advanced age, polypharmacy, having an indwelling urinary catheter, impaired sight or hearing, and low albumin levels.^13-15 The development of delirium is significantly and positively associated with regular alcohol use, benzodiazepine withdrawal, and angiotensin receptor blocker and dopamine receptor agonist usage.¹⁵ Approximately 40% of patients with delirium have symptoms of psychosis, and in contrast to the hallucinations experienced by patients with schizophrenia, visual hallucinations are the most common type of hallucinations seen in delirium (27%).¹³ In a 2021 review that included 602 patients with delirium, Tachibana et al¹⁵ found that approximately 26% experienced hallucinations, 92% of which were visual hallucinations.

Content, perceived physical properties, and reaction. Because of the limited attention and cognitive function of patients with delirium, less is known about the content of their visual hallucinations. However, much like those with primary psychotic symptoms, patients with delirium often report seeing complex, normal-sized, concrete entities, most commonly people. Tachibana et al¹⁵ found that the hallucinated person is more often a stranger than a familiar person, but (rarely) may be an ethereal being such as a devil or ghost. The next most common visually hallucinated entities were creatures, most frequently insects and animals. Other common hallucinations were visions of events or objects, such as fires, falling ceilings, or water. Similar to those with primary psychotic illness such as schizophrenia, patients with delirium often experience emotional distress, anxiety, fear, and confusion in response to the hallucinated person, object, and/or event.¹⁵

Continue to: Primary neurologic causes

 

 

Primary neurologic causes

Visual hallucinations in neurodegenerative diseases

Patients with neurodegenerative diseases such as Parkinson disease (PD), dementia with Lewy bodies (DLB), or Creutzfeldt-Jakob disease (CJD) commonly experience hallucinations as a feature of their condition. However, the true cause of these hallucinations often cannot be directly attributed to any specific pathophysiology because these patients often have multiple coexisting risk factors, such as advanced age, major depressive disorder, use of neuroactive medications, and co-occurring somatic illness. Though the prevalence of visual hallucinations varies widely between studies, with 15% to 40% reported in patients with PD, the prevalence roughly doubles in patients with PD-associated dementia (30% to 60%), and is reported by 60% to 90% of those with DLB.^16-18 Hallucinations are generally thought to be less common in Alzheimer disease; such patients most commonly experience visual hallucinations, although the reported prevalence ranges widely (4% to 59%).^19,20 Notably, similarly to hallucinations experienced in patients with delirium, and in contrast to those with psychosis, visual hallucinations are more common than auditory hallucinations in neurodegenerative diseases.²⁰ Hallucinations are not common in individuals with CJD but are a key defining feature of the Heidenhain variant of CJD, which makes up approximately 5% of cases.²¹

Content, perceived physical properties, and reaction. Similar to the visual hallucinations experienced by patients with psychosis or delirium, those experienced in patients with PD, DLB, or CJD are often complex, most commonly of people, followed by animals and objects. The presence of “passage hallucinations”—in which a person or animal is seen in a patient’s peripheral vision, but passes out of their visual field before the entity can be directly visualized—is common.²⁰ Those with PD also commonly have visual hallucinations in which the form of an object appears distorted (dysmorphopsia) or the color of an object appears distorted (metachromatopsia), though these would better be classified as illusions because a real object is being perceived with distortion.²²

Hallucinations are more common in the evening and at night. “Presence hallucinations” are a common type of hallucination that cannot be directly related to a specific sensory modality such as vision, though they are commonly described by patients with PD as a seen or perceived image (usually a person) that is not directly in the individual’s visual field.¹⁷ These presence hallucinations are often described as being behind the patient or in a visualized scene of what was about to happen. Before developing the dementia and myoclonus also seen in sporadic CJD, patients with the Heidenhain variant of CJD describe illusions such as metachromatopsia, dysmorphia, and micropsia that eventually develop into frank visual hallucinations, which have been poorly reported in medical literature.^22,23 There are no generalizable trends in the temporal nature of visual hallucinations in patients with neuro­degenerative diseases. In most cases of visual hallucinations in patients with PD and dementia, insight relating to the perception varies widely based on the patient’s cognitive status. Subsequently, patients’ reactions to the hallucinations also vary widely.

Visual hallucinations in epileptic seizures

Occipital lobe epilepsies represent 1% to 4.6% of all epilepsies; however, these represent 20% to 30% of benign childhood partial epilepsies.^24,25 These are commonly associated with various types of visual hallucinations depending upon the location of the seizure onset within the occipital lobe. These are referred to as visual auras.²⁶ Visual auras are classified into simple visual hallucinations, complex visual hallucinations, visual illusions, and ictal amaurosis (hemifield blindness or complete blindness).

Content, perceived physical properties, and reaction. Simple visual hallucinations are often described as brief, stereotypical flashing lights of various shapes and colors. These images may flicker, change shape, or take on a geometric or irregular pattern. Appearances can be repetitive and stereotyped, are often reported as moving horizontally from the periphery to the center of the visual field, and can spread to the entire visual field. Most often, these hallucinations occur for 5 to 30 seconds, and have no discernible provoking factors. Complex visual hallucinations consist of formed images of animals, people, or elaborate scenes. These are believed to reflect activation of a larger area of cortex in the temporo-parieto-occipital region, which is the visual association cortex. Very rarely, occipital lobe seizures can manifest with ictal amaurosis.²⁴

Continue to: Simple visual auras...

Simple visual auras have a very high localizing value to the occipital lobe. The primary visual cortex (Brodmann area 17) is situated in the banks of calcarine fissure and activation of this region produces these simple hallucinations. If the hallucinations are consistently lateralized, the seizures are very likely to be coming from the contralateral occipital lobe.

Visual hallucinations in brain tumors

In general, a tumor anywhere along the optic path can produce visual hallucinations; however, the exact causal mechanism of the hallucinations is unknown. Moreover, tumors in different locations—namely the occipital lobes, temporal lobes, and frontal lobes—appear to produce visual hallucinations with substantially different characteristics.^27-29 Further complicating the search for the mechanism of these hallucinations is the fact that tumors are epileptogenic. In addition, 36% to 48% of patients with brain tumors have mood symptoms (depression/mania), and 22% to 24% have psychotic symptoms (delusions/hallucinations); these symptoms are considerably location-dependent.^30-32

Content and associated signs/symptoms. There are some grouped symptoms and/or hallucination characteristics associated with cerebral tumors in different lobes of the brain, though these symptoms are not specific. The visual hallucinations associated with brain tumors are typically confined to the field of vision that corresponds to the location of the tumor. Additionally, many such patients have a baseline visual field defect to some extent due to the tumor location.

In patients with occipital lobe tumors, visual hallucinations closely resemble those experienced in occipital lobe seizures, specifically bright flashes of light in colorful simple and complex shapes. Interestingly, those with occipital lobe tumors report xanthopsia, a form of chromatopsia in which objects in their field of view appear abnormally colored a yellowish shade.^26,27

In patients with temporal lobe tumors, more complex visual hallucinations of people, objects, and events occurring around them are often accompanied by auditory hallucinations, olfactory hallucinations, and/or anosmia.²⁸In those with frontal lobe tumors, similar complex visual hallucinations of people, objects, and events are seen, and olfactory hallucinations and/or anosmia are often experienced. However, these patients often have a lower likelihood of experiencing auditory hallucinations, and a higher likelihood of developing personality changes and depression than other psychotic symptoms. The visual hallucinations experienced in those with frontal lobe tumors are more likely to have violent content.²⁹

Continue to: Visual hallucinations in migraine with aura

Visual hallucinations in migraine with aura

The estimated prevalence of migraine in the general population is 15% to 29%; 31% of those with migraine experience auras.^33-35 Approximately 99% of those with migraine auras experience some type of associated visual phenomena.^33,36 The pathophysiology of migraine is believed to be related to spreading cortical depression, in which a slowly propagating wave of neuroelectric depolarization travels over the cortex, followed by a depression of normal brain activity. Visual aura is thought to occur due to the resulting changes in cortical activity in the visual cortex; however, the exact electro­physiology of visual migraine aura is not entirely known.^37,38 Though most patients with visual migraine aura experience simple visual hallucinations, complex hallucinations have been reported in the (very rare) cases of migraine coma and familial hemiplegic migraine.³⁹

Content and associated signs/symptoms. The most common hallucinated entities reported by patients with migraine with aura are zigzag, flashing/sparkling, black and white curved figure(s) in the center of the visual field, commonly called a scintillating phosphene or scintillating scotoma.³⁶ The perceived entity is often singular and gradually moves from the center to the periphery of the visual field. These visual hallucinations appear in front of all other objects in the visual field and do not interact with the environment or observer, or resemble or morph into any real-world objects, though they may change in contour, size, and color. The scintillating nature of the hallucination often resolves within minutes, usually leaving a scotoma, or area of vision loss, in the area, with resolution back to baseline vision within 1 hour. The straight, zigzag, and usually black-and-white nature of the scintillating phosphenes of migraine are in notable contrast to the colorful, often circular visual hallucinations experienced in patients with occipital lobe seizures.²⁵

Visual hallucinations in peduncular hallucinosis

Peduncular hallucinosis is a syndrome of predominantly dreamlike visual hallucinations that occurs in the setting of lesions in the midbrain and/or thalamus.⁴⁰ A recent review of the lesion etiology found that approximately 63% are caused by focal infarction and approximately 15% are caused by mass lesions; subarachnoid hemorrhage, intracerebral hemorrhage, and demyelination cause approximately 5% of cases each.⁴⁰ Additionally, a review of the affected brainstem anatomy showed almost all lesions were found in the paramedian reticular formations of the midbrain and pons, with the vast majority of lesions affecting or adjacent to the oculomotor and raphe nuclei of the midbrain.³⁹ Due to the commonly involved visual pathway, some researchers have suggested these hallucinations may be the result of a release phenomenon.³⁹

Content and associated signs/symptoms. The visual hallucinations of peduncular hallucinosis usually start 1 to 5 days after the causal lesion forms, last several minutes to hours, and most stop after 1 to 3 weeks; however, cases of hallucinations lasting for years have been reported. These hallucinations have a diurnal pattern of usually appearing while the patient is resting in the evening and/or preparing for sleep. The characteristics of visual hallucinations vary widely from simple distortions in how real objects appear to colorful and vivid hallucinated events and people who can interact with the observer. The content of the visual hallucinations often changes in nature during the hallucination, or from one hallucination to the next. The hallucinated entities can be worldly or extraterrestrial. Once these patients fall asleep, they often have equally vivid and unusual dreams, with content similar to their visual hallucinations. Due to the anatomical involvement of the nigrostriatal pathway and oculomotor nuclei, co-occurring parkinsonism, ataxia, and oculomotor nerve palsy are common and can be a key clinical feature in establishing the diagnosis. Though patients with peduncular hallucinations commonly fear their hallucinations, they often eventually gain insight, which eases their anxiety.³⁹

Other causes

Visual hallucinations in visual impairment

Visual hallucinations are a diagnostic requirement for Charles Bonnet syndrome, in which individuals with vision loss experience visual hallucinations in the corresponding field of vision loss.⁴¹ A lesion at any point in the visual pathway that produces visual loss can lead to Charles Bonnet syndrome; however, age-related macular degeneration is the most common cause.⁴² The hallucinations of Charles Bonnet syndrome are believed to be a release phenomenon, given the defective visual pathway and resultant dysfunction in visual processing. The prevalence of Charles Bonnet syndrome ranges widely by study. Larger studies report a prevalence of 11% to 27% in patients with age-related macular degeneration, depending on the severity of vision loss.^43,44 Because there are many causes of Charles Bonnet syndrome, and because a recent study found that only 15% of patients with this syndrome told their eye care clinician and that 21% had not reported their hallucinatory symptoms to anyone, the true prevalence is unknown.⁴² Though the onset of visual hallucinations correlates with the onset of vision loss, there appears to be no association between the nature or complexity of the hallucinations and the severity or progression of the patient’s vision loss.⁴⁵ Some studies have reported either the onset of or a higher frequency of visual hallucinations at a time of visual recovery (for example, treatment or exudative age-related macular degeneration), which suggests that hallucinations may be triggered by fluctuations in visual acuity.^46,47 Additional risk factors for experiencing visual hallucinations in the setting of visual pathway deficit include a history of stroke, social isolation, poor cognitive function, poor lighting, and age ≥65.

Continue to: Content and associated signs/symptoms

Content and associated signs/symptoms. The visual hallucinations of patients with Charles Bonnet syndrome appear almost exclusively in the defective visual field. Images tend to be complex, colored, with moving parts, and appear in front of the patient. The hallucinations are usually of familiar or normal-appearing people or mundane objects, and as such, the patient often does not realize the hallucinated entity is not real. In patients without comorbid psychiatric disease, visual hallucinations are not accompanied by any other types of hallucinations. The most commonly hallucinated entities are people, followed by simple visual hallucinations of geometric patterns, and then by faces (natural or cartoon-like) and inanimate objects. Hallucinations most commonly occur daily or weekly, and upon waking. These hallucinations most often last several minutes, though they can last just a few seconds or for hours. Hallucinations are usually emotionally neutral, but most patients report feeling confused by their appearance and having a fear of underlying psychiatric disease. They often gain insight to the unreal nature of the hallucinations after counseling.⁴⁸

Visual hallucinations at the sleep/wake interface

Hypnagogic and hypnopompic hallucinations are fleeting perceptual experiences that occur while an individual is falling asleep or waking, respectively.⁴⁹ Because by definition visual hallucinations occur while the individual is fully awake, categorizing hallucination-like experiences such as hypnagogia and hypnopompia is difficult, especially since these are similar to other states in which alterations in perception are expected (namely a dream state). They are commonly associated with sleep disorders such as narcolepsy, cataplexy, and sleep paralysis.^50,51 In a study of 13,057 individuals in the general population, Ohayon et al⁴ found the overall prevalence of hypnagogic or hypnopompic hallucinations was 24.8% (5.3% visual) and 6.6% (1.5% visual), respectively. Approximately one-third of participants reported having experienced ≥1 hallucinatory experience in their lifetime, regardless of being asleep or awake.⁴ There was a higher prevalence of hypnagogic/hypnopompic experiences among those who also reported daytime hallucinations or other psychotic features.

Content and associated signs/symptoms. Unfortunately, because of the frequent co-occurrence of sleep disorders and psychiatric conditions, as well as the general paucity of research, it is difficult to characterize the visual phenomenology of hypnagogic/hypnopompic hallucinations. Some evidence suggests the nature of the perception of the objects hallucinated is substantially impacted by the presence of preexisting psychotic symptoms. Insight into the reality of these hallucinations also depends upon the presence of comorbid psychiatric disease. Hypnagogic/hypnopompic hallucinations are often described as complex, colorful, vivid, and dream-like, as if the patient was in a “half sleep” state.⁵² They are usually described as highly detailed events involving people and/or animals, though they may be grotesque in nature. Perceived entities are often described as undergoing a transformation or being mobile in their environment. Rarely do these perceptions invoke emotion or change the patient’s beliefs. Hypnagogia/hypnopompia also often have an auditory or haptic component to them. Visual phenomena can either appear to take place within an alternative background environment or appear superimposed on the patient’s actual physical environment.

How to determine the cause

In many of the studies cited in this review, the participants had a considerable amount of psychiatric comorbidity, which makes it difficult to discriminate between pure neurologic and pure psychiatric causes of hallucinations. Though the visual content of the hallucinations (people, objects, shapes, lights) can help clinicians broadly differentiate causes, many other characteristics of both the hallucinations and the patient can help determine the cause (Table^{3,4,12-39,41-52}). The most useful characteristics for discerning the etiology of an individual’s visual hallucinations are the patient’s age, the visual field in which the hallucination occurs, and the complexity/simplicity of the hallucination.

Patient age. Hallucinations associated with primary psychosis decrease with age. The average age of onset of migraine with aura is 21. Occipital lobe seizures occur in early childhood to age 40, but most commonly occur in the second decade.^32,36 No trend in age can be reliably determined in individuals who experience hypnagogia/hypnopompia. In contrast, other potential causes of visual hallucinations, such as delirium, neurodegenerative disease, eye disease, and peduncular hallucinosis, are more commonly associated with advanced age.

Continue to: The visual field(s)

The visual field(s) in which the hallucination occurs can help differentiate possible causes in patients with seizure, brain tumor, migraine, or visual impairment. In patients with psychosis, delirium, peduncular hallucinosis, or hypnagogia/hypnopompia, hallucinations can occur in any visual field. Those with neurodegenerative disease, particularly PD, commonly describe seeing so-called passage hallucinations and presence hallucinations, which occur outside of the patient’s direct vision. Visual hallucinations associated with seizure are often unilateral (homonymous left or right hemifield), and contralateral to the affected neurologic structures in the visual neural pathway; they start in the left or right peripheral vision and gradually move to the central visual field. In hallucinations experienced by patients with brain tumors, the hallucinated entities typically appear on the visual field contralateral to the underlying tumor. Visual hallucinations seen in migraine often include a figure that moves from central vision to more lateral in the visual field. The visual hallucinations seen in eye disease (namely Charles Bonnet syndrome) are almost exclusively perceived in the visual fields affected by decreased visual acuity, though non-side-locked visual hallucinations are common in patients with age-related macular degeneration.

Content and complexity. The visual hallucinations perceived in those with psychosis, delirium, neurodegenerative disease, and sleep disorders are generally complex. These hallucinations tend to be of people, animals, scenes, or faces and include color and associated sound, with moving parts and interactivity with either the patient or the environment. These are in contrast to the simple visual hallucinations of visual cortex seizures, brain tumors, and migraine aura, which are often reported as brightly colored or black/white lights, flashes, and shapes, with or without associated auditory, olfactory, or somatic sensation. Furthermore, hallucinations due to seizure and brain tumor (also likely due to seizure) are often of brightly colored shapes and lights with curved edges, while patients with migraine more commonly report singular sparkling black/white objects with straight lines.

Bottom Line

Though there are no features known to be specific to only 1 cause of visual hallucinations, some characteristics of both the patient and the hallucinations can help direct the diagnostic differential. The most useful characteristics are the patient’s age, the visual field in which the hallucination occurs, and the complexity/ simplicity of the hallucination.

Related Resources

• Wang J, Patel D, Francois D. Elaborate hallucinations, but is it a psychotic disorder? Current Psychiatry. 2021;20(2):46-50. doi:10.12788/cp.0091
• O’Brien J, Taylor JP, Ballard C, et al. Visual hallucinations in neurological and ophthalmological disease: pathophysiology and management. J Neurol Neurosurg Psychiatry. 2020; 91(5):512-519. doi:10.1136/jnnp-2019-322702

A visual hallucination is a visual percept experienced when awake that is not elicited by an external stimulus. Historically, hallucinations have been synonymous with psychiatric disease, most notably schizophrenia; however, over recent decades, hallucinations have been categorized based on their underlying etiology as psychodynamic (primary psychiatric), psychophysiologic (primary neurologic/structural), and psychobiochemical (neurotransmitter dysfunction).¹ Presently, visual hallucinations are known to be caused by a wide variety of primary psychiatric, neurologic, ophthalmologic, and chemically-mediated conditions. Despite these causes, clinically differentiating the characteristics and qualities of visual hallucinations is often a lesser-known skillset among clinicians. The utility of this skillset is important for the clinician’s ability to differentiate the expected and unexpected characteristics of visual hallucinations in patients with both known and unknown neuropsychiatric conditions.

Though many primary psychiatric and neurologic conditions have been associated with and/or known to cause visual hallucinations, this review focuses on the following grouped causes:

• Primary psychiatric causes: psychiatric disorders with psychotic features and delirium; and
• Primary neurologic causes: neurodegenerative disease/dementias, seizure disorders, migraine disorders, vision loss, peduncular hallucinosis, and hypnagogic/hypnopompic phenomena.

Because the accepted definition of visual hallucinations excludes visual percepts elicited by external stimuli, drug-induced hallucinations would not qualify for either of these categories. Additionally, most studies reporting on the effects of drug-induced hallucinations did not control for underlying comorbid psychiatric conditions, dementia, or delirium, and thus the results cannot be attributed to the drug alone, nor is it possible to identify reliable trends in the properties of the hallucinations.² The goals of this review are to characterize visual hallucinations experienced as a result of primary psychiatric and primary neurologic conditions and describe key grouping and differentiating features to help guide the diagnosis.

Visual hallucinations in the general population

A review of 6 studies (N = 42,519) reported that the prevalence of visual hallucinations in the general population is 7.3%.³ The prevalence decreases to 6% when visual hallucinations arising from physical illness or drug/chemical consumption are excluded. The prevalence of visual hallucinations in the general population has been associated with comorbid anxiety, stress, bereavement, and psychotic pathology.^4,5 Regarding the age of occurrence of visual hallucinations in the general population, there appears to be a bimodal distribution.³ One peak appears in later adolescence and early adulthood, which corresponds with higher rates of psychosis, and another peak occurs late in life, which corresponds to a higher prevalence of neurodegenerative conditions and visual impairment.

Primary psychiatric causes

Most studies of visual hallucinations in primary psychiatric conditions have specifically evaluated patients with schizophrenia and mood disorders with psychotic features.^6,7 In a review of 29 studies (N = 5,873) that specifically examined visual hallucinations in individuals diagnosed with schizophrenia, Waters et al³ found a wide range of reported prevalence (4% to 65%) and a weighted mean prevalence of 27%. In contrast, the prevalence of auditory hallucinations in these participants ranged from 25% to 86%, with a weighted mean of 59%.³

Hallucinations are a known but less common symptom of mood disorders that present with psychotic features.⁸ Waters et al³ also examined the prevalence of visual and auditory hallucinations in mood disorders (including mania, bipolar disorder, and depression) reported in 12 studies (N = 2,892).³ They found the prevalence of visual hallucinations in patients with mood disorders ranged from 6% to 27%, with a weighted mean of 15%, compared to the weighted mean of 28% who experienced auditory hallucinations. Visual hallucinations in primary psychiatric conditions are associated with more severe disease, longer hospitalizations, and poorer prognoses.^9-11

Visual hallucinations of psychosis

In patients with psychotic symptoms, the characteristics of the visually hallucinated entity as well as the cognitive and emotional perception of the hallucinations are notably different than in patients with other, nonpsychiatric causes of visual hallucations.³

Continue to: Content and perceived physical properties

Content and perceived physical properties. Hallucinated entities are most often perceived as solid, 3-dimensional, well-detailed, life-sized people, animals, and objects (often fire) or events existing in the real world.³ The entity is almost always perceived as real, with accurate form and color, fine edges, and shadow; is often out of reach of the perceiver; and can be stationary or moving within the physical properties of the external environment.³

Timing and triggers. The temporal properties vary widely. Hallucinations can last from seconds to minutes and occur at any time of day, though by definition, they must occur while the individual is awake.³ Visual hallucinations in psychosis are more common during times of acute stress, strong emotions, and tiredness.³

Patient reaction and belief. Because of realistic qualities of the visual hallucination and the perception that it is real, patients commonly attempt to participate in some activity in relation to the hallucination, such as moving away from or attempting to interact with it.³ Additionally, patients usually perceive the hallucinated entity as uncontrollable, and are surprised when the entity appears or disappears. Though the content of the hallucination is usually impersonal, the meaning the patient attributes to the presence of the hallucinated entity is usually perceived as very personal and often requiring action. The hallucination may represent a harbinger, sign, or omen, and is often interpreted religiously or spiritually and accompanied by comorbid delusions.³

Visual hallucinations of delirium

Delirium is a syndrome of altered mentation—most notably consciousness, attention, and orientation—that occurs as a result of ≥1 metabolic, infectious, drug-induced, or other medical conditions and often manifests as an acute secondary psychotic illness.¹² Multiple patient and environmental characteristics have been identified as risk factors for developing delirium, including multiple and/or severe medical illnesses, preexisting dementia, depression, advanced age, polypharmacy, having an indwelling urinary catheter, impaired sight or hearing, and low albumin levels.^13-15 The development of delirium is significantly and positively associated with regular alcohol use, benzodiazepine withdrawal, and angiotensin receptor blocker and dopamine receptor agonist usage.¹⁵ Approximately 40% of patients with delirium have symptoms of psychosis, and in contrast to the hallucinations experienced by patients with schizophrenia, visual hallucinations are the most common type of hallucinations seen in delirium (27%).¹³ In a 2021 review that included 602 patients with delirium, Tachibana et al¹⁵ found that approximately 26% experienced hallucinations, 92% of which were visual hallucinations.

Content, perceived physical properties, and reaction. Because of the limited attention and cognitive function of patients with delirium, less is known about the content of their visual hallucinations. However, much like those with primary psychotic symptoms, patients with delirium often report seeing complex, normal-sized, concrete entities, most commonly people. Tachibana et al¹⁵ found that the hallucinated person is more often a stranger than a familiar person, but (rarely) may be an ethereal being such as a devil or ghost. The next most common visually hallucinated entities were creatures, most frequently insects and animals. Other common hallucinations were visions of events or objects, such as fires, falling ceilings, or water. Similar to those with primary psychotic illness such as schizophrenia, patients with delirium often experience emotional distress, anxiety, fear, and confusion in response to the hallucinated person, object, and/or event.¹⁵

Continue to: Primary neurologic causes

 

 

Primary neurologic causes

Visual hallucinations in neurodegenerative diseases

Patients with neurodegenerative diseases such as Parkinson disease (PD), dementia with Lewy bodies (DLB), or Creutzfeldt-Jakob disease (CJD) commonly experience hallucinations as a feature of their condition. However, the true cause of these hallucinations often cannot be directly attributed to any specific pathophysiology because these patients often have multiple coexisting risk factors, such as advanced age, major depressive disorder, use of neuroactive medications, and co-occurring somatic illness. Though the prevalence of visual hallucinations varies widely between studies, with 15% to 40% reported in patients with PD, the prevalence roughly doubles in patients with PD-associated dementia (30% to 60%), and is reported by 60% to 90% of those with DLB.^16-18 Hallucinations are generally thought to be less common in Alzheimer disease; such patients most commonly experience visual hallucinations, although the reported prevalence ranges widely (4% to 59%).^19,20 Notably, similarly to hallucinations experienced in patients with delirium, and in contrast to those with psychosis, visual hallucinations are more common than auditory hallucinations in neurodegenerative diseases.²⁰ Hallucinations are not common in individuals with CJD but are a key defining feature of the Heidenhain variant of CJD, which makes up approximately 5% of cases.²¹

Content, perceived physical properties, and reaction. Similar to the visual hallucinations experienced by patients with psychosis or delirium, those experienced in patients with PD, DLB, or CJD are often complex, most commonly of people, followed by animals and objects. The presence of “passage hallucinations”—in which a person or animal is seen in a patient’s peripheral vision, but passes out of their visual field before the entity can be directly visualized—is common.²⁰ Those with PD also commonly have visual hallucinations in which the form of an object appears distorted (dysmorphopsia) or the color of an object appears distorted (metachromatopsia), though these would better be classified as illusions because a real object is being perceived with distortion.²²

Hallucinations are more common in the evening and at night. “Presence hallucinations” are a common type of hallucination that cannot be directly related to a specific sensory modality such as vision, though they are commonly described by patients with PD as a seen or perceived image (usually a person) that is not directly in the individual’s visual field.¹⁷ These presence hallucinations are often described as being behind the patient or in a visualized scene of what was about to happen. Before developing the dementia and myoclonus also seen in sporadic CJD, patients with the Heidenhain variant of CJD describe illusions such as metachromatopsia, dysmorphia, and micropsia that eventually develop into frank visual hallucinations, which have been poorly reported in medical literature.^22,23 There are no generalizable trends in the temporal nature of visual hallucinations in patients with neuro­degenerative diseases. In most cases of visual hallucinations in patients with PD and dementia, insight relating to the perception varies widely based on the patient’s cognitive status. Subsequently, patients’ reactions to the hallucinations also vary widely.

Visual hallucinations in epileptic seizures

Occipital lobe epilepsies represent 1% to 4.6% of all epilepsies; however, these represent 20% to 30% of benign childhood partial epilepsies.^24,25 These are commonly associated with various types of visual hallucinations depending upon the location of the seizure onset within the occipital lobe. These are referred to as visual auras.²⁶ Visual auras are classified into simple visual hallucinations, complex visual hallucinations, visual illusions, and ictal amaurosis (hemifield blindness or complete blindness).

Content, perceived physical properties, and reaction. Simple visual hallucinations are often described as brief, stereotypical flashing lights of various shapes and colors. These images may flicker, change shape, or take on a geometric or irregular pattern. Appearances can be repetitive and stereotyped, are often reported as moving horizontally from the periphery to the center of the visual field, and can spread to the entire visual field. Most often, these hallucinations occur for 5 to 30 seconds, and have no discernible provoking factors. Complex visual hallucinations consist of formed images of animals, people, or elaborate scenes. These are believed to reflect activation of a larger area of cortex in the temporo-parieto-occipital region, which is the visual association cortex. Very rarely, occipital lobe seizures can manifest with ictal amaurosis.²⁴

Continue to: Simple visual auras...

Simple visual auras have a very high localizing value to the occipital lobe. The primary visual cortex (Brodmann area 17) is situated in the banks of calcarine fissure and activation of this region produces these simple hallucinations. If the hallucinations are consistently lateralized, the seizures are very likely to be coming from the contralateral occipital lobe.

Visual hallucinations in brain tumors

In general, a tumor anywhere along the optic path can produce visual hallucinations; however, the exact causal mechanism of the hallucinations is unknown. Moreover, tumors in different locations—namely the occipital lobes, temporal lobes, and frontal lobes—appear to produce visual hallucinations with substantially different characteristics.^27-29 Further complicating the search for the mechanism of these hallucinations is the fact that tumors are epileptogenic. In addition, 36% to 48% of patients with brain tumors have mood symptoms (depression/mania), and 22% to 24% have psychotic symptoms (delusions/hallucinations); these symptoms are considerably location-dependent.^30-32

Content and associated signs/symptoms. There are some grouped symptoms and/or hallucination characteristics associated with cerebral tumors in different lobes of the brain, though these symptoms are not specific. The visual hallucinations associated with brain tumors are typically confined to the field of vision that corresponds to the location of the tumor. Additionally, many such patients have a baseline visual field defect to some extent due to the tumor location.

In patients with occipital lobe tumors, visual hallucinations closely resemble those experienced in occipital lobe seizures, specifically bright flashes of light in colorful simple and complex shapes. Interestingly, those with occipital lobe tumors report xanthopsia, a form of chromatopsia in which objects in their field of view appear abnormally colored a yellowish shade.^26,27

In patients with temporal lobe tumors, more complex visual hallucinations of people, objects, and events occurring around them are often accompanied by auditory hallucinations, olfactory hallucinations, and/or anosmia.²⁸In those with frontal lobe tumors, similar complex visual hallucinations of people, objects, and events are seen, and olfactory hallucinations and/or anosmia are often experienced. However, these patients often have a lower likelihood of experiencing auditory hallucinations, and a higher likelihood of developing personality changes and depression than other psychotic symptoms. The visual hallucinations experienced in those with frontal lobe tumors are more likely to have violent content.²⁹

Continue to: Visual hallucinations in migraine with aura

Visual hallucinations in migraine with aura

The estimated prevalence of migraine in the general population is 15% to 29%; 31% of those with migraine experience auras.^33-35 Approximately 99% of those with migraine auras experience some type of associated visual phenomena.^33,36 The pathophysiology of migraine is believed to be related to spreading cortical depression, in which a slowly propagating wave of neuroelectric depolarization travels over the cortex, followed by a depression of normal brain activity. Visual aura is thought to occur due to the resulting changes in cortical activity in the visual cortex; however, the exact electro­physiology of visual migraine aura is not entirely known.^37,38 Though most patients with visual migraine aura experience simple visual hallucinations, complex hallucinations have been reported in the (very rare) cases of migraine coma and familial hemiplegic migraine.³⁹

Content and associated signs/symptoms. The most common hallucinated entities reported by patients with migraine with aura are zigzag, flashing/sparkling, black and white curved figure(s) in the center of the visual field, commonly called a scintillating phosphene or scintillating scotoma.³⁶ The perceived entity is often singular and gradually moves from the center to the periphery of the visual field. These visual hallucinations appear in front of all other objects in the visual field and do not interact with the environment or observer, or resemble or morph into any real-world objects, though they may change in contour, size, and color. The scintillating nature of the hallucination often resolves within minutes, usually leaving a scotoma, or area of vision loss, in the area, with resolution back to baseline vision within 1 hour. The straight, zigzag, and usually black-and-white nature of the scintillating phosphenes of migraine are in notable contrast to the colorful, often circular visual hallucinations experienced in patients with occipital lobe seizures.²⁵

Visual hallucinations in peduncular hallucinosis

Peduncular hallucinosis is a syndrome of predominantly dreamlike visual hallucinations that occurs in the setting of lesions in the midbrain and/or thalamus.⁴⁰ A recent review of the lesion etiology found that approximately 63% are caused by focal infarction and approximately 15% are caused by mass lesions; subarachnoid hemorrhage, intracerebral hemorrhage, and demyelination cause approximately 5% of cases each.⁴⁰ Additionally, a review of the affected brainstem anatomy showed almost all lesions were found in the paramedian reticular formations of the midbrain and pons, with the vast majority of lesions affecting or adjacent to the oculomotor and raphe nuclei of the midbrain.³⁹ Due to the commonly involved visual pathway, some researchers have suggested these hallucinations may be the result of a release phenomenon.³⁹

Content and associated signs/symptoms. The visual hallucinations of peduncular hallucinosis usually start 1 to 5 days after the causal lesion forms, last several minutes to hours, and most stop after 1 to 3 weeks; however, cases of hallucinations lasting for years have been reported. These hallucinations have a diurnal pattern of usually appearing while the patient is resting in the evening and/or preparing for sleep. The characteristics of visual hallucinations vary widely from simple distortions in how real objects appear to colorful and vivid hallucinated events and people who can interact with the observer. The content of the visual hallucinations often changes in nature during the hallucination, or from one hallucination to the next. The hallucinated entities can be worldly or extraterrestrial. Once these patients fall asleep, they often have equally vivid and unusual dreams, with content similar to their visual hallucinations. Due to the anatomical involvement of the nigrostriatal pathway and oculomotor nuclei, co-occurring parkinsonism, ataxia, and oculomotor nerve palsy are common and can be a key clinical feature in establishing the diagnosis. Though patients with peduncular hallucinations commonly fear their hallucinations, they often eventually gain insight, which eases their anxiety.³⁹

Other causes

Visual hallucinations in visual impairment

Visual hallucinations are a diagnostic requirement for Charles Bonnet syndrome, in which individuals with vision loss experience visual hallucinations in the corresponding field of vision loss.⁴¹ A lesion at any point in the visual pathway that produces visual loss can lead to Charles Bonnet syndrome; however, age-related macular degeneration is the most common cause.⁴² The hallucinations of Charles Bonnet syndrome are believed to be a release phenomenon, given the defective visual pathway and resultant dysfunction in visual processing. The prevalence of Charles Bonnet syndrome ranges widely by study. Larger studies report a prevalence of 11% to 27% in patients with age-related macular degeneration, depending on the severity of vision loss.^43,44 Because there are many causes of Charles Bonnet syndrome, and because a recent study found that only 15% of patients with this syndrome told their eye care clinician and that 21% had not reported their hallucinatory symptoms to anyone, the true prevalence is unknown.⁴² Though the onset of visual hallucinations correlates with the onset of vision loss, there appears to be no association between the nature or complexity of the hallucinations and the severity or progression of the patient’s vision loss.⁴⁵ Some studies have reported either the onset of or a higher frequency of visual hallucinations at a time of visual recovery (for example, treatment or exudative age-related macular degeneration), which suggests that hallucinations may be triggered by fluctuations in visual acuity.^46,47 Additional risk factors for experiencing visual hallucinations in the setting of visual pathway deficit include a history of stroke, social isolation, poor cognitive function, poor lighting, and age ≥65.

Continue to: Content and associated signs/symptoms

Content and associated signs/symptoms. The visual hallucinations of patients with Charles Bonnet syndrome appear almost exclusively in the defective visual field. Images tend to be complex, colored, with moving parts, and appear in front of the patient. The hallucinations are usually of familiar or normal-appearing people or mundane objects, and as such, the patient often does not realize the hallucinated entity is not real. In patients without comorbid psychiatric disease, visual hallucinations are not accompanied by any other types of hallucinations. The most commonly hallucinated entities are people, followed by simple visual hallucinations of geometric patterns, and then by faces (natural or cartoon-like) and inanimate objects. Hallucinations most commonly occur daily or weekly, and upon waking. These hallucinations most often last several minutes, though they can last just a few seconds or for hours. Hallucinations are usually emotionally neutral, but most patients report feeling confused by their appearance and having a fear of underlying psychiatric disease. They often gain insight to the unreal nature of the hallucinations after counseling.⁴⁸

Visual hallucinations at the sleep/wake interface

Hypnagogic and hypnopompic hallucinations are fleeting perceptual experiences that occur while an individual is falling asleep or waking, respectively.⁴⁹ Because by definition visual hallucinations occur while the individual is fully awake, categorizing hallucination-like experiences such as hypnagogia and hypnopompia is difficult, especially since these are similar to other states in which alterations in perception are expected (namely a dream state). They are commonly associated with sleep disorders such as narcolepsy, cataplexy, and sleep paralysis.^50,51 In a study of 13,057 individuals in the general population, Ohayon et al⁴ found the overall prevalence of hypnagogic or hypnopompic hallucinations was 24.8% (5.3% visual) and 6.6% (1.5% visual), respectively. Approximately one-third of participants reported having experienced ≥1 hallucinatory experience in their lifetime, regardless of being asleep or awake.⁴ There was a higher prevalence of hypnagogic/hypnopompic experiences among those who also reported daytime hallucinations or other psychotic features.

Content and associated signs/symptoms. Unfortunately, because of the frequent co-occurrence of sleep disorders and psychiatric conditions, as well as the general paucity of research, it is difficult to characterize the visual phenomenology of hypnagogic/hypnopompic hallucinations. Some evidence suggests the nature of the perception of the objects hallucinated is substantially impacted by the presence of preexisting psychotic symptoms. Insight into the reality of these hallucinations also depends upon the presence of comorbid psychiatric disease. Hypnagogic/hypnopompic hallucinations are often described as complex, colorful, vivid, and dream-like, as if the patient was in a “half sleep” state.⁵² They are usually described as highly detailed events involving people and/or animals, though they may be grotesque in nature. Perceived entities are often described as undergoing a transformation or being mobile in their environment. Rarely do these perceptions invoke emotion or change the patient’s beliefs. Hypnagogia/hypnopompia also often have an auditory or haptic component to them. Visual phenomena can either appear to take place within an alternative background environment or appear superimposed on the patient’s actual physical environment.

How to determine the cause

In many of the studies cited in this review, the participants had a considerable amount of psychiatric comorbidity, which makes it difficult to discriminate between pure neurologic and pure psychiatric causes of hallucinations. Though the visual content of the hallucinations (people, objects, shapes, lights) can help clinicians broadly differentiate causes, many other characteristics of both the hallucinations and the patient can help determine the cause (Table^{3,4,12-39,41-52}). The most useful characteristics for discerning the etiology of an individual’s visual hallucinations are the patient’s age, the visual field in which the hallucination occurs, and the complexity/simplicity of the hallucination.

Patient age. Hallucinations associated with primary psychosis decrease with age. The average age of onset of migraine with aura is 21. Occipital lobe seizures occur in early childhood to age 40, but most commonly occur in the second decade.^32,36 No trend in age can be reliably determined in individuals who experience hypnagogia/hypnopompia. In contrast, other potential causes of visual hallucinations, such as delirium, neurodegenerative disease, eye disease, and peduncular hallucinosis, are more commonly associated with advanced age.

Continue to: The visual field(s)

The visual field(s) in which the hallucination occurs can help differentiate possible causes in patients with seizure, brain tumor, migraine, or visual impairment. In patients with psychosis, delirium, peduncular hallucinosis, or hypnagogia/hypnopompia, hallucinations can occur in any visual field. Those with neurodegenerative disease, particularly PD, commonly describe seeing so-called passage hallucinations and presence hallucinations, which occur outside of the patient’s direct vision. Visual hallucinations associated with seizure are often unilateral (homonymous left or right hemifield), and contralateral to the affected neurologic structures in the visual neural pathway; they start in the left or right peripheral vision and gradually move to the central visual field. In hallucinations experienced by patients with brain tumors, the hallucinated entities typically appear on the visual field contralateral to the underlying tumor. Visual hallucinations seen in migraine often include a figure that moves from central vision to more lateral in the visual field. The visual hallucinations seen in eye disease (namely Charles Bonnet syndrome) are almost exclusively perceived in the visual fields affected by decreased visual acuity, though non-side-locked visual hallucinations are common in patients with age-related macular degeneration.

Content and complexity. The visual hallucinations perceived in those with psychosis, delirium, neurodegenerative disease, and sleep disorders are generally complex. These hallucinations tend to be of people, animals, scenes, or faces and include color and associated sound, with moving parts and interactivity with either the patient or the environment. These are in contrast to the simple visual hallucinations of visual cortex seizures, brain tumors, and migraine aura, which are often reported as brightly colored or black/white lights, flashes, and shapes, with or without associated auditory, olfactory, or somatic sensation. Furthermore, hallucinations due to seizure and brain tumor (also likely due to seizure) are often of brightly colored shapes and lights with curved edges, while patients with migraine more commonly report singular sparkling black/white objects with straight lines.

Bottom Line

Though there are no features known to be specific to only 1 cause of visual hallucinations, some characteristics of both the patient and the hallucinations can help direct the diagnostic differential. The most useful characteristics are the patient’s age, the visual field in which the hallucination occurs, and the complexity/ simplicity of the hallucination.

Related Resources

• Wang J, Patel D, Francois D. Elaborate hallucinations, but is it a psychotic disorder? Current Psychiatry. 2021;20(2):46-50. doi:10.12788/cp.0091
• O’Brien J, Taylor JP, Ballard C, et al. Visual hallucinations in neurological and ophthalmological disease: pathophysiology and management. J Neurol Neurosurg Psychiatry. 2020; 91(5):512-519. doi:10.1136/jnnp-2019-322702

Psychogenic nonepileptic seizures (PNES) are a physical manifestation of a psychological disturbance. They are characterized by episodes of altered subjective experience and movements that can resemble epilepsy, syncope, or other paroxysmal disorders, but are not caused by neuronal hypersynchronization or other epileptic semiology.¹ Asynchronous movements, closed eyes, crying, stuttering, side-to-side head movement, and pelvic thrusting may be observed, all of which are atypical of epileptic seizures.¹ PNES, a syndrome of “pseudo-seizures,” is recognized in 11% of convulsive seizure cases presenting to the emergency department (ED).² PNES can co-occur with epilepsy; in 2 population-based studies, the pooled rate of EEG-confirmed comorbid epilepsy in PNES was 14%.³

Patients with PNES may present to multiple clinicians and hospitals for assessment. Access to outside hospital records can be limited, which can lead to redundant testing and increased health care costs and burden. Additionally, repeat presentations can increase stigmatization of the patient and delay or prevent appropriate therapeutic management, which might exacerbate a patient’s underlying psychiatric condition and could be dangerous in a patient with a co-occurring true seizure disorder. Though obtaining and reviewing external medical records can be cumbersome, doing so may prevent unnecessary testing, guide medical treatment, and strengthen the patient-doctor therapeutic alliance.

In this article, I discuss our treatment team’s management of a patient with PNES who, based on our careful review of records from previous hospitalizations, may have had a co-occurring true seizure disorder.

Case report

Ms. M, age 31, has a medical history of anxiety, depression, first-degree atrioventricular block, type 2 diabetes, and PNES. She presented to the ED with witnessed seizure activity at home.

According to collateral information, earlier that day Ms. M said she felt like she was seizing and began mumbling, but returned to baseline within a few minutes. Later, she demonstrated intermittent upper and lower extremity shaking for more than 1 hour. At one point, Ms. M appeared to be not breathing. However, upon initiation of chest compressions, she began gasping for air and immediately returned to baseline.

In the ED, Ms. M demonstrated multiple seizure-like episodes every 5 minutes, each lasting 5 to 10 seconds. These episodes were described as thrashing of the bilateral limbs and head crossing midline with eyes closed. No urinary incontinence or tongue biting was observed. Following each episode, Ms. M was unresponsive to verbal or tactile stimuli but intermittently opened her eyes. Laboratory test results were notable for an elevated serum lactate and positive for cannabinoids on urine drug screen.

Ms. M expressed frustration when told that her seizures were psychogenic. She was adamant that she had a true seizure disorder, demanded testing, and threatened to leave against medical advice without it. She said her brother had epilepsy, and thus she knew how seizures present. The interview was complicated by Ms. M’s mistrust and Cluster B personality disorder traits, such as splitting staff into “good and bad.” Ultimately, she was able to be reassured and did not leave the hospital.

Continue to: The treatment team...

The treatment team reviewed external records from 2 hospitals, Hospital A and Hospital B. These records showed well-documented inpatient and outpatient Psychiatry and Neurology diagnoses of PNES and other conversion disorders. Her medications included 2 anticonvulsants—topiramate 200 mg every 12 hours and oxcarbazepine 300 mg every 12 hours—as well as clonazepam 0.5 mg as needed for seizures and anxiety.

Ms. M’s first lifetime documented seizure occurred in May 2020, when she woke up with tongue biting, extremity shaking (laterality was unclear), and urinary incontinence followed by fatigue. She did not go to the hospital after this first episode. In June 2020, she presented and was admitted to Hospital A after similar seizure-like activity. While admitted and monitored on continuous EEG (cEEG), she had numerous events consistent with a nonepileptic etiology without a postictal state. A brain MRI was unremarkable, and Ms. M was diagnosed with PNES.

She presented to Hospital B in October 2020 reporting seizure-like activity. Hospital B reviewed Hospital A’s brain MRI and found right temporal lobe cortical dysplasia that was not noted in Hospital A’s MRI read. Ms. M again underwent cEEG while at Hospital B and had 2 recorded nonepileptic events. Interestingly, the cEEG demonstrated right temporal spikes that were consistent with the dysplasia location on the MRI. Ms. M was discharged and instructed to keep a seizure journal until outpatient follow-up.

Ms. M documented 3 seizure-like events between October and December 2020. She documented activity with and without full-body convulsions, some with laterality, some with loss of consciousness, and some preceded by an aura of impending doom. Ms. M was referred to psychotherapy and instructed to continue topiramate 100 mg every 12 hours for seizure prophylaxis.

Ms. M presented to Hospital B again in March 2022 reporting seizure-like activity. A brain MRI found cortical dysplasia in the right temporal lobe, consistent with the MRI at Hospital A in June 2020. cEEG was also repeated at Hospital B and was unremarkable. Oxcarbazepine 300 mg every 12 hours was added to Ms. M’s medications.

Ultimately, based on an external record review, our team (at Hospital C) concluded Ms. M had a possible true seizure co-occurrence with PNES. To avoid redundant testing, we did not repeat imaging or cEEG. Instead, we increased the patient’s oxcarbazepine to 450 mg every 12 hours, for both its effectiveness in temporal seizures and its mood-stabilizing properties. Moreover, in collecting our own data to draw a conclusion by a thorough record review, we gained Ms. M’s trust and strengthened the therapeutic alliance. She was agreeable to forgo more testing and continue outpatient follow-up with our hospital’s Neurology team.

Take-home points

Although PNES and true seizure disorder may not frequently co-occur, this case highlights the importance of clinician due diligence when evaluating a potential psychogenic illness, both for patient safety and clinician liability. By trusting our patients and drawing our own data-based conclusions, we can cultivate a safer and more satisfactory patient-clinician experience in the context of psychosomatic disorders.

Psychogenic nonepileptic seizures (PNES) are a physical manifestation of a psychological disturbance. They are characterized by episodes of altered subjective experience and movements that can resemble epilepsy, syncope, or other paroxysmal disorders, but are not caused by neuronal hypersynchronization or other epileptic semiology.¹ Asynchronous movements, closed eyes, crying, stuttering, side-to-side head movement, and pelvic thrusting may be observed, all of which are atypical of epileptic seizures.¹ PNES, a syndrome of “pseudo-seizures,” is recognized in 11% of convulsive seizure cases presenting to the emergency department (ED).² PNES can co-occur with epilepsy; in 2 population-based studies, the pooled rate of EEG-confirmed comorbid epilepsy in PNES was 14%.³

Patients with PNES may present to multiple clinicians and hospitals for assessment. Access to outside hospital records can be limited, which can lead to redundant testing and increased health care costs and burden. Additionally, repeat presentations can increase stigmatization of the patient and delay or prevent appropriate therapeutic management, which might exacerbate a patient’s underlying psychiatric condition and could be dangerous in a patient with a co-occurring true seizure disorder. Though obtaining and reviewing external medical records can be cumbersome, doing so may prevent unnecessary testing, guide medical treatment, and strengthen the patient-doctor therapeutic alliance.

In this article, I discuss our treatment team’s management of a patient with PNES who, based on our careful review of records from previous hospitalizations, may have had a co-occurring true seizure disorder.

Case report

Ms. M, age 31, has a medical history of anxiety, depression, first-degree atrioventricular block, type 2 diabetes, and PNES. She presented to the ED with witnessed seizure activity at home.

According to collateral information, earlier that day Ms. M said she felt like she was seizing and began mumbling, but returned to baseline within a few minutes. Later, she demonstrated intermittent upper and lower extremity shaking for more than 1 hour. At one point, Ms. M appeared to be not breathing. However, upon initiation of chest compressions, she began gasping for air and immediately returned to baseline.

In the ED, Ms. M demonstrated multiple seizure-like episodes every 5 minutes, each lasting 5 to 10 seconds. These episodes were described as thrashing of the bilateral limbs and head crossing midline with eyes closed. No urinary incontinence or tongue biting was observed. Following each episode, Ms. M was unresponsive to verbal or tactile stimuli but intermittently opened her eyes. Laboratory test results were notable for an elevated serum lactate and positive for cannabinoids on urine drug screen.

Ms. M expressed frustration when told that her seizures were psychogenic. She was adamant that she had a true seizure disorder, demanded testing, and threatened to leave against medical advice without it. She said her brother had epilepsy, and thus she knew how seizures present. The interview was complicated by Ms. M’s mistrust and Cluster B personality disorder traits, such as splitting staff into “good and bad.” Ultimately, she was able to be reassured and did not leave the hospital.

Continue to: The treatment team...

The treatment team reviewed external records from 2 hospitals, Hospital A and Hospital B. These records showed well-documented inpatient and outpatient Psychiatry and Neurology diagnoses of PNES and other conversion disorders. Her medications included 2 anticonvulsants—topiramate 200 mg every 12 hours and oxcarbazepine 300 mg every 12 hours—as well as clonazepam 0.5 mg as needed for seizures and anxiety.

Ms. M’s first lifetime documented seizure occurred in May 2020, when she woke up with tongue biting, extremity shaking (laterality was unclear), and urinary incontinence followed by fatigue. She did not go to the hospital after this first episode. In June 2020, she presented and was admitted to Hospital A after similar seizure-like activity. While admitted and monitored on continuous EEG (cEEG), she had numerous events consistent with a nonepileptic etiology without a postictal state. A brain MRI was unremarkable, and Ms. M was diagnosed with PNES.

She presented to Hospital B in October 2020 reporting seizure-like activity. Hospital B reviewed Hospital A’s brain MRI and found right temporal lobe cortical dysplasia that was not noted in Hospital A’s MRI read. Ms. M again underwent cEEG while at Hospital B and had 2 recorded nonepileptic events. Interestingly, the cEEG demonstrated right temporal spikes that were consistent with the dysplasia location on the MRI. Ms. M was discharged and instructed to keep a seizure journal until outpatient follow-up.

Ms. M documented 3 seizure-like events between October and December 2020. She documented activity with and without full-body convulsions, some with laterality, some with loss of consciousness, and some preceded by an aura of impending doom. Ms. M was referred to psychotherapy and instructed to continue topiramate 100 mg every 12 hours for seizure prophylaxis.

Ms. M presented to Hospital B again in March 2022 reporting seizure-like activity. A brain MRI found cortical dysplasia in the right temporal lobe, consistent with the MRI at Hospital A in June 2020. cEEG was also repeated at Hospital B and was unremarkable. Oxcarbazepine 300 mg every 12 hours was added to Ms. M’s medications.

Ultimately, based on an external record review, our team (at Hospital C) concluded Ms. M had a possible true seizure co-occurrence with PNES. To avoid redundant testing, we did not repeat imaging or cEEG. Instead, we increased the patient’s oxcarbazepine to 450 mg every 12 hours, for both its effectiveness in temporal seizures and its mood-stabilizing properties. Moreover, in collecting our own data to draw a conclusion by a thorough record review, we gained Ms. M’s trust and strengthened the therapeutic alliance. She was agreeable to forgo more testing and continue outpatient follow-up with our hospital’s Neurology team.

Take-home points

Although PNES and true seizure disorder may not frequently co-occur, this case highlights the importance of clinician due diligence when evaluating a potential psychogenic illness, both for patient safety and clinician liability. By trusting our patients and drawing our own data-based conclusions, we can cultivate a safer and more satisfactory patient-clinician experience in the context of psychosomatic disorders.

Psychogenic nonepileptic seizures (PNES) are a physical manifestation of a psychological disturbance. They are characterized by episodes of altered subjective experience and movements that can resemble epilepsy, syncope, or other paroxysmal disorders, but are not caused by neuronal hypersynchronization or other epileptic semiology.¹ Asynchronous movements, closed eyes, crying, stuttering, side-to-side head movement, and pelvic thrusting may be observed, all of which are atypical of epileptic seizures.¹ PNES, a syndrome of “pseudo-seizures,” is recognized in 11% of convulsive seizure cases presenting to the emergency department (ED).² PNES can co-occur with epilepsy; in 2 population-based studies, the pooled rate of EEG-confirmed comorbid epilepsy in PNES was 14%.³

Patients with PNES may present to multiple clinicians and hospitals for assessment. Access to outside hospital records can be limited, which can lead to redundant testing and increased health care costs and burden. Additionally, repeat presentations can increase stigmatization of the patient and delay or prevent appropriate therapeutic management, which might exacerbate a patient’s underlying psychiatric condition and could be dangerous in a patient with a co-occurring true seizure disorder. Though obtaining and reviewing external medical records can be cumbersome, doing so may prevent unnecessary testing, guide medical treatment, and strengthen the patient-doctor therapeutic alliance.

In this article, I discuss our treatment team’s management of a patient with PNES who, based on our careful review of records from previous hospitalizations, may have had a co-occurring true seizure disorder.

Case report

Ms. M, age 31, has a medical history of anxiety, depression, first-degree atrioventricular block, type 2 diabetes, and PNES. She presented to the ED with witnessed seizure activity at home.

According to collateral information, earlier that day Ms. M said she felt like she was seizing and began mumbling, but returned to baseline within a few minutes. Later, she demonstrated intermittent upper and lower extremity shaking for more than 1 hour. At one point, Ms. M appeared to be not breathing. However, upon initiation of chest compressions, she began gasping for air and immediately returned to baseline.

In the ED, Ms. M demonstrated multiple seizure-like episodes every 5 minutes, each lasting 5 to 10 seconds. These episodes were described as thrashing of the bilateral limbs and head crossing midline with eyes closed. No urinary incontinence or tongue biting was observed. Following each episode, Ms. M was unresponsive to verbal or tactile stimuli but intermittently opened her eyes. Laboratory test results were notable for an elevated serum lactate and positive for cannabinoids on urine drug screen.

Ms. M expressed frustration when told that her seizures were psychogenic. She was adamant that she had a true seizure disorder, demanded testing, and threatened to leave against medical advice without it. She said her brother had epilepsy, and thus she knew how seizures present. The interview was complicated by Ms. M’s mistrust and Cluster B personality disorder traits, such as splitting staff into “good and bad.” Ultimately, she was able to be reassured and did not leave the hospital.

Continue to: The treatment team...

The treatment team reviewed external records from 2 hospitals, Hospital A and Hospital B. These records showed well-documented inpatient and outpatient Psychiatry and Neurology diagnoses of PNES and other conversion disorders. Her medications included 2 anticonvulsants—topiramate 200 mg every 12 hours and oxcarbazepine 300 mg every 12 hours—as well as clonazepam 0.5 mg as needed for seizures and anxiety.

Ms. M’s first lifetime documented seizure occurred in May 2020, when she woke up with tongue biting, extremity shaking (laterality was unclear), and urinary incontinence followed by fatigue. She did not go to the hospital after this first episode. In June 2020, she presented and was admitted to Hospital A after similar seizure-like activity. While admitted and monitored on continuous EEG (cEEG), she had numerous events consistent with a nonepileptic etiology without a postictal state. A brain MRI was unremarkable, and Ms. M was diagnosed with PNES.

She presented to Hospital B in October 2020 reporting seizure-like activity. Hospital B reviewed Hospital A’s brain MRI and found right temporal lobe cortical dysplasia that was not noted in Hospital A’s MRI read. Ms. M again underwent cEEG while at Hospital B and had 2 recorded nonepileptic events. Interestingly, the cEEG demonstrated right temporal spikes that were consistent with the dysplasia location on the MRI. Ms. M was discharged and instructed to keep a seizure journal until outpatient follow-up.

Ms. M documented 3 seizure-like events between October and December 2020. She documented activity with and without full-body convulsions, some with laterality, some with loss of consciousness, and some preceded by an aura of impending doom. Ms. M was referred to psychotherapy and instructed to continue topiramate 100 mg every 12 hours for seizure prophylaxis.

Ms. M presented to Hospital B again in March 2022 reporting seizure-like activity. A brain MRI found cortical dysplasia in the right temporal lobe, consistent with the MRI at Hospital A in June 2020. cEEG was also repeated at Hospital B and was unremarkable. Oxcarbazepine 300 mg every 12 hours was added to Ms. M’s medications.

Ultimately, based on an external record review, our team (at Hospital C) concluded Ms. M had a possible true seizure co-occurrence with PNES. To avoid redundant testing, we did not repeat imaging or cEEG. Instead, we increased the patient’s oxcarbazepine to 450 mg every 12 hours, for both its effectiveness in temporal seizures and its mood-stabilizing properties. Moreover, in collecting our own data to draw a conclusion by a thorough record review, we gained Ms. M’s trust and strengthened the therapeutic alliance. She was agreeable to forgo more testing and continue outpatient follow-up with our hospital’s Neurology team.

Take-home points

Although PNES and true seizure disorder may not frequently co-occur, this case highlights the importance of clinician due diligence when evaluating a potential psychogenic illness, both for patient safety and clinician liability. By trusting our patients and drawing our own data-based conclusions, we can cultivate a safer and more satisfactory patient-clinician experience in the context of psychosomatic disorders.

A multipart study reports that erythritol – a sugar alcohol (polyol) increasingly used as an artificial sweetener that is also made in the body – is associated with risk of major adverse cardiovascular events (MACE) and promotes clotting (thrombosis).

Erythritol is one of the most widely used artificial sweeteners with rapidly increasing prevalence in processed and “keto-related” foods. Artificial sweeteners are “generally recognized as safe” (GRAS) by the U.S. Food and Drug Administration, so there is no requirement for long-term safety studies, and little is known about the long-term health effects.

The current research, published online in Nature Medicine by Marco Witkowski, MD, of the Lerner Research Institute at Cleveland Clinic and colleagues, had multiple parts.

First, in a group of patients undergoing cardiac risk assessment, the researchers found that high levels of polyols, especially erythritol, were associated with increased 3-year risk of MACE, defined as cardiovascular death or nonfatal myocardial infarction or stroke. 

Next, the association of erythritol with this outcome was reproduced in two large U.S. and European groups of stable patients undergoing elective cardiac evaluation.

Next, adding erythritol to whole blood or platelets led to clot activation. And lastly, in eight healthy volunteers, ingesting 30 g of an erythritol-sweetened drink – comparable to a single can of commercially available beverage or a pint of keto ice cream – induced marked and sustained (> 2 day) increases in levels of plasma erythritol.

“Our study shows that when participants consumed an artificially sweetened beverage with an amount of erythritol found in many processed foods, markedly elevated levels in the blood are observed for days – levels well above those observed to enhance clotting risks,” said senior author Stanley L. Hazen, MD, PhD.  

“It is important that further safety studies are conducted to examine the long-term effects of artificial sweeteners in general, and erythritol specifically, on risks for heart attack and stroke, particularly in people at higher risk for cardiovascular disease,” Dr. Hazen, co–section head of preventive cardiology at Cleveland Clinic, said in a press release from his institution.

“Sweeteners like erythritol have rapidly increased in popularity in recent years, but there needs to be more in-depth research into their long-term effects. Cardiovascular disease builds over time, and heart disease is the leading cause of death globally. We need to make sure the foods we eat aren’t hidden contributors,” Dr. Hazen urged.

The topic remains controversial.

Duane Mellor, PhD, a registered dietitian and senior teaching fellow at Aston University, Birmingham, England, told the U.K. Science Media Centre: “This paper effectively shows multiple pieces of a jigsaw exploring the effects of erythritol – although it claims to show an associated risk with the use of erythritol as an artificial sweetener and cardiovascular disease, I believe it fails to do so, as ultimately, erythritol can be made inside our bodies and the intake in most people’s diet is much lower than the amount given in this study.” 

Dr. Hazen countered that data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) in the United States show that, in some individuals, daily intake of erythritol is estimated to reach 30 g/day. 

“Many try and reduce sugar intake by taking many teaspoons of erythritol in their tea, coffee, etc., instead of sugar,” Dr. Hazen added. “Or they eat keto processed foods that have significant quantities of erythritol within it.”

“These studies are a warning for how our processed food (keto and zero sugar, especially) may inadvertently be causing risk/harm. … in the very subset of subjects who are most vulnerable,” according to Dr. Hazen.
 

Erythritol marketed as ‘zero calorie’, ‘non-nutritive’, or ‘natural’

Patients with type 2 diabetes and obesity are often advised to replace sugar with artificial sweeteners for better glucose control and weight loss, but growing epidemiologic evidence links artificial sweetener consumption with weight gain, insulin resistance, type 2 diabetes, and cardiovascular disease, the researchers write.

Erythritol is naturally present in low amounts in fruits and vegetables; the artificial sweetener erythritol that is produced from corn is only 70% as sweet as sugar.

Upon ingestion it is poorly metabolized, and most is excreted in the urine, so it is characterized as a “zero-calorie,” “non-nutritive,” or “natural sweetener.” It is predicted to double in marketshare in the sweetener sector in the next 5 years.
 

Multipart study

In the first part of their study, in a discovery cohort in 1,157 patients undergoing cardiovascular assessment with 3-year outcomes, the researchers identified polyols that were associated with MACE, and erythritol was among the top MACE-associated molecules.

Next, in a U.S. validation cohort of 2,149 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 1.8-fold higher risk of MACE than patients in the lowest quartile (P = .007), after adjusting for cardiovascular risk factors.

In a European validation cohort of 833 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 2.21-fold higher risk of MACE than patients in the lowest quartile (P = .010, after adjustment).

At physiologic levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo.

Finally, in a prospective pilot intervention study, erythritol ingestion in healthy volunteers induced marked and sustained increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies.
 

Others weigh in

“While I think the finding certainly warrants further investigation, don’t throw out your sweeteners just yet,” commented Oliver Jones, PhD, professor of chemistry at the Royal Melbourne Institute of Technology.

“This study only looks at erythritol, and artificial sweeteners are generally considered safe. Any possible (and, as yet unproven) risks of excess erythritol would also need to be balanced against the very real health risks of excess glucose consumption,” he said.

Dr. Hazen responded: “True enough. Erythritol is but one of many artificial sweeteners. That is why it is important to read labels. This study can make patients be informed about how to potentially avoid something that might cause them inadvertent harm.”

“The key findings of this study are that high blood levels of erythritol are strongly associated with cardiovascular outcomes in high-risk patients, which has been replicated in separate validation studies,” said Tom Sanders, DSc, PhD, professor emeritus of nutrition and dietetics, King’s College London.

“Diabetes UK currently advises diabetes patients not to use polyols,” he added.

Dr. Hazen noted that “About three-quarters of the participants had coronary disease, high blood pressure, and about a fifth had diabetes.”

The researchers acknowledge, however, that the observational studies cannot show cause and effect.

The study was supported by the Office of Dietary Supplements at the National Institutes of Health, the Leducq Foundation, and the German Research Foundation (Deutsche Forschungsgemeinschaft). Dr. Mellor, Dr. Jones, and Dr. Sanders have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A multipart study reports that erythritol – a sugar alcohol (polyol) increasingly used as an artificial sweetener that is also made in the body – is associated with risk of major adverse cardiovascular events (MACE) and promotes clotting (thrombosis).

Erythritol is one of the most widely used artificial sweeteners with rapidly increasing prevalence in processed and “keto-related” foods. Artificial sweeteners are “generally recognized as safe” (GRAS) by the U.S. Food and Drug Administration, so there is no requirement for long-term safety studies, and little is known about the long-term health effects.

The current research, published online in Nature Medicine by Marco Witkowski, MD, of the Lerner Research Institute at Cleveland Clinic and colleagues, had multiple parts.

First, in a group of patients undergoing cardiac risk assessment, the researchers found that high levels of polyols, especially erythritol, were associated with increased 3-year risk of MACE, defined as cardiovascular death or nonfatal myocardial infarction or stroke. 

Next, the association of erythritol with this outcome was reproduced in two large U.S. and European groups of stable patients undergoing elective cardiac evaluation.

Next, adding erythritol to whole blood or platelets led to clot activation. And lastly, in eight healthy volunteers, ingesting 30 g of an erythritol-sweetened drink – comparable to a single can of commercially available beverage or a pint of keto ice cream – induced marked and sustained (> 2 day) increases in levels of plasma erythritol.

“Our study shows that when participants consumed an artificially sweetened beverage with an amount of erythritol found in many processed foods, markedly elevated levels in the blood are observed for days – levels well above those observed to enhance clotting risks,” said senior author Stanley L. Hazen, MD, PhD.  

“It is important that further safety studies are conducted to examine the long-term effects of artificial sweeteners in general, and erythritol specifically, on risks for heart attack and stroke, particularly in people at higher risk for cardiovascular disease,” Dr. Hazen, co–section head of preventive cardiology at Cleveland Clinic, said in a press release from his institution.

“Sweeteners like erythritol have rapidly increased in popularity in recent years, but there needs to be more in-depth research into their long-term effects. Cardiovascular disease builds over time, and heart disease is the leading cause of death globally. We need to make sure the foods we eat aren’t hidden contributors,” Dr. Hazen urged.

The topic remains controversial.

Duane Mellor, PhD, a registered dietitian and senior teaching fellow at Aston University, Birmingham, England, told the U.K. Science Media Centre: “This paper effectively shows multiple pieces of a jigsaw exploring the effects of erythritol – although it claims to show an associated risk with the use of erythritol as an artificial sweetener and cardiovascular disease, I believe it fails to do so, as ultimately, erythritol can be made inside our bodies and the intake in most people’s diet is much lower than the amount given in this study.” 

Dr. Hazen countered that data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) in the United States show that, in some individuals, daily intake of erythritol is estimated to reach 30 g/day. 

“Many try and reduce sugar intake by taking many teaspoons of erythritol in their tea, coffee, etc., instead of sugar,” Dr. Hazen added. “Or they eat keto processed foods that have significant quantities of erythritol within it.”

“These studies are a warning for how our processed food (keto and zero sugar, especially) may inadvertently be causing risk/harm. … in the very subset of subjects who are most vulnerable,” according to Dr. Hazen.
 

Erythritol marketed as ‘zero calorie’, ‘non-nutritive’, or ‘natural’

Patients with type 2 diabetes and obesity are often advised to replace sugar with artificial sweeteners for better glucose control and weight loss, but growing epidemiologic evidence links artificial sweetener consumption with weight gain, insulin resistance, type 2 diabetes, and cardiovascular disease, the researchers write.

Erythritol is naturally present in low amounts in fruits and vegetables; the artificial sweetener erythritol that is produced from corn is only 70% as sweet as sugar.

Upon ingestion it is poorly metabolized, and most is excreted in the urine, so it is characterized as a “zero-calorie,” “non-nutritive,” or “natural sweetener.” It is predicted to double in marketshare in the sweetener sector in the next 5 years.
 

Multipart study

In the first part of their study, in a discovery cohort in 1,157 patients undergoing cardiovascular assessment with 3-year outcomes, the researchers identified polyols that were associated with MACE, and erythritol was among the top MACE-associated molecules.

Next, in a U.S. validation cohort of 2,149 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 1.8-fold higher risk of MACE than patients in the lowest quartile (P = .007), after adjusting for cardiovascular risk factors.

In a European validation cohort of 833 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 2.21-fold higher risk of MACE than patients in the lowest quartile (P = .010, after adjustment).

At physiologic levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo.

Finally, in a prospective pilot intervention study, erythritol ingestion in healthy volunteers induced marked and sustained increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies.
 

Others weigh in

“While I think the finding certainly warrants further investigation, don’t throw out your sweeteners just yet,” commented Oliver Jones, PhD, professor of chemistry at the Royal Melbourne Institute of Technology.

“This study only looks at erythritol, and artificial sweeteners are generally considered safe. Any possible (and, as yet unproven) risks of excess erythritol would also need to be balanced against the very real health risks of excess glucose consumption,” he said.

Dr. Hazen responded: “True enough. Erythritol is but one of many artificial sweeteners. That is why it is important to read labels. This study can make patients be informed about how to potentially avoid something that might cause them inadvertent harm.”

“The key findings of this study are that high blood levels of erythritol are strongly associated with cardiovascular outcomes in high-risk patients, which has been replicated in separate validation studies,” said Tom Sanders, DSc, PhD, professor emeritus of nutrition and dietetics, King’s College London.

“Diabetes UK currently advises diabetes patients not to use polyols,” he added.

Dr. Hazen noted that “About three-quarters of the participants had coronary disease, high blood pressure, and about a fifth had diabetes.”

The researchers acknowledge, however, that the observational studies cannot show cause and effect.

The study was supported by the Office of Dietary Supplements at the National Institutes of Health, the Leducq Foundation, and the German Research Foundation (Deutsche Forschungsgemeinschaft). Dr. Mellor, Dr. Jones, and Dr. Sanders have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A multipart study reports that erythritol – a sugar alcohol (polyol) increasingly used as an artificial sweetener that is also made in the body – is associated with risk of major adverse cardiovascular events (MACE) and promotes clotting (thrombosis).

Erythritol is one of the most widely used artificial sweeteners with rapidly increasing prevalence in processed and “keto-related” foods. Artificial sweeteners are “generally recognized as safe” (GRAS) by the U.S. Food and Drug Administration, so there is no requirement for long-term safety studies, and little is known about the long-term health effects.

The current research, published online in Nature Medicine by Marco Witkowski, MD, of the Lerner Research Institute at Cleveland Clinic and colleagues, had multiple parts.

First, in a group of patients undergoing cardiac risk assessment, the researchers found that high levels of polyols, especially erythritol, were associated with increased 3-year risk of MACE, defined as cardiovascular death or nonfatal myocardial infarction or stroke. 

Next, the association of erythritol with this outcome was reproduced in two large U.S. and European groups of stable patients undergoing elective cardiac evaluation.

Next, adding erythritol to whole blood or platelets led to clot activation. And lastly, in eight healthy volunteers, ingesting 30 g of an erythritol-sweetened drink – comparable to a single can of commercially available beverage or a pint of keto ice cream – induced marked and sustained (> 2 day) increases in levels of plasma erythritol.

“Our study shows that when participants consumed an artificially sweetened beverage with an amount of erythritol found in many processed foods, markedly elevated levels in the blood are observed for days – levels well above those observed to enhance clotting risks,” said senior author Stanley L. Hazen, MD, PhD.  

“It is important that further safety studies are conducted to examine the long-term effects of artificial sweeteners in general, and erythritol specifically, on risks for heart attack and stroke, particularly in people at higher risk for cardiovascular disease,” Dr. Hazen, co–section head of preventive cardiology at Cleveland Clinic, said in a press release from his institution.

“Sweeteners like erythritol have rapidly increased in popularity in recent years, but there needs to be more in-depth research into their long-term effects. Cardiovascular disease builds over time, and heart disease is the leading cause of death globally. We need to make sure the foods we eat aren’t hidden contributors,” Dr. Hazen urged.

The topic remains controversial.

Duane Mellor, PhD, a registered dietitian and senior teaching fellow at Aston University, Birmingham, England, told the U.K. Science Media Centre: “This paper effectively shows multiple pieces of a jigsaw exploring the effects of erythritol – although it claims to show an associated risk with the use of erythritol as an artificial sweetener and cardiovascular disease, I believe it fails to do so, as ultimately, erythritol can be made inside our bodies and the intake in most people’s diet is much lower than the amount given in this study.” 

Dr. Hazen countered that data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) in the United States show that, in some individuals, daily intake of erythritol is estimated to reach 30 g/day. 

“Many try and reduce sugar intake by taking many teaspoons of erythritol in their tea, coffee, etc., instead of sugar,” Dr. Hazen added. “Or they eat keto processed foods that have significant quantities of erythritol within it.”

“These studies are a warning for how our processed food (keto and zero sugar, especially) may inadvertently be causing risk/harm. … in the very subset of subjects who are most vulnerable,” according to Dr. Hazen.
 

Erythritol marketed as ‘zero calorie’, ‘non-nutritive’, or ‘natural’

Patients with type 2 diabetes and obesity are often advised to replace sugar with artificial sweeteners for better glucose control and weight loss, but growing epidemiologic evidence links artificial sweetener consumption with weight gain, insulin resistance, type 2 diabetes, and cardiovascular disease, the researchers write.

Erythritol is naturally present in low amounts in fruits and vegetables; the artificial sweetener erythritol that is produced from corn is only 70% as sweet as sugar.

Upon ingestion it is poorly metabolized, and most is excreted in the urine, so it is characterized as a “zero-calorie,” “non-nutritive,” or “natural sweetener.” It is predicted to double in marketshare in the sweetener sector in the next 5 years.
 

Multipart study

In the first part of their study, in a discovery cohort in 1,157 patients undergoing cardiovascular assessment with 3-year outcomes, the researchers identified polyols that were associated with MACE, and erythritol was among the top MACE-associated molecules.

Next, in a U.S. validation cohort of 2,149 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 1.8-fold higher risk of MACE than patients in the lowest quartile (P = .007), after adjusting for cardiovascular risk factors.

In a European validation cohort of 833 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 2.21-fold higher risk of MACE than patients in the lowest quartile (P = .010, after adjustment).

At physiologic levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo.

Finally, in a prospective pilot intervention study, erythritol ingestion in healthy volunteers induced marked and sustained increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies.
 

Others weigh in

“While I think the finding certainly warrants further investigation, don’t throw out your sweeteners just yet,” commented Oliver Jones, PhD, professor of chemistry at the Royal Melbourne Institute of Technology.

“This study only looks at erythritol, and artificial sweeteners are generally considered safe. Any possible (and, as yet unproven) risks of excess erythritol would also need to be balanced against the very real health risks of excess glucose consumption,” he said.

Dr. Hazen responded: “True enough. Erythritol is but one of many artificial sweeteners. That is why it is important to read labels. This study can make patients be informed about how to potentially avoid something that might cause them inadvertent harm.”

“The key findings of this study are that high blood levels of erythritol are strongly associated with cardiovascular outcomes in high-risk patients, which has been replicated in separate validation studies,” said Tom Sanders, DSc, PhD, professor emeritus of nutrition and dietetics, King’s College London.

“Diabetes UK currently advises diabetes patients not to use polyols,” he added.

Dr. Hazen noted that “About three-quarters of the participants had coronary disease, high blood pressure, and about a fifth had diabetes.”

The researchers acknowledge, however, that the observational studies cannot show cause and effect.

The study was supported by the Office of Dietary Supplements at the National Institutes of Health, the Leducq Foundation, and the German Research Foundation (Deutsche Forschungsgemeinschaft). Dr. Mellor, Dr. Jones, and Dr. Sanders have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Combining ketamine and psychotherapy is a promising approach for treating PTSD, new research suggests.

In a systematic review and meta-analysis of four studies investigating combined use of psychotherapy and ketamine for PTSD, results showed that all the studies showed a significant reduction in PTSD symptom scores.

Overall, the treatment was “highly effective, as seen by the significant improvements in symptoms on multiple measures,” Aaron E. Philipp-Muller, BScH, Centre for Neuroscience Studies, Queen’s University, Kingston, Ont., and colleagues write.

Furthermore, the study “demonstrates the potential feasibility of this treatment model and corroborates previous work,” the investigators write.

However, a limitation they note was that only 34 participants were included in the analysis.

The findings were published online in the Journal of Clinical Psychiatry.
 

Emerging treatment

Ketamine is an “emerging treatment for a number of psychopathologies, such as major depressive disorder and PTSD, with a higher response than other pharmacologic agents,” the researchers write.

It is hypothesized that ketamine rapidly facilitates long-term potentiation, “thereby allowing a patient to disengage from an established pattern of thought more readily,” they write.

However, ketamine has several drawbacks, including the fact that it brings only 1 week of relief for PTSD. Also, because it must be administered intravenously, it is “impractical for long-term weekly administration,” they note.

Pharmacologically enhanced psychotherapy is a potential way to prolong ketamine’s effects. Several prior studies have investigated this model using other psychedelic medications, with encouraging results.

The current investigators decided to review all literature to date on the subject of ketamine plus psychotherapy for the treatment of PTSD.

To be included, the study had to include patients diagnosed with PTSD, an intervention involving ketamine alongside any form of psychotherapy, and assessment of all patients before and after treatment using the Clinician-Administered PTSD Scale (CAPS) or the PTSD Checklist (PCL).

Four studies met inclusion criteria. Of these, two were of “moderate” quality and two were of “low” quality, based on the GRADE assessment. The studies encompassed a total of 34 patients with “diverse traumatic experiences” and included several types of ketamine administration protocols, including one used previously for treating depression and another used previously for chronic pain.

The psychotherapy modalities also differed between the studies. In two studies, patients received 12 sessions of trauma interventions using mindfulness-based extinction and reconsolidation therapy; in a third study, patients received 10 weekly sessions of prolonged exposure therapy; and in the fourth study, patients received five daily sessions of exposure therapy.

Across the studies, the psychotherapies were paired differently with ketamine administration, such as the number of ketamine administrations in conjunction with therapy.

Despite the differences in protocols, all the studies of ketamine plus psychotherapy showed a significant reduction in PTSD symptoms, with a pooled standardized mean difference (SMD) of –7.26 (95% CI, –12.28 to –2.25; P = .005) for the CAPS and a pooled SMD of –5.17 (95% CI, –7.99 to –2.35; P < .001) for the PCL.

The researchers acknowledge that the sample size was very small “due to the novelty of this research area.” This prompted the inclusion of nonrandomized studies that “lowered the quality of the evidence,” they note.

Nevertheless, “these preliminary findings indicate the potential of ketamine-assisted psychotherapy for PTSD,” the investigators write.
 

A promising avenue?

In a comment, Dan Iosifescu, MD, professor of psychiatry, New York University School of Medicine, called the combination of ketamine and psychotherapy in PTSD “a very promising treatment avenue.”

Dr. Iosifescu, who was not involved with the research, noted that “several PTSD-focused psychotherapies are ultimately very effective but very hard to tolerate for participants.” For example, prolonged exposure therapy has dropout rates as high as 50%.

In addition, ketamine has rapid but not sustained effects in PTSD, he said.

“So in theory, a course of ketamine could help PTSD patients improve rapidly and tolerate the psychotherapy, which could provide sustained benefits,” he added.

However, Dr. Iosifescu cautioned that the data supporting this “is very sparse for now.”

He also noted that the meta-analysis included only “four tiny studies” and had only 34 total participants. In addition, several of the studies had no comparison group and the study designs were all different – “both with respect to the administration of ketamine and to the paired PTSD psychotherapy.”

For this reason, “any conclusions are only a very preliminary suggestion that this may be a fruitful avenue,” he said.

Dr. Iosifescu added that additional studies on this topic are ongoing. The largest one at the Veterans Administration will hopefully include 100 participants and “will provide more reliable evidence for this important topic,” he said.

The study was indirectly supported by the Internal Faculty Grant from the department of psychiatry, Queen’s University. Dr. Iosifescu reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Combining ketamine and psychotherapy is a promising approach for treating PTSD, new research suggests.

In a systematic review and meta-analysis of four studies investigating combined use of psychotherapy and ketamine for PTSD, results showed that all the studies showed a significant reduction in PTSD symptom scores.

Overall, the treatment was “highly effective, as seen by the significant improvements in symptoms on multiple measures,” Aaron E. Philipp-Muller, BScH, Centre for Neuroscience Studies, Queen’s University, Kingston, Ont., and colleagues write.

Furthermore, the study “demonstrates the potential feasibility of this treatment model and corroborates previous work,” the investigators write.

However, a limitation they note was that only 34 participants were included in the analysis.

The findings were published online in the Journal of Clinical Psychiatry.
 

Emerging treatment

Ketamine is an “emerging treatment for a number of psychopathologies, such as major depressive disorder and PTSD, with a higher response than other pharmacologic agents,” the researchers write.

It is hypothesized that ketamine rapidly facilitates long-term potentiation, “thereby allowing a patient to disengage from an established pattern of thought more readily,” they write.

However, ketamine has several drawbacks, including the fact that it brings only 1 week of relief for PTSD. Also, because it must be administered intravenously, it is “impractical for long-term weekly administration,” they note.

Pharmacologically enhanced psychotherapy is a potential way to prolong ketamine’s effects. Several prior studies have investigated this model using other psychedelic medications, with encouraging results.

The current investigators decided to review all literature to date on the subject of ketamine plus psychotherapy for the treatment of PTSD.

To be included, the study had to include patients diagnosed with PTSD, an intervention involving ketamine alongside any form of psychotherapy, and assessment of all patients before and after treatment using the Clinician-Administered PTSD Scale (CAPS) or the PTSD Checklist (PCL).

Four studies met inclusion criteria. Of these, two were of “moderate” quality and two were of “low” quality, based on the GRADE assessment. The studies encompassed a total of 34 patients with “diverse traumatic experiences” and included several types of ketamine administration protocols, including one used previously for treating depression and another used previously for chronic pain.

The psychotherapy modalities also differed between the studies. In two studies, patients received 12 sessions of trauma interventions using mindfulness-based extinction and reconsolidation therapy; in a third study, patients received 10 weekly sessions of prolonged exposure therapy; and in the fourth study, patients received five daily sessions of exposure therapy.

Across the studies, the psychotherapies were paired differently with ketamine administration, such as the number of ketamine administrations in conjunction with therapy.

Despite the differences in protocols, all the studies of ketamine plus psychotherapy showed a significant reduction in PTSD symptoms, with a pooled standardized mean difference (SMD) of –7.26 (95% CI, –12.28 to –2.25; P = .005) for the CAPS and a pooled SMD of –5.17 (95% CI, –7.99 to –2.35; P < .001) for the PCL.

The researchers acknowledge that the sample size was very small “due to the novelty of this research area.” This prompted the inclusion of nonrandomized studies that “lowered the quality of the evidence,” they note.

Nevertheless, “these preliminary findings indicate the potential of ketamine-assisted psychotherapy for PTSD,” the investigators write.
 

A promising avenue?

In a comment, Dan Iosifescu, MD, professor of psychiatry, New York University School of Medicine, called the combination of ketamine and psychotherapy in PTSD “a very promising treatment avenue.”

Dr. Iosifescu, who was not involved with the research, noted that “several PTSD-focused psychotherapies are ultimately very effective but very hard to tolerate for participants.” For example, prolonged exposure therapy has dropout rates as high as 50%.

In addition, ketamine has rapid but not sustained effects in PTSD, he said.

“So in theory, a course of ketamine could help PTSD patients improve rapidly and tolerate the psychotherapy, which could provide sustained benefits,” he added.

However, Dr. Iosifescu cautioned that the data supporting this “is very sparse for now.”

He also noted that the meta-analysis included only “four tiny studies” and had only 34 total participants. In addition, several of the studies had no comparison group and the study designs were all different – “both with respect to the administration of ketamine and to the paired PTSD psychotherapy.”

For this reason, “any conclusions are only a very preliminary suggestion that this may be a fruitful avenue,” he said.

Dr. Iosifescu added that additional studies on this topic are ongoing. The largest one at the Veterans Administration will hopefully include 100 participants and “will provide more reliable evidence for this important topic,” he said.

The study was indirectly supported by the Internal Faculty Grant from the department of psychiatry, Queen’s University. Dr. Iosifescu reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Combining ketamine and psychotherapy is a promising approach for treating PTSD, new research suggests.

In a systematic review and meta-analysis of four studies investigating combined use of psychotherapy and ketamine for PTSD, results showed that all the studies showed a significant reduction in PTSD symptom scores.

Overall, the treatment was “highly effective, as seen by the significant improvements in symptoms on multiple measures,” Aaron E. Philipp-Muller, BScH, Centre for Neuroscience Studies, Queen’s University, Kingston, Ont., and colleagues write.

Furthermore, the study “demonstrates the potential feasibility of this treatment model and corroborates previous work,” the investigators write.

However, a limitation they note was that only 34 participants were included in the analysis.

The findings were published online in the Journal of Clinical Psychiatry.
 

Emerging treatment

Ketamine is an “emerging treatment for a number of psychopathologies, such as major depressive disorder and PTSD, with a higher response than other pharmacologic agents,” the researchers write.

It is hypothesized that ketamine rapidly facilitates long-term potentiation, “thereby allowing a patient to disengage from an established pattern of thought more readily,” they write.

However, ketamine has several drawbacks, including the fact that it brings only 1 week of relief for PTSD. Also, because it must be administered intravenously, it is “impractical for long-term weekly administration,” they note.

Pharmacologically enhanced psychotherapy is a potential way to prolong ketamine’s effects. Several prior studies have investigated this model using other psychedelic medications, with encouraging results.

The current investigators decided to review all literature to date on the subject of ketamine plus psychotherapy for the treatment of PTSD.

To be included, the study had to include patients diagnosed with PTSD, an intervention involving ketamine alongside any form of psychotherapy, and assessment of all patients before and after treatment using the Clinician-Administered PTSD Scale (CAPS) or the PTSD Checklist (PCL).

Four studies met inclusion criteria. Of these, two were of “moderate” quality and two were of “low” quality, based on the GRADE assessment. The studies encompassed a total of 34 patients with “diverse traumatic experiences” and included several types of ketamine administration protocols, including one used previously for treating depression and another used previously for chronic pain.

The psychotherapy modalities also differed between the studies. In two studies, patients received 12 sessions of trauma interventions using mindfulness-based extinction and reconsolidation therapy; in a third study, patients received 10 weekly sessions of prolonged exposure therapy; and in the fourth study, patients received five daily sessions of exposure therapy.

Across the studies, the psychotherapies were paired differently with ketamine administration, such as the number of ketamine administrations in conjunction with therapy.

Despite the differences in protocols, all the studies of ketamine plus psychotherapy showed a significant reduction in PTSD symptoms, with a pooled standardized mean difference (SMD) of –7.26 (95% CI, –12.28 to –2.25; P = .005) for the CAPS and a pooled SMD of –5.17 (95% CI, –7.99 to –2.35; P < .001) for the PCL.

The researchers acknowledge that the sample size was very small “due to the novelty of this research area.” This prompted the inclusion of nonrandomized studies that “lowered the quality of the evidence,” they note.

Nevertheless, “these preliminary findings indicate the potential of ketamine-assisted psychotherapy for PTSD,” the investigators write.
 

A promising avenue?

In a comment, Dan Iosifescu, MD, professor of psychiatry, New York University School of Medicine, called the combination of ketamine and psychotherapy in PTSD “a very promising treatment avenue.”

Dr. Iosifescu, who was not involved with the research, noted that “several PTSD-focused psychotherapies are ultimately very effective but very hard to tolerate for participants.” For example, prolonged exposure therapy has dropout rates as high as 50%.

In addition, ketamine has rapid but not sustained effects in PTSD, he said.

“So in theory, a course of ketamine could help PTSD patients improve rapidly and tolerate the psychotherapy, which could provide sustained benefits,” he added.

However, Dr. Iosifescu cautioned that the data supporting this “is very sparse for now.”

He also noted that the meta-analysis included only “four tiny studies” and had only 34 total participants. In addition, several of the studies had no comparison group and the study designs were all different – “both with respect to the administration of ketamine and to the paired PTSD psychotherapy.”

For this reason, “any conclusions are only a very preliminary suggestion that this may be a fruitful avenue,” he said.

Dr. Iosifescu added that additional studies on this topic are ongoing. The largest one at the Veterans Administration will hopefully include 100 participants and “will provide more reliable evidence for this important topic,” he said.

The study was indirectly supported by the Internal Faculty Grant from the department of psychiatry, Queen’s University. Dr. Iosifescu reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Dementia risk is significantly higher in women than in men worldwide, and social and economic disadvantages among women could be to blame, a study suggests.

Prior research has found a higher lifetime dementia risk in women, and one explanation cited has been that women tend to live longer than men.

However, this new analysis of data from nearly 30,000 people in 18 countries found almost no evidence of sex differences in most known risk factors for dementia, including age.

The risk of dementia among women was significantly higher in poorer countries, pointing to economic disadvantages as a possible explanation.

“In general, we found that the greater dementia risk found in women compared to men was more pronounced in poorer countries, which points to the need for greater efforts to narrow the gaps in health disparities between women and men in these countries,” lead investigator Jessica Gong, MSc, a doctoral student at the George Institute for Global Health, Newtown, Australia, told this news organization. “It is likely that socioeconomic factors are potentially more important than biological factors when assessing dementia risk.”

The findings were published online in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
 

Global data

Most previous studies that examined sex differences in dementia risk were conducted in high-income countries, Ms. Gong noted, leaving a gap in the literature on risk in low- and middle-income countries.

To address this issue, researchers conducted an individual participant meta-analysis of 21 studies from the Cohort Studies of Memory in an International Consortium. Data analysis included information on 29,850 people from 18 countries on six continents. None of the participants had dementia at baseline, and the average age was 71.6 years.

Over a median of 4.6 years, incident dementia was reported in 2,089 people, 66% of whom were women.

Overall, women had higher dementia risk (hazard ratio, 1.12; 95% confidence interval, 1.02-1.23) than men, but the rates were highest in low- to middle-income economies (HR, 1.73; P = .03).

Dementia risk in women was higher than in men in 14 countries. Risk was highest in Nigeria, where dementia risk was more than double in women (aHR, 2.11; 95% CI, 1.46-3.04), and lowest in Brazil, where risk was 46% lower in women than in men (aHR, 0.54; 95% CI, 0.29-1.00).

In the United States, dementia risk was 7% higher in women than men (aHR, 1.07; 0.73-1.57).
 

Similar risk factors

In both women and men, older age, diabetes, depression, hearing impairment, and apo E–epsilon 4 carriage were associated with a greater risk of dementia, and more years of education, higher hip circumference, current alcohol use (vs. never), and high physical activity (vs. none to minimal) were associated with a lower risk of dementia.

Among all these risk factors, sex differences were only significant for longer education and former alcohol use, with both demonstrating a stronger association in men than women.

Global dementia rates are expected to triple over the next 25 years unless steps are taken to reduce risk factors. A 2020 report found that dementia risk could be reduced by addressing 12 modifiable risk factors, including obesity, air pollution, diabetes, social isolation, and hypertension. All of these risk factors are more common in low- to middle-income countries, Ms. Gong noted.

“These findings justify ongoing efforts to support programs to improve sex and gender equity in brain health, particularly in underrepresented and underserved populations, in turn to narrow the gaps within and between country,” Ms. Gong said.
 

Understanding the puzzle

Commenting on the findings for Medscape Medical News, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, said the findings add to the body of work about sex differences in dementia risk.

“This is an interesting study looking at risk factors for dementia and suggests that, while some risk factors are more pronounced in men than in women, women may be more at risk of progressing to dementia,” Dr. Snyder said. “The findings outline the importance of understanding how the underlying biology, particularly biology that differs in males and females, may be contributing to risk.”

Data on the country and geographical variations highlighted in the study also point to a potential risk influencer, she said.

“Studying geography-specific risk factors is important because it helps us understand the ‘why’ behind geographic differences in dementia risk,” Dr. Snyder said. “This type of collaboration among countries and researchers is essential for us to understand these puzzle pieces.”

Funding for the study was provided by the U.K. Medical Research Council Skills Development Fellowship, Australian National Health and Medical Research Council Investigator Grant, National Institute on Aging, among others. See the original article for full funding sources. Ms. Gong reported no relevant financial conflicts. Dr. Snyder is employed by the Alzheimer’s Association.

A version of this article originally appeared on Medscape.com.

Dementia risk is significantly higher in women than in men worldwide, and social and economic disadvantages among women could be to blame, a study suggests.

Prior research has found a higher lifetime dementia risk in women, and one explanation cited has been that women tend to live longer than men.

However, this new analysis of data from nearly 30,000 people in 18 countries found almost no evidence of sex differences in most known risk factors for dementia, including age.

The risk of dementia among women was significantly higher in poorer countries, pointing to economic disadvantages as a possible explanation.

“In general, we found that the greater dementia risk found in women compared to men was more pronounced in poorer countries, which points to the need for greater efforts to narrow the gaps in health disparities between women and men in these countries,” lead investigator Jessica Gong, MSc, a doctoral student at the George Institute for Global Health, Newtown, Australia, told this news organization. “It is likely that socioeconomic factors are potentially more important than biological factors when assessing dementia risk.”

The findings were published online in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
 

Global data

Most previous studies that examined sex differences in dementia risk were conducted in high-income countries, Ms. Gong noted, leaving a gap in the literature on risk in low- and middle-income countries.

To address this issue, researchers conducted an individual participant meta-analysis of 21 studies from the Cohort Studies of Memory in an International Consortium. Data analysis included information on 29,850 people from 18 countries on six continents. None of the participants had dementia at baseline, and the average age was 71.6 years.

Over a median of 4.6 years, incident dementia was reported in 2,089 people, 66% of whom were women.

Overall, women had higher dementia risk (hazard ratio, 1.12; 95% confidence interval, 1.02-1.23) than men, but the rates were highest in low- to middle-income economies (HR, 1.73; P = .03).

Dementia risk in women was higher than in men in 14 countries. Risk was highest in Nigeria, where dementia risk was more than double in women (aHR, 2.11; 95% CI, 1.46-3.04), and lowest in Brazil, where risk was 46% lower in women than in men (aHR, 0.54; 95% CI, 0.29-1.00).

In the United States, dementia risk was 7% higher in women than men (aHR, 1.07; 0.73-1.57).
 

Similar risk factors

In both women and men, older age, diabetes, depression, hearing impairment, and apo E–epsilon 4 carriage were associated with a greater risk of dementia, and more years of education, higher hip circumference, current alcohol use (vs. never), and high physical activity (vs. none to minimal) were associated with a lower risk of dementia.

Among all these risk factors, sex differences were only significant for longer education and former alcohol use, with both demonstrating a stronger association in men than women.

Global dementia rates are expected to triple over the next 25 years unless steps are taken to reduce risk factors. A 2020 report found that dementia risk could be reduced by addressing 12 modifiable risk factors, including obesity, air pollution, diabetes, social isolation, and hypertension. All of these risk factors are more common in low- to middle-income countries, Ms. Gong noted.

“These findings justify ongoing efforts to support programs to improve sex and gender equity in brain health, particularly in underrepresented and underserved populations, in turn to narrow the gaps within and between country,” Ms. Gong said.
 

Understanding the puzzle

Commenting on the findings for Medscape Medical News, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, said the findings add to the body of work about sex differences in dementia risk.

“This is an interesting study looking at risk factors for dementia and suggests that, while some risk factors are more pronounced in men than in women, women may be more at risk of progressing to dementia,” Dr. Snyder said. “The findings outline the importance of understanding how the underlying biology, particularly biology that differs in males and females, may be contributing to risk.”

Data on the country and geographical variations highlighted in the study also point to a potential risk influencer, she said.

“Studying geography-specific risk factors is important because it helps us understand the ‘why’ behind geographic differences in dementia risk,” Dr. Snyder said. “This type of collaboration among countries and researchers is essential for us to understand these puzzle pieces.”

Funding for the study was provided by the U.K. Medical Research Council Skills Development Fellowship, Australian National Health and Medical Research Council Investigator Grant, National Institute on Aging, among others. See the original article for full funding sources. Ms. Gong reported no relevant financial conflicts. Dr. Snyder is employed by the Alzheimer’s Association.

A version of this article originally appeared on Medscape.com.

Dementia risk is significantly higher in women than in men worldwide, and social and economic disadvantages among women could be to blame, a study suggests.

Prior research has found a higher lifetime dementia risk in women, and one explanation cited has been that women tend to live longer than men.

However, this new analysis of data from nearly 30,000 people in 18 countries found almost no evidence of sex differences in most known risk factors for dementia, including age.

The risk of dementia among women was significantly higher in poorer countries, pointing to economic disadvantages as a possible explanation.

“In general, we found that the greater dementia risk found in women compared to men was more pronounced in poorer countries, which points to the need for greater efforts to narrow the gaps in health disparities between women and men in these countries,” lead investigator Jessica Gong, MSc, a doctoral student at the George Institute for Global Health, Newtown, Australia, told this news organization. “It is likely that socioeconomic factors are potentially more important than biological factors when assessing dementia risk.”

The findings were published online in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
 

Global data

Most previous studies that examined sex differences in dementia risk were conducted in high-income countries, Ms. Gong noted, leaving a gap in the literature on risk in low- and middle-income countries.

To address this issue, researchers conducted an individual participant meta-analysis of 21 studies from the Cohort Studies of Memory in an International Consortium. Data analysis included information on 29,850 people from 18 countries on six continents. None of the participants had dementia at baseline, and the average age was 71.6 years.

Over a median of 4.6 years, incident dementia was reported in 2,089 people, 66% of whom were women.

Overall, women had higher dementia risk (hazard ratio, 1.12; 95% confidence interval, 1.02-1.23) than men, but the rates were highest in low- to middle-income economies (HR, 1.73; P = .03).

Dementia risk in women was higher than in men in 14 countries. Risk was highest in Nigeria, where dementia risk was more than double in women (aHR, 2.11; 95% CI, 1.46-3.04), and lowest in Brazil, where risk was 46% lower in women than in men (aHR, 0.54; 95% CI, 0.29-1.00).

In the United States, dementia risk was 7% higher in women than men (aHR, 1.07; 0.73-1.57).
 

Similar risk factors

In both women and men, older age, diabetes, depression, hearing impairment, and apo E–epsilon 4 carriage were associated with a greater risk of dementia, and more years of education, higher hip circumference, current alcohol use (vs. never), and high physical activity (vs. none to minimal) were associated with a lower risk of dementia.

Among all these risk factors, sex differences were only significant for longer education and former alcohol use, with both demonstrating a stronger association in men than women.

Global dementia rates are expected to triple over the next 25 years unless steps are taken to reduce risk factors. A 2020 report found that dementia risk could be reduced by addressing 12 modifiable risk factors, including obesity, air pollution, diabetes, social isolation, and hypertension. All of these risk factors are more common in low- to middle-income countries, Ms. Gong noted.

“These findings justify ongoing efforts to support programs to improve sex and gender equity in brain health, particularly in underrepresented and underserved populations, in turn to narrow the gaps within and between country,” Ms. Gong said.
 

Understanding the puzzle

Commenting on the findings for Medscape Medical News, Heather Snyder, PhD, Alzheimer’s Association vice president of medical and scientific relations, said the findings add to the body of work about sex differences in dementia risk.

“This is an interesting study looking at risk factors for dementia and suggests that, while some risk factors are more pronounced in men than in women, women may be more at risk of progressing to dementia,” Dr. Snyder said. “The findings outline the importance of understanding how the underlying biology, particularly biology that differs in males and females, may be contributing to risk.”

Data on the country and geographical variations highlighted in the study also point to a potential risk influencer, she said.

“Studying geography-specific risk factors is important because it helps us understand the ‘why’ behind geographic differences in dementia risk,” Dr. Snyder said. “This type of collaboration among countries and researchers is essential for us to understand these puzzle pieces.”

Funding for the study was provided by the U.K. Medical Research Council Skills Development Fellowship, Australian National Health and Medical Research Council Investigator Grant, National Institute on Aging, among others. See the original article for full funding sources. Ms. Gong reported no relevant financial conflicts. Dr. Snyder is employed by the Alzheimer’s Association.

A version of this article originally appeared on Medscape.com.

Regular use of over-the-counter laxatives has been tied to a significantly increased risk of dementia, particularly among those who use multiple types of laxatives or osmotic laxatives.

Among more than 500,000 middle-aged or older adults in the UK Biobank, those who reported regular laxative use had a 51% increased risk of dementia due to any cause, compared with their counterparts who did not regularly use laxatives.

Individuals who used only osmotic laxatives had a 64% increased risk, compared with peers who did not use laxatives, while those using one or more types of laxatives, including bulk-forming, stool-softening, or stimulating laxatives, had a 90% increased risk.

“Constipation and laxative use are common among middle-aged and older adults,” study investigator Feng Sha, PhD, with the Chinese Academy of Sciences in Guangdong, China, said in a news release.

“However, regular laxative use may change the microbiome of the gut, possibly affecting nerve signaling from the gut to the brain or increasing the production of intestinal toxins that may affect the brain,” Dr. Sha noted.

The study was published online in Neurology.
 

Robust link

The findings are based on 502,229 people (54% women; mean age, 57 at baseline) from the UK biobank database. All were dementia-free at baseline.

A total of 18,235 participants (3.6%) said they used over-the-counter laxatives regularly, which was defined as using them most days of the week during the month before the study.

Over an average of 9.8 years, dementia was recorded in 218 (1.3%) of those who regularly used laxatives and in 1,969 (0.4%) of those did not.

After adjusting for factors such as age, sex, education, other illnesses, medication use, and a family history of dementia, regular use of laxatives was significantly associated with increased risk of all-cause dementia (adjusted hazard ratio, 1.51; 95% confidence interval, 1.30-1.75) and vascular dementia (aHR, 1.65; 95% CI, 1.21-2.27), with no significant association observed for Alzheimer’s disease (aHR, 1.05; 95% CI, 0.79-1.40).

The risk of dementia also increased with the number of laxative types used. All-cause dementia risk increased by 28% (aHR, 1.28; 95% CI, 1.03-1.61) for those using a single laxative type and by 90% (aHR, 1.90; 95% CI, 1.20-3.01) for those using two or more types, compared with nonuse.

Among those who reported using only one type of laxative, only those using osmotic laxatives had a statistically significant higher risk of all-cause dementia (aHR, 1.64; 95% CI, 1.20-2.24) and vascular dementia (aHR, 1.97; 95% CI, 1.04-3.75).

“These results remained robust in various subgroup and sensitivity analyses,” the investigators report.

They caution that they had no data on laxative dosage and so they were unable to explore the relationship between various laxative dosages and dementia risk.
 

Interpret with caution

Commenting on the findings for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the results are “interesting and demonstrate an association between laxative use and later life risk of dementia.”

However, “there is no proven causation, and there are some caveats,” Dr. Snyder said. “It’s unclear what may be driving this association, though other lines of research have suggested a linkage between our overall gut health, our immune system, and our brain health.”

Dr. Snyder said it’s also worth noting that the data came from the UK Biobank, which, “while a wealth of information for research purposes, is not representative of other countries. More research is needed.”

The Alzheimer’s Association is leading a 2-year clinical trial, U.S. Pointer, to examine the impact of behavioral interventions on the gut-brain axis to “better understand how our gut health may affect our brains,” Dr. Snyder told this news organization.

“While we await the results of that study, people should talk to their doctor about the risks and benefits of laxatives for their health, as well as discuss alternative methods of alleviating constipation, such as increasing dietary fiber and drinking more water,” she advised.

The study was funded by the National Natural Science Foundation of China, Shenzhen Science and Technology Program, and the Chinese Academy of Sciences. The authors and Dr. Snyder have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Regular use of over-the-counter laxatives has been tied to a significantly increased risk of dementia, particularly among those who use multiple types of laxatives or osmotic laxatives.

Among more than 500,000 middle-aged or older adults in the UK Biobank, those who reported regular laxative use had a 51% increased risk of dementia due to any cause, compared with their counterparts who did not regularly use laxatives.

Individuals who used only osmotic laxatives had a 64% increased risk, compared with peers who did not use laxatives, while those using one or more types of laxatives, including bulk-forming, stool-softening, or stimulating laxatives, had a 90% increased risk.

“Constipation and laxative use are common among middle-aged and older adults,” study investigator Feng Sha, PhD, with the Chinese Academy of Sciences in Guangdong, China, said in a news release.

“However, regular laxative use may change the microbiome of the gut, possibly affecting nerve signaling from the gut to the brain or increasing the production of intestinal toxins that may affect the brain,” Dr. Sha noted.

The study was published online in Neurology.
 

Robust link

The findings are based on 502,229 people (54% women; mean age, 57 at baseline) from the UK biobank database. All were dementia-free at baseline.

A total of 18,235 participants (3.6%) said they used over-the-counter laxatives regularly, which was defined as using them most days of the week during the month before the study.

Over an average of 9.8 years, dementia was recorded in 218 (1.3%) of those who regularly used laxatives and in 1,969 (0.4%) of those did not.

After adjusting for factors such as age, sex, education, other illnesses, medication use, and a family history of dementia, regular use of laxatives was significantly associated with increased risk of all-cause dementia (adjusted hazard ratio, 1.51; 95% confidence interval, 1.30-1.75) and vascular dementia (aHR, 1.65; 95% CI, 1.21-2.27), with no significant association observed for Alzheimer’s disease (aHR, 1.05; 95% CI, 0.79-1.40).

The risk of dementia also increased with the number of laxative types used. All-cause dementia risk increased by 28% (aHR, 1.28; 95% CI, 1.03-1.61) for those using a single laxative type and by 90% (aHR, 1.90; 95% CI, 1.20-3.01) for those using two or more types, compared with nonuse.

Among those who reported using only one type of laxative, only those using osmotic laxatives had a statistically significant higher risk of all-cause dementia (aHR, 1.64; 95% CI, 1.20-2.24) and vascular dementia (aHR, 1.97; 95% CI, 1.04-3.75).

“These results remained robust in various subgroup and sensitivity analyses,” the investigators report.

They caution that they had no data on laxative dosage and so they were unable to explore the relationship between various laxative dosages and dementia risk.
 

Interpret with caution

Commenting on the findings for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the results are “interesting and demonstrate an association between laxative use and later life risk of dementia.”

However, “there is no proven causation, and there are some caveats,” Dr. Snyder said. “It’s unclear what may be driving this association, though other lines of research have suggested a linkage between our overall gut health, our immune system, and our brain health.”

Dr. Snyder said it’s also worth noting that the data came from the UK Biobank, which, “while a wealth of information for research purposes, is not representative of other countries. More research is needed.”

The Alzheimer’s Association is leading a 2-year clinical trial, U.S. Pointer, to examine the impact of behavioral interventions on the gut-brain axis to “better understand how our gut health may affect our brains,” Dr. Snyder told this news organization.

“While we await the results of that study, people should talk to their doctor about the risks and benefits of laxatives for their health, as well as discuss alternative methods of alleviating constipation, such as increasing dietary fiber and drinking more water,” she advised.

The study was funded by the National Natural Science Foundation of China, Shenzhen Science and Technology Program, and the Chinese Academy of Sciences. The authors and Dr. Snyder have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Regular use of over-the-counter laxatives has been tied to a significantly increased risk of dementia, particularly among those who use multiple types of laxatives or osmotic laxatives.

Among more than 500,000 middle-aged or older adults in the UK Biobank, those who reported regular laxative use had a 51% increased risk of dementia due to any cause, compared with their counterparts who did not regularly use laxatives.

Individuals who used only osmotic laxatives had a 64% increased risk, compared with peers who did not use laxatives, while those using one or more types of laxatives, including bulk-forming, stool-softening, or stimulating laxatives, had a 90% increased risk.

“Constipation and laxative use are common among middle-aged and older adults,” study investigator Feng Sha, PhD, with the Chinese Academy of Sciences in Guangdong, China, said in a news release.

“However, regular laxative use may change the microbiome of the gut, possibly affecting nerve signaling from the gut to the brain or increasing the production of intestinal toxins that may affect the brain,” Dr. Sha noted.

The study was published online in Neurology.
 

Robust link

The findings are based on 502,229 people (54% women; mean age, 57 at baseline) from the UK biobank database. All were dementia-free at baseline.

A total of 18,235 participants (3.6%) said they used over-the-counter laxatives regularly, which was defined as using them most days of the week during the month before the study.

Over an average of 9.8 years, dementia was recorded in 218 (1.3%) of those who regularly used laxatives and in 1,969 (0.4%) of those did not.

After adjusting for factors such as age, sex, education, other illnesses, medication use, and a family history of dementia, regular use of laxatives was significantly associated with increased risk of all-cause dementia (adjusted hazard ratio, 1.51; 95% confidence interval, 1.30-1.75) and vascular dementia (aHR, 1.65; 95% CI, 1.21-2.27), with no significant association observed for Alzheimer’s disease (aHR, 1.05; 95% CI, 0.79-1.40).

The risk of dementia also increased with the number of laxative types used. All-cause dementia risk increased by 28% (aHR, 1.28; 95% CI, 1.03-1.61) for those using a single laxative type and by 90% (aHR, 1.90; 95% CI, 1.20-3.01) for those using two or more types, compared with nonuse.

Among those who reported using only one type of laxative, only those using osmotic laxatives had a statistically significant higher risk of all-cause dementia (aHR, 1.64; 95% CI, 1.20-2.24) and vascular dementia (aHR, 1.97; 95% CI, 1.04-3.75).

“These results remained robust in various subgroup and sensitivity analyses,” the investigators report.

They caution that they had no data on laxative dosage and so they were unable to explore the relationship between various laxative dosages and dementia risk.
 

Interpret with caution

Commenting on the findings for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the results are “interesting and demonstrate an association between laxative use and later life risk of dementia.”

However, “there is no proven causation, and there are some caveats,” Dr. Snyder said. “It’s unclear what may be driving this association, though other lines of research have suggested a linkage between our overall gut health, our immune system, and our brain health.”

Dr. Snyder said it’s also worth noting that the data came from the UK Biobank, which, “while a wealth of information for research purposes, is not representative of other countries. More research is needed.”

The Alzheimer’s Association is leading a 2-year clinical trial, U.S. Pointer, to examine the impact of behavioral interventions on the gut-brain axis to “better understand how our gut health may affect our brains,” Dr. Snyder told this news organization.

“While we await the results of that study, people should talk to their doctor about the risks and benefits of laxatives for their health, as well as discuss alternative methods of alleviating constipation, such as increasing dietary fiber and drinking more water,” she advised.

The study was funded by the National Natural Science Foundation of China, Shenzhen Science and Technology Program, and the Chinese Academy of Sciences. The authors and Dr. Snyder have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Last night I invested an hour and a half watching the first half of the Super Bowl ... because ... well, just because. As exciting as it might have been to watch, investing another 2 hours on the second half would have kept me up well past my bedtime. As I lay in bed with the thwack-thwack-thud of helmets hitting pads still reverberating in my ears, my thoughts drifted to the ever-shifting landscape of concussion management.

More than 2 decades ago, concussions were just beginning to exit the dark ages when loss of consciousness was the defining symptom or sign that most folks (and here I am including physicians) used to separate the run-of-the-mill stinger or bell-ringer from a “real” concussion.

The new era dawned with the appearance of clinics devoted to concussion management and the development of protocols that limited everything from physical exertion to reading and screen time. Schools were coaxed into subjecting their athletes to preparticipation testing sessions with the hope that creating a baseline cognitive assessment would somehow make the diagnosis and management of concussion feel more scientific. Many of the recommended management strategies were based on the intuitive but flawed notion of “brain rest.” If reading or bright lights aggravate patient’s symptoms, they should be avoided but otherwise resting the brain doesn’t seem to make sense.

Fortunately, there were, and hopefully will continue to be, clinicians willing to question hastily developed management protocols. One recent cohort study from Canada has found that, surprisingly, (to some experts), “early return to school was associated with a lower symptom burden” This association held true for both age groups the researches studied (8-12 years and 13-18 years). The authors conclude that delayed return to school “may be detrimental to recovery.” In this study, early return to school was defined as less than 3 days.

In another study, this one in the journal Pediatrics, the authors found that “the association of early screen time with postconcussion symptoms is not linear.” Their conclusion was that the best approach to clinical management of concussion should include a moderate amount of screen time.

After reading both of these studies I am heartened that we are now hearing voices suggesting a return to concussion management based on careful observation of the individual patient and common sense. A concussed brain is not a torn hamstring or a broken clavicle that under most circumstances will heal in a predictable amount of time. It is prudent to exclude the concussed patient from activities that carry a significant risk of reinjury until the symptoms have subsided. However, postconcussion symptoms are often vague and can be mistaken for or aggravated by a host of other conditions including learning disabilities, anxiety, and depression.

I hope that our experience with the COVID pandemic has taught us that removing children from school and their usual activities can have a serious negative effect on their emotional health and academic achievement. This seems to be particularly true for the young people who were already struggling to adjust to being a student. Getting out of the habit of going to school often intensifies the anxieties of an emotionally or academically challenged student. Each day away from the school atmosphere can compound the symptoms that may or may not have been triggered by the concussion.

The message here is clear that, whether we are talking about concussions or appendectomies or mononucleosis, the sooner we can return the child to something close to their old normal the more successful we will be in a helping them adjust to the new normal.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Last night I invested an hour and a half watching the first half of the Super Bowl ... because ... well, just because. As exciting as it might have been to watch, investing another 2 hours on the second half would have kept me up well past my bedtime. As I lay in bed with the thwack-thwack-thud of helmets hitting pads still reverberating in my ears, my thoughts drifted to the ever-shifting landscape of concussion management.

More than 2 decades ago, concussions were just beginning to exit the dark ages when loss of consciousness was the defining symptom or sign that most folks (and here I am including physicians) used to separate the run-of-the-mill stinger or bell-ringer from a “real” concussion.

The new era dawned with the appearance of clinics devoted to concussion management and the development of protocols that limited everything from physical exertion to reading and screen time. Schools were coaxed into subjecting their athletes to preparticipation testing sessions with the hope that creating a baseline cognitive assessment would somehow make the diagnosis and management of concussion feel more scientific. Many of the recommended management strategies were based on the intuitive but flawed notion of “brain rest.” If reading or bright lights aggravate patient’s symptoms, they should be avoided but otherwise resting the brain doesn’t seem to make sense.

Fortunately, there were, and hopefully will continue to be, clinicians willing to question hastily developed management protocols. One recent cohort study from Canada has found that, surprisingly, (to some experts), “early return to school was associated with a lower symptom burden” This association held true for both age groups the researches studied (8-12 years and 13-18 years). The authors conclude that delayed return to school “may be detrimental to recovery.” In this study, early return to school was defined as less than 3 days.

In another study, this one in the journal Pediatrics, the authors found that “the association of early screen time with postconcussion symptoms is not linear.” Their conclusion was that the best approach to clinical management of concussion should include a moderate amount of screen time.

After reading both of these studies I am heartened that we are now hearing voices suggesting a return to concussion management based on careful observation of the individual patient and common sense. A concussed brain is not a torn hamstring or a broken clavicle that under most circumstances will heal in a predictable amount of time. It is prudent to exclude the concussed patient from activities that carry a significant risk of reinjury until the symptoms have subsided. However, postconcussion symptoms are often vague and can be mistaken for or aggravated by a host of other conditions including learning disabilities, anxiety, and depression.

I hope that our experience with the COVID pandemic has taught us that removing children from school and their usual activities can have a serious negative effect on their emotional health and academic achievement. This seems to be particularly true for the young people who were already struggling to adjust to being a student. Getting out of the habit of going to school often intensifies the anxieties of an emotionally or academically challenged student. Each day away from the school atmosphere can compound the symptoms that may or may not have been triggered by the concussion.

The message here is clear that, whether we are talking about concussions or appendectomies or mononucleosis, the sooner we can return the child to something close to their old normal the more successful we will be in a helping them adjust to the new normal.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Last night I invested an hour and a half watching the first half of the Super Bowl ... because ... well, just because. As exciting as it might have been to watch, investing another 2 hours on the second half would have kept me up well past my bedtime. As I lay in bed with the thwack-thwack-thud of helmets hitting pads still reverberating in my ears, my thoughts drifted to the ever-shifting landscape of concussion management.

More than 2 decades ago, concussions were just beginning to exit the dark ages when loss of consciousness was the defining symptom or sign that most folks (and here I am including physicians) used to separate the run-of-the-mill stinger or bell-ringer from a “real” concussion.

The new era dawned with the appearance of clinics devoted to concussion management and the development of protocols that limited everything from physical exertion to reading and screen time. Schools were coaxed into subjecting their athletes to preparticipation testing sessions with the hope that creating a baseline cognitive assessment would somehow make the diagnosis and management of concussion feel more scientific. Many of the recommended management strategies were based on the intuitive but flawed notion of “brain rest.” If reading or bright lights aggravate patient’s symptoms, they should be avoided but otherwise resting the brain doesn’t seem to make sense.

Fortunately, there were, and hopefully will continue to be, clinicians willing to question hastily developed management protocols. One recent cohort study from Canada has found that, surprisingly, (to some experts), “early return to school was associated with a lower symptom burden” This association held true for both age groups the researches studied (8-12 years and 13-18 years). The authors conclude that delayed return to school “may be detrimental to recovery.” In this study, early return to school was defined as less than 3 days.

In another study, this one in the journal Pediatrics, the authors found that “the association of early screen time with postconcussion symptoms is not linear.” Their conclusion was that the best approach to clinical management of concussion should include a moderate amount of screen time.

After reading both of these studies I am heartened that we are now hearing voices suggesting a return to concussion management based on careful observation of the individual patient and common sense. A concussed brain is not a torn hamstring or a broken clavicle that under most circumstances will heal in a predictable amount of time. It is prudent to exclude the concussed patient from activities that carry a significant risk of reinjury until the symptoms have subsided. However, postconcussion symptoms are often vague and can be mistaken for or aggravated by a host of other conditions including learning disabilities, anxiety, and depression.

I hope that our experience with the COVID pandemic has taught us that removing children from school and their usual activities can have a serious negative effect on their emotional health and academic achievement. This seems to be particularly true for the young people who were already struggling to adjust to being a student. Getting out of the habit of going to school often intensifies the anxieties of an emotionally or academically challenged student. Each day away from the school atmosphere can compound the symptoms that may or may not have been triggered by the concussion.

The message here is clear that, whether we are talking about concussions or appendectomies or mononucleosis, the sooner we can return the child to something close to their old normal the more successful we will be in a helping them adjust to the new normal.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].