Neurology Reviews

Intravenous (IV) administration of the antiplatelet agent tirofiban for 72 hours was associated with a reduction in early neurologic deterioration compared with oral aspirin therapy in patients with acute ischemic stroke, in the randomized TREND trial.

The results were presented at the International Stroke Conference 2024, held on February 7-9 in Phoenix, Arizona.

Lead author Zhao Wenbo, MD, Xuanwu Hospital, Beijing, China, noted that neurologic deterioration, characterized by a sudden onset and quick peak of neurologic deficits, is a common phenomenon in acute ischemic stroke and is strongly associated with poor clinical outcomes.

Ischemic stroke progression is the main cause of neurologic deterioration, especially during the first few days after onset, Dr. Wenbo said. Several clinical studies have found that intensive antiplatelet therapy may prevent early neurologic deterioration and improve functional outcomes, but administering oral antiplatelet agents can be difficult because of dysphagia, he reported.

The TREND trial was conducted to investigate whether IV tirofiban could prevent early neurologic deterioration without increasing the risk for symptomatic intracerebral hemorrhage in acute ischemic stroke.

The study included 426 patients with acute ischemic stroke within 24 hours of symptom onset who had a neurologic deficit attributed to focal cerebral ischemia and a National Institutes of Health Stroke Scale (NIHSS) score between 4 and 20 points and who were not treated with thrombolysis or endovascular thrombectomy. Patients with cardioembolic stroke were also excluded.

Patients were a median of 10-12 hours from symptom onset and had a baseline NIHSS score of 5.

They were randomized to IV tirofiban or oral aspirin for 72 hours. All patients were then continued on oral antiplatelet therapy.

The primary efficacy outcome was neurologic deterioration within 72 hours after randomization, defined as an increase in NIHSS score of 4 points or more.

This occurred in nine patients (4.2%) in the tirofiban group vs 28 (13.2%) in the control group (relative risk, 0.32; 95% CI, 0.15-0.66; P = .002).

A consistent benefit of IV tirofiban was seen across all subgroups.

The secondary endpoint of neurologic deterioration within 72 hours after randomization, defined as an increase of NIHSS score of 2 points or more, was also significantly reduced. This occurred in 11.7% of the tirofiban group vs 23.6% of the aspirin group (RR, 0.49; 95% CI, 0.32-0.75; P = .001).

An excellent outcome on the modified Rankin Scale (mRS) disability score (mRS, 0-1) at 90 days was seen in 75% of tirofiban vs 68% of aspirin patients, a nonsignificant difference.

A good outcome (mRS, 0-2) occurred in 89% of tirofiban vs 86% of aspirin patients, again a nonsignificant difference.

There were no symptomatic intracerebral hemorrhages within 72 hours after randomization (the primary safety endpoint) in either group, and the incidence of systemic bleeding also did not differ significantly between the groups.

Dr. Wenbo concluded that further randomized clinical trials are needed to determine the efficacy of tirofiban on functional outcomes.

‘Promising Results’

Commenting on the study for this news organization, conference chair, Tudor Jovin, MD, Cooper Medical School of Rowan University, Camden, New Jersey, and vice-chair, Lauren Sansing, MD, Yale School of Medicine, New Haven, Connecticut, both said they thought the results were promising.

“This study didn’t show any long-term outcome benefit, but this was a smaller study, and the results need to be replicated in a larger study with sufficient power to look at longer-term outcomes,” Sansing noted. “But we don’t have anything better than aspirin at present for these patients, so it’s exciting that there may be something in the pipeline for this group.”

Dr. Jovin pointed out that the TREND trial selected patients on the cause of their stroke, in line with the practice of precision medicine.

“By excluding patients who received thrombolysis or thrombectomy and those who had cardioembolic strokes, we are left with a population who we don’t have many treatment options for,” he said. “These are patients with smaller or moderate strokes who may arrive too late for thrombolysis. It would be great to be able to do something more than just aspirin for these patients.”

Dr. Jovin noted that the study was underpowered to show long-term benefits, but there were some promising trends.

“It stands to reason that if neurologic function does not get worse in the early hours and days after stroke, then the long-term outcomes are likely to be better,” he noted. “But this needs to be confirmed in larger trials.”

Interestingly, another study, the MOST trial, also presented at the ISC-24 meeting, showed no benefit with the IV antithrombotic agents argatroban or eptifibatide on 90-day functional outcomes when added to thrombolysis in acute ischemic stroke.

Dr. Jovin pointed out that the MOST and TREND trials included different populations of patients — the MOST patients received thrombolysis, while the TREND patients did not. And in the MOST trial, about half the patients had a large vessel occlusion and underwent thrombectomy, whereas these patients were excluded in TREND.

Dr. Sansing added that patients in the TREND trial may have had small vessel disease or other atherosclerotic disease, or strokes due to the narrowing of vessels or due to an unknown cause. They were also given 3 days of IV tirofiban, whereas the duration of antithrombotic treatment in MOST was shorter.

The TREND study was funded by the National Key Research and Development Program of China, the National Science Foundation of Beijing Municipality, and the Beijing Municipal Science and Technology Commission.

A version of this article appeared on Medscape.com.

Intravenous (IV) administration of the antiplatelet agent tirofiban for 72 hours was associated with a reduction in early neurologic deterioration compared with oral aspirin therapy in patients with acute ischemic stroke, in the randomized TREND trial.

The results were presented at the International Stroke Conference 2024, held on February 7-9 in Phoenix, Arizona.

Lead author Zhao Wenbo, MD, Xuanwu Hospital, Beijing, China, noted that neurologic deterioration, characterized by a sudden onset and quick peak of neurologic deficits, is a common phenomenon in acute ischemic stroke and is strongly associated with poor clinical outcomes.

Ischemic stroke progression is the main cause of neurologic deterioration, especially during the first few days after onset, Dr. Wenbo said. Several clinical studies have found that intensive antiplatelet therapy may prevent early neurologic deterioration and improve functional outcomes, but administering oral antiplatelet agents can be difficult because of dysphagia, he reported.

The TREND trial was conducted to investigate whether IV tirofiban could prevent early neurologic deterioration without increasing the risk for symptomatic intracerebral hemorrhage in acute ischemic stroke.

The study included 426 patients with acute ischemic stroke within 24 hours of symptom onset who had a neurologic deficit attributed to focal cerebral ischemia and a National Institutes of Health Stroke Scale (NIHSS) score between 4 and 20 points and who were not treated with thrombolysis or endovascular thrombectomy. Patients with cardioembolic stroke were also excluded.

Patients were a median of 10-12 hours from symptom onset and had a baseline NIHSS score of 5.

They were randomized to IV tirofiban or oral aspirin for 72 hours. All patients were then continued on oral antiplatelet therapy.

The primary efficacy outcome was neurologic deterioration within 72 hours after randomization, defined as an increase in NIHSS score of 4 points or more.

This occurred in nine patients (4.2%) in the tirofiban group vs 28 (13.2%) in the control group (relative risk, 0.32; 95% CI, 0.15-0.66; P = .002).

A consistent benefit of IV tirofiban was seen across all subgroups.

The secondary endpoint of neurologic deterioration within 72 hours after randomization, defined as an increase of NIHSS score of 2 points or more, was also significantly reduced. This occurred in 11.7% of the tirofiban group vs 23.6% of the aspirin group (RR, 0.49; 95% CI, 0.32-0.75; P = .001).

An excellent outcome on the modified Rankin Scale (mRS) disability score (mRS, 0-1) at 90 days was seen in 75% of tirofiban vs 68% of aspirin patients, a nonsignificant difference.

A good outcome (mRS, 0-2) occurred in 89% of tirofiban vs 86% of aspirin patients, again a nonsignificant difference.

There were no symptomatic intracerebral hemorrhages within 72 hours after randomization (the primary safety endpoint) in either group, and the incidence of systemic bleeding also did not differ significantly between the groups.

Dr. Wenbo concluded that further randomized clinical trials are needed to determine the efficacy of tirofiban on functional outcomes.

‘Promising Results’

Commenting on the study for this news organization, conference chair, Tudor Jovin, MD, Cooper Medical School of Rowan University, Camden, New Jersey, and vice-chair, Lauren Sansing, MD, Yale School of Medicine, New Haven, Connecticut, both said they thought the results were promising.

“This study didn’t show any long-term outcome benefit, but this was a smaller study, and the results need to be replicated in a larger study with sufficient power to look at longer-term outcomes,” Sansing noted. “But we don’t have anything better than aspirin at present for these patients, so it’s exciting that there may be something in the pipeline for this group.”

Dr. Jovin pointed out that the TREND trial selected patients on the cause of their stroke, in line with the practice of precision medicine.

“By excluding patients who received thrombolysis or thrombectomy and those who had cardioembolic strokes, we are left with a population who we don’t have many treatment options for,” he said. “These are patients with smaller or moderate strokes who may arrive too late for thrombolysis. It would be great to be able to do something more than just aspirin for these patients.”

Dr. Jovin noted that the study was underpowered to show long-term benefits, but there were some promising trends.

“It stands to reason that if neurologic function does not get worse in the early hours and days after stroke, then the long-term outcomes are likely to be better,” he noted. “But this needs to be confirmed in larger trials.”

Interestingly, another study, the MOST trial, also presented at the ISC-24 meeting, showed no benefit with the IV antithrombotic agents argatroban or eptifibatide on 90-day functional outcomes when added to thrombolysis in acute ischemic stroke.

Dr. Jovin pointed out that the MOST and TREND trials included different populations of patients — the MOST patients received thrombolysis, while the TREND patients did not. And in the MOST trial, about half the patients had a large vessel occlusion and underwent thrombectomy, whereas these patients were excluded in TREND.

Dr. Sansing added that patients in the TREND trial may have had small vessel disease or other atherosclerotic disease, or strokes due to the narrowing of vessels or due to an unknown cause. They were also given 3 days of IV tirofiban, whereas the duration of antithrombotic treatment in MOST was shorter.

The TREND study was funded by the National Key Research and Development Program of China, the National Science Foundation of Beijing Municipality, and the Beijing Municipal Science and Technology Commission.

A version of this article appeared on Medscape.com.

Intravenous (IV) administration of the antiplatelet agent tirofiban for 72 hours was associated with a reduction in early neurologic deterioration compared with oral aspirin therapy in patients with acute ischemic stroke, in the randomized TREND trial.

The results were presented at the International Stroke Conference 2024, held on February 7-9 in Phoenix, Arizona.

Lead author Zhao Wenbo, MD, Xuanwu Hospital, Beijing, China, noted that neurologic deterioration, characterized by a sudden onset and quick peak of neurologic deficits, is a common phenomenon in acute ischemic stroke and is strongly associated with poor clinical outcomes.

Ischemic stroke progression is the main cause of neurologic deterioration, especially during the first few days after onset, Dr. Wenbo said. Several clinical studies have found that intensive antiplatelet therapy may prevent early neurologic deterioration and improve functional outcomes, but administering oral antiplatelet agents can be difficult because of dysphagia, he reported.

The TREND trial was conducted to investigate whether IV tirofiban could prevent early neurologic deterioration without increasing the risk for symptomatic intracerebral hemorrhage in acute ischemic stroke.

The study included 426 patients with acute ischemic stroke within 24 hours of symptom onset who had a neurologic deficit attributed to focal cerebral ischemia and a National Institutes of Health Stroke Scale (NIHSS) score between 4 and 20 points and who were not treated with thrombolysis or endovascular thrombectomy. Patients with cardioembolic stroke were also excluded.

Patients were a median of 10-12 hours from symptom onset and had a baseline NIHSS score of 5.

They were randomized to IV tirofiban or oral aspirin for 72 hours. All patients were then continued on oral antiplatelet therapy.

The primary efficacy outcome was neurologic deterioration within 72 hours after randomization, defined as an increase in NIHSS score of 4 points or more.

This occurred in nine patients (4.2%) in the tirofiban group vs 28 (13.2%) in the control group (relative risk, 0.32; 95% CI, 0.15-0.66; P = .002).

A consistent benefit of IV tirofiban was seen across all subgroups.

The secondary endpoint of neurologic deterioration within 72 hours after randomization, defined as an increase of NIHSS score of 2 points or more, was also significantly reduced. This occurred in 11.7% of the tirofiban group vs 23.6% of the aspirin group (RR, 0.49; 95% CI, 0.32-0.75; P = .001).

An excellent outcome on the modified Rankin Scale (mRS) disability score (mRS, 0-1) at 90 days was seen in 75% of tirofiban vs 68% of aspirin patients, a nonsignificant difference.

A good outcome (mRS, 0-2) occurred in 89% of tirofiban vs 86% of aspirin patients, again a nonsignificant difference.

There were no symptomatic intracerebral hemorrhages within 72 hours after randomization (the primary safety endpoint) in either group, and the incidence of systemic bleeding also did not differ significantly between the groups.

Dr. Wenbo concluded that further randomized clinical trials are needed to determine the efficacy of tirofiban on functional outcomes.

‘Promising Results’

Commenting on the study for this news organization, conference chair, Tudor Jovin, MD, Cooper Medical School of Rowan University, Camden, New Jersey, and vice-chair, Lauren Sansing, MD, Yale School of Medicine, New Haven, Connecticut, both said they thought the results were promising.

“This study didn’t show any long-term outcome benefit, but this was a smaller study, and the results need to be replicated in a larger study with sufficient power to look at longer-term outcomes,” Sansing noted. “But we don’t have anything better than aspirin at present for these patients, so it’s exciting that there may be something in the pipeline for this group.”

Dr. Jovin pointed out that the TREND trial selected patients on the cause of their stroke, in line with the practice of precision medicine.

“By excluding patients who received thrombolysis or thrombectomy and those who had cardioembolic strokes, we are left with a population who we don’t have many treatment options for,” he said. “These are patients with smaller or moderate strokes who may arrive too late for thrombolysis. It would be great to be able to do something more than just aspirin for these patients.”

Dr. Jovin noted that the study was underpowered to show long-term benefits, but there were some promising trends.

“It stands to reason that if neurologic function does not get worse in the early hours and days after stroke, then the long-term outcomes are likely to be better,” he noted. “But this needs to be confirmed in larger trials.”

Interestingly, another study, the MOST trial, also presented at the ISC-24 meeting, showed no benefit with the IV antithrombotic agents argatroban or eptifibatide on 90-day functional outcomes when added to thrombolysis in acute ischemic stroke.

Dr. Jovin pointed out that the MOST and TREND trials included different populations of patients — the MOST patients received thrombolysis, while the TREND patients did not. And in the MOST trial, about half the patients had a large vessel occlusion and underwent thrombectomy, whereas these patients were excluded in TREND.

Dr. Sansing added that patients in the TREND trial may have had small vessel disease or other atherosclerotic disease, or strokes due to the narrowing of vessels or due to an unknown cause. They were also given 3 days of IV tirofiban, whereas the duration of antithrombotic treatment in MOST was shorter.

The TREND study was funded by the National Key Research and Development Program of China, the National Science Foundation of Beijing Municipality, and the Beijing Municipal Science and Technology Commission.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the Division of Medical Ethics at the New York University Grossman School of Medicine in New York City.

I think we had a breakthrough on a very controversial subject over the past month. Over and over again, debates have been breaking out, cases have been going to court, and fights have been coming to ethics committees about brain death. How do we know what brain death is, how do we diagnose it, and what rights do families have with respect to the diagnosis?

The American Academy of Neurology decided to form a task force, and they just issued guidelines on the definition, tests to use it, and the rights of families. Whether you›re a neurologist, someone involved in actually diagnosing brain death, or you›re dealing with very ill people whose families are trying to direct the kinds of things that you or the nurses can do, these guidelines, I think, are excellent. They did a wonderful job, in my view. They›ve achieved clarity.

First, they tried to handle both adults and children. Children are, if you will, more difficult — and that’s been known — to test for brain death. Their brains are smaller. You get more interference and false signals coming from muscle or nerve activity that might be going on elsewhere in their bodies.

The guidelines say we’re going to try to see whether a person can breathe without support. If it’s an adult, one test over a 24-hour period would be sufficient. If you had them off the ventilator and they can’t breathe and show no signs of being able to do that, that’s a very fundamental test for brain death. For children, you’re going to have to do it twice. The guidelines are saying to be cautious.

Second, they say it’s very important to know the cause of the suspected brain death condition. If someone has a massive head injury, that’s different from a situation in which someone overdoses from drugs or drowns. Those conditions can be a little deceptive. In the case of drowning, sometimes the brain has protective mechanisms to protect circulation to the brain naturally for a little bit of time. I’m talking about minutes, not hours.

You want to be careful to make sure that you know the cause of the massive brain injury or insult that makes someone believe that the patient is brain-dead, whether it’s a stroke, an embolism, a bleed, a gunshot wound, or trauma to the head. Those factors really drive the certainty with which brain death should be pronounced. I think that’s very, very important.

They also said that brain death means the permanent loss of brain function. You may get a few cells still firing or you may be in a situation, because the life support is still there, where the body looks pink and perhaps might appear to still be alive to someone. When you know that the damage to the brain is so severe that there’s nothing that can be done to bring back the support of heart function, breathing, and most likely any ability to sense or feel anything, that is death.

I believe it’s very important, when talking to families, to say there are two ways that we pronounce people dead, and they’re equal: One is to say their heart has stopped, their breathing has stopped, and there’s nothing we can do to resuscitate them, which is cardiac death. The other is to say their brain has permanently ceased to function in any kind of integrated way. That means no heartbeat, no breathing, and no mental sensations. That is death.

In approaching families, it is critical that doctors and nurses don’t say, “Your relative is brain-dead.” That gives the family a sense that maybe they’re only “partially dead” or maybe there’s one key organ that has stopped working but maybe you can bring it back. Death is death. The law recognizes both cardiac death and brain death as death.

When you approach a family, if you believe that death has occurred, you say, “I’m very sorry. With regret, I have to tell you, your loved one is dead.” If they ask how you know, you can say, “We’ve determined it through brain death or through cardiac death.” You don’t give them a sense that people could be kind of dead, sort of dead, or nearly dead. Those states are comas or permanent vegetative states; they’re not the same as death.

What if the family says, “I don’t want you to do any testing. I don’t want to find out whether my relative is dead”? The American Academy of Neurology looked at this carefully and said that any test for death can be done without the permission or consent of the family. They said that because doctors need to know what steps to take to treat someone.

If a person is dead, then treatment is going to stop. It may not stop immediately. There may be issues about organ donation. There may be issues about gathering the family to come to the bedside to say goodbye, because many people think that’s more humane than saying goodbye at the morgue or in another setting.

This is all well and good, but patients cannot protect against bad news when it comes to death. We don’t want to be doing things to the dead that cost money or are futile because of death and using resources that might go to others.

We’ve got much more clarity than we have ever had with respect to the issue of brain death and how it works in any hospital. We have certain tests, including being off the ventilator and some other tests, that the guidelines supply. We know we have to be more careful with children. We want to know the etiology of the cause of the brain trauma, the devastating brain injury, to be sure that this is something that really is permanent cessation of integrated brain function.

We know that if you believe the person has died, you don’t need the consent of the family in order to do a brain-death test. You have to do it because there is no point in continuing treatment in expensive ICU settings and denying resources to others who might want to use those resources. The family can’t hold the medical team hostage.

We do know that when we approach someone with the determination, whatever it is, we should lead by saying that the person has died and then explain how that was determined, whether it be by cardiac death pronouncement — where you tried to resuscitate and the heart’s not beating — or brain-death analysis.

I’m Art Caplan at the Division of Medical Ethics at the NYU Grossman School of Medicine. Thanks for watching.

Dr. Caplan has disclosed the following relevant financial relationships: Served as a director, officer, partner, employee, advisor, consultant, or trustee for: Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position); serves as a contributing author and adviser for this news organization.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the Division of Medical Ethics at the New York University Grossman School of Medicine in New York City.

I think we had a breakthrough on a very controversial subject over the past month. Over and over again, debates have been breaking out, cases have been going to court, and fights have been coming to ethics committees about brain death. How do we know what brain death is, how do we diagnose it, and what rights do families have with respect to the diagnosis?

The American Academy of Neurology decided to form a task force, and they just issued guidelines on the definition, tests to use it, and the rights of families. Whether you›re a neurologist, someone involved in actually diagnosing brain death, or you›re dealing with very ill people whose families are trying to direct the kinds of things that you or the nurses can do, these guidelines, I think, are excellent. They did a wonderful job, in my view. They›ve achieved clarity.

First, they tried to handle both adults and children. Children are, if you will, more difficult — and that’s been known — to test for brain death. Their brains are smaller. You get more interference and false signals coming from muscle or nerve activity that might be going on elsewhere in their bodies.

The guidelines say we’re going to try to see whether a person can breathe without support. If it’s an adult, one test over a 24-hour period would be sufficient. If you had them off the ventilator and they can’t breathe and show no signs of being able to do that, that’s a very fundamental test for brain death. For children, you’re going to have to do it twice. The guidelines are saying to be cautious.

Second, they say it’s very important to know the cause of the suspected brain death condition. If someone has a massive head injury, that’s different from a situation in which someone overdoses from drugs or drowns. Those conditions can be a little deceptive. In the case of drowning, sometimes the brain has protective mechanisms to protect circulation to the brain naturally for a little bit of time. I’m talking about minutes, not hours.

You want to be careful to make sure that you know the cause of the massive brain injury or insult that makes someone believe that the patient is brain-dead, whether it’s a stroke, an embolism, a bleed, a gunshot wound, or trauma to the head. Those factors really drive the certainty with which brain death should be pronounced. I think that’s very, very important.

They also said that brain death means the permanent loss of brain function. You may get a few cells still firing or you may be in a situation, because the life support is still there, where the body looks pink and perhaps might appear to still be alive to someone. When you know that the damage to the brain is so severe that there’s nothing that can be done to bring back the support of heart function, breathing, and most likely any ability to sense or feel anything, that is death.

I believe it’s very important, when talking to families, to say there are two ways that we pronounce people dead, and they’re equal: One is to say their heart has stopped, their breathing has stopped, and there’s nothing we can do to resuscitate them, which is cardiac death. The other is to say their brain has permanently ceased to function in any kind of integrated way. That means no heartbeat, no breathing, and no mental sensations. That is death.

In approaching families, it is critical that doctors and nurses don’t say, “Your relative is brain-dead.” That gives the family a sense that maybe they’re only “partially dead” or maybe there’s one key organ that has stopped working but maybe you can bring it back. Death is death. The law recognizes both cardiac death and brain death as death.

When you approach a family, if you believe that death has occurred, you say, “I’m very sorry. With regret, I have to tell you, your loved one is dead.” If they ask how you know, you can say, “We’ve determined it through brain death or through cardiac death.” You don’t give them a sense that people could be kind of dead, sort of dead, or nearly dead. Those states are comas or permanent vegetative states; they’re not the same as death.

What if the family says, “I don’t want you to do any testing. I don’t want to find out whether my relative is dead”? The American Academy of Neurology looked at this carefully and said that any test for death can be done without the permission or consent of the family. They said that because doctors need to know what steps to take to treat someone.

If a person is dead, then treatment is going to stop. It may not stop immediately. There may be issues about organ donation. There may be issues about gathering the family to come to the bedside to say goodbye, because many people think that’s more humane than saying goodbye at the morgue or in another setting.

This is all well and good, but patients cannot protect against bad news when it comes to death. We don’t want to be doing things to the dead that cost money or are futile because of death and using resources that might go to others.

We’ve got much more clarity than we have ever had with respect to the issue of brain death and how it works in any hospital. We have certain tests, including being off the ventilator and some other tests, that the guidelines supply. We know we have to be more careful with children. We want to know the etiology of the cause of the brain trauma, the devastating brain injury, to be sure that this is something that really is permanent cessation of integrated brain function.

We know that if you believe the person has died, you don’t need the consent of the family in order to do a brain-death test. You have to do it because there is no point in continuing treatment in expensive ICU settings and denying resources to others who might want to use those resources. The family can’t hold the medical team hostage.

We do know that when we approach someone with the determination, whatever it is, we should lead by saying that the person has died and then explain how that was determined, whether it be by cardiac death pronouncement — where you tried to resuscitate and the heart’s not beating — or brain-death analysis.

I’m Art Caplan at the Division of Medical Ethics at the NYU Grossman School of Medicine. Thanks for watching.

Dr. Caplan has disclosed the following relevant financial relationships: Served as a director, officer, partner, employee, advisor, consultant, or trustee for: Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position); serves as a contributing author and adviser for this news organization.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the Division of Medical Ethics at the New York University Grossman School of Medicine in New York City.

I think we had a breakthrough on a very controversial subject over the past month. Over and over again, debates have been breaking out, cases have been going to court, and fights have been coming to ethics committees about brain death. How do we know what brain death is, how do we diagnose it, and what rights do families have with respect to the diagnosis?

The American Academy of Neurology decided to form a task force, and they just issued guidelines on the definition, tests to use it, and the rights of families. Whether you›re a neurologist, someone involved in actually diagnosing brain death, or you›re dealing with very ill people whose families are trying to direct the kinds of things that you or the nurses can do, these guidelines, I think, are excellent. They did a wonderful job, in my view. They›ve achieved clarity.

First, they tried to handle both adults and children. Children are, if you will, more difficult — and that’s been known — to test for brain death. Their brains are smaller. You get more interference and false signals coming from muscle or nerve activity that might be going on elsewhere in their bodies.

The guidelines say we’re going to try to see whether a person can breathe without support. If it’s an adult, one test over a 24-hour period would be sufficient. If you had them off the ventilator and they can’t breathe and show no signs of being able to do that, that’s a very fundamental test for brain death. For children, you’re going to have to do it twice. The guidelines are saying to be cautious.

Second, they say it’s very important to know the cause of the suspected brain death condition. If someone has a massive head injury, that’s different from a situation in which someone overdoses from drugs or drowns. Those conditions can be a little deceptive. In the case of drowning, sometimes the brain has protective mechanisms to protect circulation to the brain naturally for a little bit of time. I’m talking about minutes, not hours.

You want to be careful to make sure that you know the cause of the massive brain injury or insult that makes someone believe that the patient is brain-dead, whether it’s a stroke, an embolism, a bleed, a gunshot wound, or trauma to the head. Those factors really drive the certainty with which brain death should be pronounced. I think that’s very, very important.

They also said that brain death means the permanent loss of brain function. You may get a few cells still firing or you may be in a situation, because the life support is still there, where the body looks pink and perhaps might appear to still be alive to someone. When you know that the damage to the brain is so severe that there’s nothing that can be done to bring back the support of heart function, breathing, and most likely any ability to sense or feel anything, that is death.

I believe it’s very important, when talking to families, to say there are two ways that we pronounce people dead, and they’re equal: One is to say their heart has stopped, their breathing has stopped, and there’s nothing we can do to resuscitate them, which is cardiac death. The other is to say their brain has permanently ceased to function in any kind of integrated way. That means no heartbeat, no breathing, and no mental sensations. That is death.

In approaching families, it is critical that doctors and nurses don’t say, “Your relative is brain-dead.” That gives the family a sense that maybe they’re only “partially dead” or maybe there’s one key organ that has stopped working but maybe you can bring it back. Death is death. The law recognizes both cardiac death and brain death as death.

When you approach a family, if you believe that death has occurred, you say, “I’m very sorry. With regret, I have to tell you, your loved one is dead.” If they ask how you know, you can say, “We’ve determined it through brain death or through cardiac death.” You don’t give them a sense that people could be kind of dead, sort of dead, or nearly dead. Those states are comas or permanent vegetative states; they’re not the same as death.

What if the family says, “I don’t want you to do any testing. I don’t want to find out whether my relative is dead”? The American Academy of Neurology looked at this carefully and said that any test for death can be done without the permission or consent of the family. They said that because doctors need to know what steps to take to treat someone.

If a person is dead, then treatment is going to stop. It may not stop immediately. There may be issues about organ donation. There may be issues about gathering the family to come to the bedside to say goodbye, because many people think that’s more humane than saying goodbye at the morgue or in another setting.

This is all well and good, but patients cannot protect against bad news when it comes to death. We don’t want to be doing things to the dead that cost money or are futile because of death and using resources that might go to others.

We’ve got much more clarity than we have ever had with respect to the issue of brain death and how it works in any hospital. We have certain tests, including being off the ventilator and some other tests, that the guidelines supply. We know we have to be more careful with children. We want to know the etiology of the cause of the brain trauma, the devastating brain injury, to be sure that this is something that really is permanent cessation of integrated brain function.

We know that if you believe the person has died, you don’t need the consent of the family in order to do a brain-death test. You have to do it because there is no point in continuing treatment in expensive ICU settings and denying resources to others who might want to use those resources. The family can’t hold the medical team hostage.

We do know that when we approach someone with the determination, whatever it is, we should lead by saying that the person has died and then explain how that was determined, whether it be by cardiac death pronouncement — where you tried to resuscitate and the heart’s not beating — or brain-death analysis.

I’m Art Caplan at the Division of Medical Ethics at the NYU Grossman School of Medicine. Thanks for watching.

Dr. Caplan has disclosed the following relevant financial relationships: Served as a director, officer, partner, employee, advisor, consultant, or trustee for: Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position); serves as a contributing author and adviser for this news organization.

A version of this article appeared on Medscape.com.

In my mind’s calendar, two dates stand out. Both far enough away that I don’t have to think about them too much right now, but near enough that they can’t be forgotten about, either.

On September 30, 2028, my office lease ends, and in 2029 my neurology board certification has to be renewed. I’ll be in my early 60s then and I’ve been a practicing neurologist for 30 years.

I have no idea what I’m going to do. Of course, a lot can happen between now and then, and a lot of variables come into the calculus of when to retire.

After all these years, I still enjoy my job. It gives me the purpose that I wanted so long ago when I applied to medical school. The late William Pancoe, associate dean when I was at Creighton, always told us to remember how we felt when we got that acceptance letter — we’d need it to keep us going through medical school.

And, even now, I still remember the call from my dad that it had arrived. What a moment that was. I have no regrets. I can’t imagine doing anything else.

But in 4 years how much longer will I want to practice? Hopefully I’ll be faced with that decision. Will I want to renew the lease for 2 years? 5 years? I like my little office. It’s far from gleaming, there’s no TV or Keurig in the lobby, the carpet, paint, and furnishings are still from the early 90s when the place was built. But it’s my home away from home. I spend anywhere from 40-60 hours/week there. It’s quiet and (at least for me) cozy. Would I want to give that up and move to a smaller, shared place, for the remainder of my career? Or just close down?

Likewise, will I want to renew my board certification? Granted, that isn’t necessary to practice, but it certainly looks better to have it. To do that I’ll have to fork over a decent chunk of change to take the test, more money for a review course, and spend some time studying. Strange to think that at 63 I might be back at my desk (same desk, by the way) studying for a test like I did in college and medical school. But, if I want to keep playing doctor, that’s what I’ll have to do.

Four years to think about this. The same amount of time I spent each in high school, medical school, and residency. For that matter, the same amount of time since we all went into quarantine.

Doesn’t seem that long, does it?

I guess I’ve got some thinking to do.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In my mind’s calendar, two dates stand out. Both far enough away that I don’t have to think about them too much right now, but near enough that they can’t be forgotten about, either.

On September 30, 2028, my office lease ends, and in 2029 my neurology board certification has to be renewed. I’ll be in my early 60s then and I’ve been a practicing neurologist for 30 years.

I have no idea what I’m going to do. Of course, a lot can happen between now and then, and a lot of variables come into the calculus of when to retire.

After all these years, I still enjoy my job. It gives me the purpose that I wanted so long ago when I applied to medical school. The late William Pancoe, associate dean when I was at Creighton, always told us to remember how we felt when we got that acceptance letter — we’d need it to keep us going through medical school.

And, even now, I still remember the call from my dad that it had arrived. What a moment that was. I have no regrets. I can’t imagine doing anything else.

But in 4 years how much longer will I want to practice? Hopefully I’ll be faced with that decision. Will I want to renew the lease for 2 years? 5 years? I like my little office. It’s far from gleaming, there’s no TV or Keurig in the lobby, the carpet, paint, and furnishings are still from the early 90s when the place was built. But it’s my home away from home. I spend anywhere from 40-60 hours/week there. It’s quiet and (at least for me) cozy. Would I want to give that up and move to a smaller, shared place, for the remainder of my career? Or just close down?

Likewise, will I want to renew my board certification? Granted, that isn’t necessary to practice, but it certainly looks better to have it. To do that I’ll have to fork over a decent chunk of change to take the test, more money for a review course, and spend some time studying. Strange to think that at 63 I might be back at my desk (same desk, by the way) studying for a test like I did in college and medical school. But, if I want to keep playing doctor, that’s what I’ll have to do.

Four years to think about this. The same amount of time I spent each in high school, medical school, and residency. For that matter, the same amount of time since we all went into quarantine.

Doesn’t seem that long, does it?

I guess I’ve got some thinking to do.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In my mind’s calendar, two dates stand out. Both far enough away that I don’t have to think about them too much right now, but near enough that they can’t be forgotten about, either.

On September 30, 2028, my office lease ends, and in 2029 my neurology board certification has to be renewed. I’ll be in my early 60s then and I’ve been a practicing neurologist for 30 years.

I have no idea what I’m going to do. Of course, a lot can happen between now and then, and a lot of variables come into the calculus of when to retire.

After all these years, I still enjoy my job. It gives me the purpose that I wanted so long ago when I applied to medical school. The late William Pancoe, associate dean when I was at Creighton, always told us to remember how we felt when we got that acceptance letter — we’d need it to keep us going through medical school.

And, even now, I still remember the call from my dad that it had arrived. What a moment that was. I have no regrets. I can’t imagine doing anything else.

But in 4 years how much longer will I want to practice? Hopefully I’ll be faced with that decision. Will I want to renew the lease for 2 years? 5 years? I like my little office. It’s far from gleaming, there’s no TV or Keurig in the lobby, the carpet, paint, and furnishings are still from the early 90s when the place was built. But it’s my home away from home. I spend anywhere from 40-60 hours/week there. It’s quiet and (at least for me) cozy. Would I want to give that up and move to a smaller, shared place, for the remainder of my career? Or just close down?

Likewise, will I want to renew my board certification? Granted, that isn’t necessary to practice, but it certainly looks better to have it. To do that I’ll have to fork over a decent chunk of change to take the test, more money for a review course, and spend some time studying. Strange to think that at 63 I might be back at my desk (same desk, by the way) studying for a test like I did in college and medical school. But, if I want to keep playing doctor, that’s what I’ll have to do.

Four years to think about this. The same amount of time I spent each in high school, medical school, and residency. For that matter, the same amount of time since we all went into quarantine.

Doesn’t seem that long, does it?

I guess I’ve got some thinking to do.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Has COVID replaced syphilis as the great imitator? At the turn of the 20th century, Sir William Osler was quoted as saying, “He who knows syphilis knows medicine.”

If you have any doubts about the “imitator” analogy, simply use any broad search engine or AI portal and enter “what is the differential diagnosis of primary syphilis, or secondary syphilis, or tertiary syphilis?” A plethora of diseases across many body systems appears.
 

Another Great Pretender?

Did you or do you now have long COVID? How do you know? Do you even know what long COVID is? How would you diagnosis it?

When asked about long COVID, this is what large language model source bard.google.com had to say:

Long COVID, also known as post-COVID conditions or PASC, is a complex condition that can occur in people who have had COVID-19, even if their initial illness was mild or even asymptomatic. It’s characterized by a wide range of symptoms that can last for weeks, months, or even years after the initial infection.

Symptoms of long COVID can include: fatigue, shortness of breath, brain fog (trouble thinking or concentrating), loss of smell or taste, sleep problems, muscle pain, joint pain, headache, dizziness, depression or anxiety, heart palpitations, gastrointestinal problems.

Duh!!! It reads much like a continuation of the symptoms of acute COVID. Bard continued:

The exact cause of long COVID is still unknown, but there are several theories. One possibility is that the virus itself can damage organs and tissues, leading to ongoing symptoms. Another possibility is that the immune system’s response to the virus can continue to cause inflammation even after the virus is gone.

Human intelligence source Wikipedia says this:

Long COVID or long-haul COVID is a group of health problems persisting or developing after an initial COVID-19 infection. Symptoms can last weeks, months or years and are often debilitating. The World Health Organization defines long COVID as starting three months after infection, but other definitions put the start of long COVID at four weeks.

Highly varied, including post-exertional malaise (symptoms made worse with effort), fatigue, muscle pain, shortness of breath, chest pain, and cognitive dysfunction (brain fog).
 

Acute COVID to Long COVID

The World Health Organization estimates that 36 million people in the European region have developed long COVID in the first 3 years of the pandemic. That›s a lot.

We all know that the common signs and symptoms of acute COVID-19 include fever or chills, a dry cough and shortness of breath, feeling very tired, muscle or body aches, headache, loss of taste or smell, sore throat, congestion, runny nose, nausea, vomiting, and diarrhea. Except for the taste and smell findings, every one of these symptoms or signs could indicate a different virus infection or even some type of allergy. My point is the nonspecificity in this list.

Uncommon signs and symptoms of acute COVID include a flat skin rash covered with small bumps, discolored swollen areas on the fingers and toes (COVID toes), and hives. The skin of hands, wrists, or ankles also can be affected. Blisters, itchiness, rough skin, or pus can be seen.

Severe confusion (delirium) might be the main or only symptom of COVID-19 in older people. This COVID-19 symptom is linked with a high risk for poor outcomes, including death. Pink eye (conjunctivitis) can be a COVID-19 symptom. Other eye problems linked to COVID-19 are light sensitivity, sore eyes, and itchy eyes. Acute myocarditis, tinnitus, vertigo, and hearing loss have been reported. And 1-4 weeks after the onset of COVID-19 infection, a patient may experience de novo reactive synovitis and arthritis of any joints.

So, take your pick. Myriad symptoms, signs, diseases, diagnoses, and organ systems — still present, recurring, just appearing, apparently de novo, or after asymptomatic infection. We have so much still to learn.

What big-time symptoms, signs, and major diseases are not on any of these lists? Obviously, cancer, atherosclerotic cardiovascular diseases, obesity, bone diseases, and competitive infections. But be patient; the lingering effects of direct tissue invasion by the virus as well as a wide range of immunologic reactions may just be getting started. Mitochondrial damage, especially in muscles, is increasingly a pathophysiologic suspect.

Human diseases can be physical or mental; and in COVID, that twain not only meet but mix and mingle freely, and may even merge into psychosoma. Don’t ever forget that. Consider “fatigue.” Who among us, COVID or NOVID, does not experience that from time to time?

Or consider brain fog as a common reported symptom of COVID. What on earth is that actually? How can a person know they have brain fog, or whether they had it and are over it?

We need one or more lab or other diagnostic tests that can objectively confirm the diagnosis of long COVID.
 

Useful Progress?

A recent research paper in Science reported intriguing chemical findings that seemed to point a finger at some form of complement dysregulation as a potential disease marker for long COVID. Unfortunately, some critics have pointed out that this entire study may be invalid or irrelevant because the New York cohort was recruited in 2020, before vaccines were available. The Zurich cohort was recruited up until April 2021, so some may have been vaccinated.

Then this news organization came along in early January 2024 with an article about COVID causing not only more than a million American deaths but also more than 5000 deaths from long COVID. We physicians don’t really know what long COVID even is, but we have to sign death certificates blaming thousands of deaths on it anyway? And rolling back the clock to 2020: Are patients dying from COVID or with COVID, according to death certificates?Now, armed with the knowledge that “documented serious post–COVID-19 conditions include cardiovascular, pulmonary, neurological, renal, endocrine, hematological, and gastrointestinal complications, as well as death,” CDC has published clear and fairly concise instructions on how to address post-acute COVID sequelae on death certificates.

In late January, this news organization painted a hopeful picture by naming four phenotypes of long COVID, suggesting that such divisions might further our understanding, including prognosis, and even therapy for this condition. Among the clinical phenotypes of (1) chronic fatigue–like syndrome, headache, and memory loss; (2) respiratory syndrome (which includes cough and difficulty breathing); (3) chronic pain; and (4) neurosensorial syndrome (which causes an altered sense of taste and smell), overlap is clearly possible but isn›t addressed.

I see these recent developments as needed and useful progress, but we are still left with…not much. So, when you tell me that you do or do not have long COVID, I will say to you, “How do you know?”

I also say: She/he/they who know COVID know medicine.

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

Has COVID replaced syphilis as the great imitator? At the turn of the 20th century, Sir William Osler was quoted as saying, “He who knows syphilis knows medicine.”

If you have any doubts about the “imitator” analogy, simply use any broad search engine or AI portal and enter “what is the differential diagnosis of primary syphilis, or secondary syphilis, or tertiary syphilis?” A plethora of diseases across many body systems appears.
 

Another Great Pretender?

Did you or do you now have long COVID? How do you know? Do you even know what long COVID is? How would you diagnosis it?

When asked about long COVID, this is what large language model source bard.google.com had to say:

Long COVID, also known as post-COVID conditions or PASC, is a complex condition that can occur in people who have had COVID-19, even if their initial illness was mild or even asymptomatic. It’s characterized by a wide range of symptoms that can last for weeks, months, or even years after the initial infection.

Symptoms of long COVID can include: fatigue, shortness of breath, brain fog (trouble thinking or concentrating), loss of smell or taste, sleep problems, muscle pain, joint pain, headache, dizziness, depression or anxiety, heart palpitations, gastrointestinal problems.

Duh!!! It reads much like a continuation of the symptoms of acute COVID. Bard continued:

The exact cause of long COVID is still unknown, but there are several theories. One possibility is that the virus itself can damage organs and tissues, leading to ongoing symptoms. Another possibility is that the immune system’s response to the virus can continue to cause inflammation even after the virus is gone.

Human intelligence source Wikipedia says this:

Long COVID or long-haul COVID is a group of health problems persisting or developing after an initial COVID-19 infection. Symptoms can last weeks, months or years and are often debilitating. The World Health Organization defines long COVID as starting three months after infection, but other definitions put the start of long COVID at four weeks.

Highly varied, including post-exertional malaise (symptoms made worse with effort), fatigue, muscle pain, shortness of breath, chest pain, and cognitive dysfunction (brain fog).
 

Acute COVID to Long COVID

The World Health Organization estimates that 36 million people in the European region have developed long COVID in the first 3 years of the pandemic. That›s a lot.

We all know that the common signs and symptoms of acute COVID-19 include fever or chills, a dry cough and shortness of breath, feeling very tired, muscle or body aches, headache, loss of taste or smell, sore throat, congestion, runny nose, nausea, vomiting, and diarrhea. Except for the taste and smell findings, every one of these symptoms or signs could indicate a different virus infection or even some type of allergy. My point is the nonspecificity in this list.

Uncommon signs and symptoms of acute COVID include a flat skin rash covered with small bumps, discolored swollen areas on the fingers and toes (COVID toes), and hives. The skin of hands, wrists, or ankles also can be affected. Blisters, itchiness, rough skin, or pus can be seen.

Severe confusion (delirium) might be the main or only symptom of COVID-19 in older people. This COVID-19 symptom is linked with a high risk for poor outcomes, including death. Pink eye (conjunctivitis) can be a COVID-19 symptom. Other eye problems linked to COVID-19 are light sensitivity, sore eyes, and itchy eyes. Acute myocarditis, tinnitus, vertigo, and hearing loss have been reported. And 1-4 weeks after the onset of COVID-19 infection, a patient may experience de novo reactive synovitis and arthritis of any joints.

So, take your pick. Myriad symptoms, signs, diseases, diagnoses, and organ systems — still present, recurring, just appearing, apparently de novo, or after asymptomatic infection. We have so much still to learn.

What big-time symptoms, signs, and major diseases are not on any of these lists? Obviously, cancer, atherosclerotic cardiovascular diseases, obesity, bone diseases, and competitive infections. But be patient; the lingering effects of direct tissue invasion by the virus as well as a wide range of immunologic reactions may just be getting started. Mitochondrial damage, especially in muscles, is increasingly a pathophysiologic suspect.

Human diseases can be physical or mental; and in COVID, that twain not only meet but mix and mingle freely, and may even merge into psychosoma. Don’t ever forget that. Consider “fatigue.” Who among us, COVID or NOVID, does not experience that from time to time?

Or consider brain fog as a common reported symptom of COVID. What on earth is that actually? How can a person know they have brain fog, or whether they had it and are over it?

We need one or more lab or other diagnostic tests that can objectively confirm the diagnosis of long COVID.
 

Useful Progress?

A recent research paper in Science reported intriguing chemical findings that seemed to point a finger at some form of complement dysregulation as a potential disease marker for long COVID. Unfortunately, some critics have pointed out that this entire study may be invalid or irrelevant because the New York cohort was recruited in 2020, before vaccines were available. The Zurich cohort was recruited up until April 2021, so some may have been vaccinated.

Then this news organization came along in early January 2024 with an article about COVID causing not only more than a million American deaths but also more than 5000 deaths from long COVID. We physicians don’t really know what long COVID even is, but we have to sign death certificates blaming thousands of deaths on it anyway? And rolling back the clock to 2020: Are patients dying from COVID or with COVID, according to death certificates?Now, armed with the knowledge that “documented serious post–COVID-19 conditions include cardiovascular, pulmonary, neurological, renal, endocrine, hematological, and gastrointestinal complications, as well as death,” CDC has published clear and fairly concise instructions on how to address post-acute COVID sequelae on death certificates.

In late January, this news organization painted a hopeful picture by naming four phenotypes of long COVID, suggesting that such divisions might further our understanding, including prognosis, and even therapy for this condition. Among the clinical phenotypes of (1) chronic fatigue–like syndrome, headache, and memory loss; (2) respiratory syndrome (which includes cough and difficulty breathing); (3) chronic pain; and (4) neurosensorial syndrome (which causes an altered sense of taste and smell), overlap is clearly possible but isn›t addressed.

I see these recent developments as needed and useful progress, but we are still left with…not much. So, when you tell me that you do or do not have long COVID, I will say to you, “How do you know?”

I also say: She/he/they who know COVID know medicine.

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

Has COVID replaced syphilis as the great imitator? At the turn of the 20th century, Sir William Osler was quoted as saying, “He who knows syphilis knows medicine.”

If you have any doubts about the “imitator” analogy, simply use any broad search engine or AI portal and enter “what is the differential diagnosis of primary syphilis, or secondary syphilis, or tertiary syphilis?” A plethora of diseases across many body systems appears.
 

Another Great Pretender?

Did you or do you now have long COVID? How do you know? Do you even know what long COVID is? How would you diagnosis it?

When asked about long COVID, this is what large language model source bard.google.com had to say:

Long COVID, also known as post-COVID conditions or PASC, is a complex condition that can occur in people who have had COVID-19, even if their initial illness was mild or even asymptomatic. It’s characterized by a wide range of symptoms that can last for weeks, months, or even years after the initial infection.

Symptoms of long COVID can include: fatigue, shortness of breath, brain fog (trouble thinking or concentrating), loss of smell or taste, sleep problems, muscle pain, joint pain, headache, dizziness, depression or anxiety, heart palpitations, gastrointestinal problems.

Duh!!! It reads much like a continuation of the symptoms of acute COVID. Bard continued:

The exact cause of long COVID is still unknown, but there are several theories. One possibility is that the virus itself can damage organs and tissues, leading to ongoing symptoms. Another possibility is that the immune system’s response to the virus can continue to cause inflammation even after the virus is gone.

Human intelligence source Wikipedia says this:

Long COVID or long-haul COVID is a group of health problems persisting or developing after an initial COVID-19 infection. Symptoms can last weeks, months or years and are often debilitating. The World Health Organization defines long COVID as starting three months after infection, but other definitions put the start of long COVID at four weeks.

Highly varied, including post-exertional malaise (symptoms made worse with effort), fatigue, muscle pain, shortness of breath, chest pain, and cognitive dysfunction (brain fog).
 

Acute COVID to Long COVID

The World Health Organization estimates that 36 million people in the European region have developed long COVID in the first 3 years of the pandemic. That›s a lot.

We all know that the common signs and symptoms of acute COVID-19 include fever or chills, a dry cough and shortness of breath, feeling very tired, muscle or body aches, headache, loss of taste or smell, sore throat, congestion, runny nose, nausea, vomiting, and diarrhea. Except for the taste and smell findings, every one of these symptoms or signs could indicate a different virus infection or even some type of allergy. My point is the nonspecificity in this list.

Uncommon signs and symptoms of acute COVID include a flat skin rash covered with small bumps, discolored swollen areas on the fingers and toes (COVID toes), and hives. The skin of hands, wrists, or ankles also can be affected. Blisters, itchiness, rough skin, or pus can be seen.

Severe confusion (delirium) might be the main or only symptom of COVID-19 in older people. This COVID-19 symptom is linked with a high risk for poor outcomes, including death. Pink eye (conjunctivitis) can be a COVID-19 symptom. Other eye problems linked to COVID-19 are light sensitivity, sore eyes, and itchy eyes. Acute myocarditis, tinnitus, vertigo, and hearing loss have been reported. And 1-4 weeks after the onset of COVID-19 infection, a patient may experience de novo reactive synovitis and arthritis of any joints.

So, take your pick. Myriad symptoms, signs, diseases, diagnoses, and organ systems — still present, recurring, just appearing, apparently de novo, or after asymptomatic infection. We have so much still to learn.

What big-time symptoms, signs, and major diseases are not on any of these lists? Obviously, cancer, atherosclerotic cardiovascular diseases, obesity, bone diseases, and competitive infections. But be patient; the lingering effects of direct tissue invasion by the virus as well as a wide range of immunologic reactions may just be getting started. Mitochondrial damage, especially in muscles, is increasingly a pathophysiologic suspect.

Human diseases can be physical or mental; and in COVID, that twain not only meet but mix and mingle freely, and may even merge into psychosoma. Don’t ever forget that. Consider “fatigue.” Who among us, COVID or NOVID, does not experience that from time to time?

Or consider brain fog as a common reported symptom of COVID. What on earth is that actually? How can a person know they have brain fog, or whether they had it and are over it?

We need one or more lab or other diagnostic tests that can objectively confirm the diagnosis of long COVID.
 

Useful Progress?

A recent research paper in Science reported intriguing chemical findings that seemed to point a finger at some form of complement dysregulation as a potential disease marker for long COVID. Unfortunately, some critics have pointed out that this entire study may be invalid or irrelevant because the New York cohort was recruited in 2020, before vaccines were available. The Zurich cohort was recruited up until April 2021, so some may have been vaccinated.

Then this news organization came along in early January 2024 with an article about COVID causing not only more than a million American deaths but also more than 5000 deaths from long COVID. We physicians don’t really know what long COVID even is, but we have to sign death certificates blaming thousands of deaths on it anyway? And rolling back the clock to 2020: Are patients dying from COVID or with COVID, according to death certificates?Now, armed with the knowledge that “documented serious post–COVID-19 conditions include cardiovascular, pulmonary, neurological, renal, endocrine, hematological, and gastrointestinal complications, as well as death,” CDC has published clear and fairly concise instructions on how to address post-acute COVID sequelae on death certificates.

In late January, this news organization painted a hopeful picture by naming four phenotypes of long COVID, suggesting that such divisions might further our understanding, including prognosis, and even therapy for this condition. Among the clinical phenotypes of (1) chronic fatigue–like syndrome, headache, and memory loss; (2) respiratory syndrome (which includes cough and difficulty breathing); (3) chronic pain; and (4) neurosensorial syndrome (which causes an altered sense of taste and smell), overlap is clearly possible but isn›t addressed.

I see these recent developments as needed and useful progress, but we are still left with…not much. So, when you tell me that you do or do not have long COVID, I will say to you, “How do you know?”

I also say: She/he/they who know COVID know medicine.

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

Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating. 

Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.

Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.
 

Brain Deficits Equal to 20 Years of Brain Aging

As part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.

Patients who participated in the study were “less accurate and slower” in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.

The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.

“We found global deficits across cognition,” said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. “The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain.”
 

Proof That Symptoms Aren’t ‘Figment’ of Patients’ Imaginations

Cognitive deficits were common among all patients, but the researchers said they don’t yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren’t a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine’s COVID Recovery Clinic. 

“Even though we’re several years into this pandemic, there are still a lot of providers who don’t believe that their patients are experiencing these residual symptoms,” said Dr. Thompson, “That’s why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way.”

Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.
 

How Do COVID-Related Brain Injuries Happen?

Researchers are unsure what’s causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.

Brain scans have previously shown atrophy to the brain›s gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.

The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. “The old saying is that if it walks like a duck and talks like a duck, it’s a duck,” said Dr. Jackson. 

He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
 

A New Path Forward

Treating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. “What we’re seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis,” said Dr. Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.

There’s also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer’s disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus “rapidly accelerated structural and functional brain deterioration.” 

“We already know the role that neuroinflammation plays in the brains of patients with Alzheimer’s disease,” said Dr. Thompson. “If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study’s reported] brain aging.”
 

Still More to Learn

In some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don’t know about the impact on those who had less serious cases of the virus. 

For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they’re not getting the help they need. 

What’s more, said Dr. Al-Aly, it’s unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it’s inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? “It’s critical we find some answers,” he said.

“SARS-CoV-2 isn’t going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it,” said Dr. Al-Aly.

A version of this article appeared on Medscape.com.

Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating. 

Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.

Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.
 

Brain Deficits Equal to 20 Years of Brain Aging

As part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.

Patients who participated in the study were “less accurate and slower” in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.

The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.

“We found global deficits across cognition,” said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. “The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain.”
 

Proof That Symptoms Aren’t ‘Figment’ of Patients’ Imaginations

Cognitive deficits were common among all patients, but the researchers said they don’t yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren’t a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine’s COVID Recovery Clinic. 

“Even though we’re several years into this pandemic, there are still a lot of providers who don’t believe that their patients are experiencing these residual symptoms,” said Dr. Thompson, “That’s why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way.”

Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.
 

How Do COVID-Related Brain Injuries Happen?

Researchers are unsure what’s causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.

Brain scans have previously shown atrophy to the brain›s gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.

The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. “The old saying is that if it walks like a duck and talks like a duck, it’s a duck,” said Dr. Jackson. 

He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
 

A New Path Forward

Treating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. “What we’re seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis,” said Dr. Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.

There’s also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer’s disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus “rapidly accelerated structural and functional brain deterioration.” 

“We already know the role that neuroinflammation plays in the brains of patients with Alzheimer’s disease,” said Dr. Thompson. “If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study’s reported] brain aging.”
 

Still More to Learn

In some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don’t know about the impact on those who had less serious cases of the virus. 

For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they’re not getting the help they need. 

What’s more, said Dr. Al-Aly, it’s unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it’s inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? “It’s critical we find some answers,” he said.

“SARS-CoV-2 isn’t going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it,” said Dr. Al-Aly.

A version of this article appeared on Medscape.com.

Brain fog is one of the most common, persistent complaints in patients with long COVID. It affects as many as 46% of patients who also deal with other cognitive concerns like memory loss and difficulty concentrating. 

Now, researchers believe they know why. A new study has found that these symptoms may be the result of a viral-borne brain injury that may cause cognitive and mental health issues that persist for years.

Researchers found that 351 patients hospitalized with severe COVID-19 had evidence of a long-term brain injury a year after contracting the SARS-CoV-2 virus. The findings were based on a series of cognitive tests, self-reported symptoms, brain scans, and biomarkers.
 

Brain Deficits Equal to 20 Years of Brain Aging

As part of the preprint study, participants took a cognition test with their scores age-matched to those who had not suffered a serious bout of COVID-19. Then a blood sample was taken to look for specific biomarkers, showing that elevated levels of certain biomarkers were consistent with a brain injury. Using brain scans, researchers also found that certain regions of the brain associated with attention were reduced in volume.

Patients who participated in the study were “less accurate and slower” in their cognition, and suffered from at least one mental health condition, such as depression, anxiety, or posttraumatic stress disorder, according to researchers.

The brain deficits found in COVID-19 patients were equivalent to 20 years of brain aging and provided proof of what doctors have feared: that this virus can damage the brain and result in ongoing mental health issues.

“We found global deficits across cognition,” said lead study author Benedict Michael, PhD, director of the Infection Neuroscience Lab at the University of Liverpool in Liverpool, England. “The cognitive and memory problems that patients complained of were associated with neuroanatomical changes to the brain.”
 

Proof That Symptoms Aren’t ‘Figment’ of Patients’ Imaginations

Cognitive deficits were common among all patients, but the researchers said they don’t yet know whether the brain damage causes permanent cognitive decline. But the research provides patients who have been overlooked by some clinicians with proof that their conditions aren’t a figment of their imaginations, said Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina School of Medicine’s COVID Recovery Clinic. 

“Even though we’re several years into this pandemic, there are still a lot of providers who don’t believe that their patients are experiencing these residual symptoms,” said Dr. Thompson, “That’s why the use of biomarkers is important, because it provides an objective indication that the brain has been compromised in some way.”

Some patients with long COVID have said that getting their doctors to believe they have a physical ailment has been a persistent problem throughout the pandemic and especially as it relates to the sometimes-vague collection of symptoms associated with brain fog. One study found that as many as 79% of study respondents reported negative interactions with their healthcare providers when they sought treatment for their long-COVID symptoms.
 

How Do COVID-Related Brain Injuries Happen?

Researchers are unsure what’s causing these brain injuries, though they have identified some clues. Previous research has suggested that such injuries might be the result of a lack of oxygen to the brain, especially in patients who were hospitalized, like those in this study, and were put on ventilators.

Brain scans have previously shown atrophy to the brain›s gray matter in COVID-19 patients, likely caused by inflammation from a heightened immune response rather than the virus itself. This inflammatory response seems to affect the central nervous system. As part of the new study, researchers found some neuroprotective effects of using steroids during hospitalization to reduce brain inflammation.

The results suggest that clinicians should overcome their skepticism and consider the possibility that their patients have suffered a brain injury and should be treated appropriately, said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University School of Medicine. “The old saying is that if it walks like a duck and talks like a duck, it’s a duck,” said Dr. Jackson. 

He contends that treatments used for patients who have brain injuries have also been shown to be effective in treating long COVID–related brain fog symptoms. These may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for the treatment of related mental health concerns.
 

A New Path Forward

Treating long-COVID brain fog like a brain injury can help patients get back to some semblance of normalcy, researchers said. “What we’re seeing in terms of brain injury biomarkers and differences in brain scans correlates to real-life problems that these patients are dealing with on a daily basis,” said Dr. Jackson. These include problems at work and in life with multitasking, remembering details, meeting deadlines, synthesizing large amounts of information, and maintaining focus on the task at hand, he said.

There’s also a fear that even with treatment, the aging of the brain caused by the virus might have long-term repercussions and that this enduring injury may cause the early onset of dementia and Alzheimer’s disease in those who were already vulnerable to it. One study, from the National Institute of Neurological Disorders and Stroke (NINDS), found that in those infected with COVID-19 who already had dementia, the virus “rapidly accelerated structural and functional brain deterioration.” 

“We already know the role that neuroinflammation plays in the brains of patients with Alzheimer’s disease,” said Dr. Thompson. “If long COVID is involved in prolonged inflammation of the brain, it goes a long way in explaining the mechanism underlying [the study’s reported] brain aging.”
 

Still More to Learn

In some ways, this study raises nearly as many questions as it does answers. While it provides concrete evidence around the damage the virus is doing to the brains of patients who contracted severe COVID-19, researchers don’t know about the impact on those who had less serious cases of the virus. 

For Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System, the concern is that some long-COVID patients may be suffering from cognitive deficits that are more subtle but still impacting their daily lives, and that they’re not getting the help they need. 

What’s more, said Dr. Al-Aly, it’s unclear whether the impacts of the brain damage are permanent or how to stop them from worsening. Researchers and clinicians need a better understanding of the mechanism that allows this virus to enter the brain and do structural damage. If it’s inflammation, will anti-inflammatory or antiviral medications work at preventing it? Will steroids help to offset the damage? “It’s critical we find some answers,” he said.

“SARS-CoV-2 isn’t going anywhere. It will continue to infect the population, so if this is indeed a virus that damages the brain in the long term or permanently, we need to figure out what can be done to stop it,” said Dr. Al-Aly.

A version of this article appeared on Medscape.com.

Leading a healthy lifestyle, including regular exercise, eating fruits and vegetables, and minimal alcohol consumption, is associated with better cognitive function in older adults, new research showed.

The study, which combined longitudinal and cohort data with postmortem brain pathology reports, found that the association held even in those with Alzheimer’s disease (AD) pathology, suggesting that lifestyle factors may provide cognitive reserve and improve cognitive abilities in older age.

“While we must use caution in interpreting our findings, in part due to its cross-sectional design, these results support the role of lifestyle in providing cognitive reserve to maintain cognitive function in older adults despite the accumulation of common dementia-related brain pathologies,” Klodian Dhana, MD, of the Rush University Medical Center in Chicago, Illinois, and colleagues wrote.

The study was published online in JAMA Neurology.
 

Better Cognition

The study included 586 participants (71% female) who were followed from 1997 until 2022 as part of the Rush Memory and Aging Project longitudinal cohort study.

Investigators collected information on lifestyle and demographic factors at regular intervals, as well as information on diet, alcohol intake, and time spent participating in moderate or vigorous physical activity such as gardening, walking, calisthenics, biking, or swimming. Participants also received annual cognitive tests.

In later years, participants answered questions about whether they played card games or checkers, read, visited a museum, or did other cognitively stimulating activities.

Postmortem exams allowed the researchers to assess brain pathology (mean age at death, 91 years).

Participants were categorized as living a healthy lifestyle if they scored well in five categories: They exercised moderately or vigorously for 150 minutes per week, did not smoke, consumed one to two drinks per week, regularly played card games or did puzzles, and followed the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay diet.

For every one-point increase in the healthy lifestyle score, there were 0.120 fewer units of beta-amyloid load in the brain and a 0.22 standardized unit higher score in cognitive performance (P < .001).

After adjusting for the beta-amyloid load, phosphorated tau tangle, or other dementia-related brain pathologies, the healthy lifestyle score remained independently associated with cognition (P < .001).

More than 88% of a person’s global cognition score was a “direct association of lifestyle,” investigators noted, leaving slightly less than 12% affected by the presence of beta-amyloid.

“The mechanistic link between lifestyle and cognition could be attributed in part to the antioxidant and anti-inflammatory capacities of each lifestyle factor (eg, nutrition and physical activity) and cognitive reserve (eg, cognitive activities) that contribute to less inflammation and oxidative stress,” the authors wrote.

Further studies are necessary, they added, especially research investigating the association of lifestyle factors with markers for inflammation to understand the mechanisms of how lifestyle is associated with better cognitive scores in old age.

Study limitations include the reliance on self-reported data because cognitive impairment could interfere with inaccurate reporting. In addition, the authors noted that cognitive abilities may affect adherence to lifestyle factors.
 

‘Important Evidence’

In an accompanying editorial, Yue Leng, MD, and Kristine Yaffe, MD, of the University of San Francisco in San Francisco, California, noted that the new study adds “important evidence” to the debate over modifiable risk factors and reduction of AD risk.

“These interesting results add strength to the concept that health and lifestyle factors are important strategies for prevention and suggest that several mechanisms may be at work,” they wrote, adding that the study is “one of the first to harness brain pathology to investigate these mechanisms and is a crucial step forward in addressing these important questions.”

Still, critical questions remain regarding the mechanistic pathways linking modifiable risk factors and cognitive aging, Drs. Leng and Yaffe wrote.

“There is an urgent need for more well-designed randomized controlled trials to pave the way for dementia risk reduction in the era of precision medicine,” they wrote. “These strategies should be offered in conjunction with AD medications, similar to the approach in cardiovascular disease prevention and treatment in which medications along with lifestyle strategies are the standard of care.”

The study was funded by the National Institute on Aging. Dr. Dhana reported grants paid to his institution from the Alzheimer’s Association. No other disclosures were reported.

A version of this article appeared on Medscape.com.

Leading a healthy lifestyle, including regular exercise, eating fruits and vegetables, and minimal alcohol consumption, is associated with better cognitive function in older adults, new research showed.

The study, which combined longitudinal and cohort data with postmortem brain pathology reports, found that the association held even in those with Alzheimer’s disease (AD) pathology, suggesting that lifestyle factors may provide cognitive reserve and improve cognitive abilities in older age.

“While we must use caution in interpreting our findings, in part due to its cross-sectional design, these results support the role of lifestyle in providing cognitive reserve to maintain cognitive function in older adults despite the accumulation of common dementia-related brain pathologies,” Klodian Dhana, MD, of the Rush University Medical Center in Chicago, Illinois, and colleagues wrote.

The study was published online in JAMA Neurology.
 

Better Cognition

The study included 586 participants (71% female) who were followed from 1997 until 2022 as part of the Rush Memory and Aging Project longitudinal cohort study.

Investigators collected information on lifestyle and demographic factors at regular intervals, as well as information on diet, alcohol intake, and time spent participating in moderate or vigorous physical activity such as gardening, walking, calisthenics, biking, or swimming. Participants also received annual cognitive tests.

In later years, participants answered questions about whether they played card games or checkers, read, visited a museum, or did other cognitively stimulating activities.

Postmortem exams allowed the researchers to assess brain pathology (mean age at death, 91 years).

Participants were categorized as living a healthy lifestyle if they scored well in five categories: They exercised moderately or vigorously for 150 minutes per week, did not smoke, consumed one to two drinks per week, regularly played card games or did puzzles, and followed the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay diet.

For every one-point increase in the healthy lifestyle score, there were 0.120 fewer units of beta-amyloid load in the brain and a 0.22 standardized unit higher score in cognitive performance (P < .001).

After adjusting for the beta-amyloid load, phosphorated tau tangle, or other dementia-related brain pathologies, the healthy lifestyle score remained independently associated with cognition (P < .001).

More than 88% of a person’s global cognition score was a “direct association of lifestyle,” investigators noted, leaving slightly less than 12% affected by the presence of beta-amyloid.

“The mechanistic link between lifestyle and cognition could be attributed in part to the antioxidant and anti-inflammatory capacities of each lifestyle factor (eg, nutrition and physical activity) and cognitive reserve (eg, cognitive activities) that contribute to less inflammation and oxidative stress,” the authors wrote.

Further studies are necessary, they added, especially research investigating the association of lifestyle factors with markers for inflammation to understand the mechanisms of how lifestyle is associated with better cognitive scores in old age.

Study limitations include the reliance on self-reported data because cognitive impairment could interfere with inaccurate reporting. In addition, the authors noted that cognitive abilities may affect adherence to lifestyle factors.
 

‘Important Evidence’

In an accompanying editorial, Yue Leng, MD, and Kristine Yaffe, MD, of the University of San Francisco in San Francisco, California, noted that the new study adds “important evidence” to the debate over modifiable risk factors and reduction of AD risk.

“These interesting results add strength to the concept that health and lifestyle factors are important strategies for prevention and suggest that several mechanisms may be at work,” they wrote, adding that the study is “one of the first to harness brain pathology to investigate these mechanisms and is a crucial step forward in addressing these important questions.”

Still, critical questions remain regarding the mechanistic pathways linking modifiable risk factors and cognitive aging, Drs. Leng and Yaffe wrote.

“There is an urgent need for more well-designed randomized controlled trials to pave the way for dementia risk reduction in the era of precision medicine,” they wrote. “These strategies should be offered in conjunction with AD medications, similar to the approach in cardiovascular disease prevention and treatment in which medications along with lifestyle strategies are the standard of care.”

The study was funded by the National Institute on Aging. Dr. Dhana reported grants paid to his institution from the Alzheimer’s Association. No other disclosures were reported.

A version of this article appeared on Medscape.com.

Leading a healthy lifestyle, including regular exercise, eating fruits and vegetables, and minimal alcohol consumption, is associated with better cognitive function in older adults, new research showed.

The study, which combined longitudinal and cohort data with postmortem brain pathology reports, found that the association held even in those with Alzheimer’s disease (AD) pathology, suggesting that lifestyle factors may provide cognitive reserve and improve cognitive abilities in older age.

“While we must use caution in interpreting our findings, in part due to its cross-sectional design, these results support the role of lifestyle in providing cognitive reserve to maintain cognitive function in older adults despite the accumulation of common dementia-related brain pathologies,” Klodian Dhana, MD, of the Rush University Medical Center in Chicago, Illinois, and colleagues wrote.

The study was published online in JAMA Neurology.
 

Better Cognition

The study included 586 participants (71% female) who were followed from 1997 until 2022 as part of the Rush Memory and Aging Project longitudinal cohort study.

Investigators collected information on lifestyle and demographic factors at regular intervals, as well as information on diet, alcohol intake, and time spent participating in moderate or vigorous physical activity such as gardening, walking, calisthenics, biking, or swimming. Participants also received annual cognitive tests.

In later years, participants answered questions about whether they played card games or checkers, read, visited a museum, or did other cognitively stimulating activities.

Postmortem exams allowed the researchers to assess brain pathology (mean age at death, 91 years).

Participants were categorized as living a healthy lifestyle if they scored well in five categories: They exercised moderately or vigorously for 150 minutes per week, did not smoke, consumed one to two drinks per week, regularly played card games or did puzzles, and followed the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay diet.

For every one-point increase in the healthy lifestyle score, there were 0.120 fewer units of beta-amyloid load in the brain and a 0.22 standardized unit higher score in cognitive performance (P < .001).

After adjusting for the beta-amyloid load, phosphorated tau tangle, or other dementia-related brain pathologies, the healthy lifestyle score remained independently associated with cognition (P < .001).

More than 88% of a person’s global cognition score was a “direct association of lifestyle,” investigators noted, leaving slightly less than 12% affected by the presence of beta-amyloid.

“The mechanistic link between lifestyle and cognition could be attributed in part to the antioxidant and anti-inflammatory capacities of each lifestyle factor (eg, nutrition and physical activity) and cognitive reserve (eg, cognitive activities) that contribute to less inflammation and oxidative stress,” the authors wrote.

Further studies are necessary, they added, especially research investigating the association of lifestyle factors with markers for inflammation to understand the mechanisms of how lifestyle is associated with better cognitive scores in old age.

Study limitations include the reliance on self-reported data because cognitive impairment could interfere with inaccurate reporting. In addition, the authors noted that cognitive abilities may affect adherence to lifestyle factors.
 

‘Important Evidence’

In an accompanying editorial, Yue Leng, MD, and Kristine Yaffe, MD, of the University of San Francisco in San Francisco, California, noted that the new study adds “important evidence” to the debate over modifiable risk factors and reduction of AD risk.

“These interesting results add strength to the concept that health and lifestyle factors are important strategies for prevention and suggest that several mechanisms may be at work,” they wrote, adding that the study is “one of the first to harness brain pathology to investigate these mechanisms and is a crucial step forward in addressing these important questions.”

Still, critical questions remain regarding the mechanistic pathways linking modifiable risk factors and cognitive aging, Drs. Leng and Yaffe wrote.

“There is an urgent need for more well-designed randomized controlled trials to pave the way for dementia risk reduction in the era of precision medicine,” they wrote. “These strategies should be offered in conjunction with AD medications, similar to the approach in cardiovascular disease prevention and treatment in which medications along with lifestyle strategies are the standard of care.”

The study was funded by the National Institute on Aging. Dr. Dhana reported grants paid to his institution from the Alzheimer’s Association. No other disclosures were reported.

A version of this article appeared on Medscape.com.

Exposure to even moderate concentrations of radon is associated with a significant increase in stroke risk, new research suggests.

An analysis of radon exposures in more than 150,000 postmenopausal women in the Women’s Health Initiative revealed a 14% higher stroke risk in those exposed to the highest concentrations compared with those exposed to the lowest concentrations. Even moderate concentrations of radon were associated with a 6% higher stroke risk.

Radon is the second leading cause of lung cancer, but little was known about how exposure to the gas might affect stroke risk in women. 

“Our research found an increased risk of stroke among participants exposed to radon above — and as many as 2 picocuries per liter (pCi/L) below — concentrations that usually trigger Environmental Protection Agency recommendations to install a home radon mitigation system,” senior author Eric A. Whitsel, MD, MPH, professor of epidemiology and medicine, University of North Carolina, Chapel Hill, said in a news release.

The study was published online on January 31, 2024, in Neurology.

Women Particularly Affected

Radon is a naturally occurring odorless radioactive gas produced when uranium or radium break down in rocks and soil. Its presence is increasing as a result of climate change, and it is increasingly being found in people’s homes. When inhaled, this air pollutant releases ionizing radiation in the lungs and is seen as second only to smoking as an established cause of lung cancer.

The National Radon Action Plan of the US Environmental Protection Agency (EPA) lays out testing and mitigation guidelines based on the known role of radon in lung carcinogenesis. But radon testing and mitigation are less common than recommended, and the EPA’s action plan doesn’t cover diseases other than lung cancer.

Compared with men, women have a higher rate of stroke and, in the US, typically spend about 11% more hours per day indoors at home, which investigators note highlights a “potential role of the residential environment among other risk factors specific to women.”

Researchers examined longitudinal associations between home radon exposure and incident stroke in 158,910 women at baseline (mean age 63.2 years; 83% White) over a mean follow-up of 13.4 years. During this time, participants experienced a total of 6979 strokes.

Participants’ home addresses were linked to radon concentration data drawn from the US Geological Survey and the EPA, which recommends that average indoor radon concentrations not exceed 4 pCi/L. 

The highest radon exposure group resided in areas where average radon concentrations were < 4 pCi/L; the middle exposure group lived in regions with average concentrations of 2-4 pCi/L; and the lowest exposure group lived in areas with average concentrations < 2 pCi/L. 

The researchers adjusted for demographic, social, behavioral, and clinical characteristics.

Public Health Implications

The incidence rates of stroke per 100,000 women in the lowest, middle, and highest radon concentration areas were 333, 343, and 349, respectively.

Stroke risk was 6% higher among those in the middle exposure group (adjusted hazard ratio [aHR], 1.06; 95% CI, 0.99-1.13) and 14% higher in the highest exposure group (aHR, 1.14; 95% CI, 1.05-1.22) compared with the lowest exposure group.

Notably, stroke risk was significant even at concentrations ranging from 2 to 4 pCi/L (P = .0004) vs < 2 pCi/L, which is below the EPA›s Radon Action Level for mitigation. 

The findings remained robust in sensitivity analyses, although the associations were slightly stronger for ischemic stroke (especially cardioembolic, small-vessel occlusive, and very large artery atherosclerotic) compared with hemorrhagic stroke.

“Radon is an indoor air pollutant that can only be detected through testing that measures concentrations of the gas in homes,” Dr. Whitsel said in the release. “More studies are needed to confirm our findings. Confirmation would present an opportunity to improve public health by addressing an emerging risk factor for stroke.”

The study lacked gender and racial/ethnic diversity, so the findings may not be generalizable to other populations. 

“Replication studies of individual-level radon exposures are needed to confirm this positive radon-stroke association,” the authors write. “Confirmation would present a potential opportunity to affect public health by addressing a pervasive environmental risk factor for stroke and thereby merit reconsideration of extant radon policy.”

The study was funded by the National Institute of Environmental Health Sciences and National Heart, Lung, and Blood Institute. Dr. Whitsel and coauthors report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Exposure to even moderate concentrations of radon is associated with a significant increase in stroke risk, new research suggests.

An analysis of radon exposures in more than 150,000 postmenopausal women in the Women’s Health Initiative revealed a 14% higher stroke risk in those exposed to the highest concentrations compared with those exposed to the lowest concentrations. Even moderate concentrations of radon were associated with a 6% higher stroke risk.

Radon is the second leading cause of lung cancer, but little was known about how exposure to the gas might affect stroke risk in women. 

“Our research found an increased risk of stroke among participants exposed to radon above — and as many as 2 picocuries per liter (pCi/L) below — concentrations that usually trigger Environmental Protection Agency recommendations to install a home radon mitigation system,” senior author Eric A. Whitsel, MD, MPH, professor of epidemiology and medicine, University of North Carolina, Chapel Hill, said in a news release.

The study was published online on January 31, 2024, in Neurology.

Women Particularly Affected

Radon is a naturally occurring odorless radioactive gas produced when uranium or radium break down in rocks and soil. Its presence is increasing as a result of climate change, and it is increasingly being found in people’s homes. When inhaled, this air pollutant releases ionizing radiation in the lungs and is seen as second only to smoking as an established cause of lung cancer.

The National Radon Action Plan of the US Environmental Protection Agency (EPA) lays out testing and mitigation guidelines based on the known role of radon in lung carcinogenesis. But radon testing and mitigation are less common than recommended, and the EPA’s action plan doesn’t cover diseases other than lung cancer.

Compared with men, women have a higher rate of stroke and, in the US, typically spend about 11% more hours per day indoors at home, which investigators note highlights a “potential role of the residential environment among other risk factors specific to women.”

Researchers examined longitudinal associations between home radon exposure and incident stroke in 158,910 women at baseline (mean age 63.2 years; 83% White) over a mean follow-up of 13.4 years. During this time, participants experienced a total of 6979 strokes.

Participants’ home addresses were linked to radon concentration data drawn from the US Geological Survey and the EPA, which recommends that average indoor radon concentrations not exceed 4 pCi/L. 

The highest radon exposure group resided in areas where average radon concentrations were < 4 pCi/L; the middle exposure group lived in regions with average concentrations of 2-4 pCi/L; and the lowest exposure group lived in areas with average concentrations < 2 pCi/L. 

The researchers adjusted for demographic, social, behavioral, and clinical characteristics.

Public Health Implications

The incidence rates of stroke per 100,000 women in the lowest, middle, and highest radon concentration areas were 333, 343, and 349, respectively.

Stroke risk was 6% higher among those in the middle exposure group (adjusted hazard ratio [aHR], 1.06; 95% CI, 0.99-1.13) and 14% higher in the highest exposure group (aHR, 1.14; 95% CI, 1.05-1.22) compared with the lowest exposure group.

Notably, stroke risk was significant even at concentrations ranging from 2 to 4 pCi/L (P = .0004) vs < 2 pCi/L, which is below the EPA›s Radon Action Level for mitigation. 

The findings remained robust in sensitivity analyses, although the associations were slightly stronger for ischemic stroke (especially cardioembolic, small-vessel occlusive, and very large artery atherosclerotic) compared with hemorrhagic stroke.

“Radon is an indoor air pollutant that can only be detected through testing that measures concentrations of the gas in homes,” Dr. Whitsel said in the release. “More studies are needed to confirm our findings. Confirmation would present an opportunity to improve public health by addressing an emerging risk factor for stroke.”

The study lacked gender and racial/ethnic diversity, so the findings may not be generalizable to other populations. 

“Replication studies of individual-level radon exposures are needed to confirm this positive radon-stroke association,” the authors write. “Confirmation would present a potential opportunity to affect public health by addressing a pervasive environmental risk factor for stroke and thereby merit reconsideration of extant radon policy.”

The study was funded by the National Institute of Environmental Health Sciences and National Heart, Lung, and Blood Institute. Dr. Whitsel and coauthors report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Exposure to even moderate concentrations of radon is associated with a significant increase in stroke risk, new research suggests.

An analysis of radon exposures in more than 150,000 postmenopausal women in the Women’s Health Initiative revealed a 14% higher stroke risk in those exposed to the highest concentrations compared with those exposed to the lowest concentrations. Even moderate concentrations of radon were associated with a 6% higher stroke risk.

Radon is the second leading cause of lung cancer, but little was known about how exposure to the gas might affect stroke risk in women. 

“Our research found an increased risk of stroke among participants exposed to radon above — and as many as 2 picocuries per liter (pCi/L) below — concentrations that usually trigger Environmental Protection Agency recommendations to install a home radon mitigation system,” senior author Eric A. Whitsel, MD, MPH, professor of epidemiology and medicine, University of North Carolina, Chapel Hill, said in a news release.

The study was published online on January 31, 2024, in Neurology.

Women Particularly Affected

Radon is a naturally occurring odorless radioactive gas produced when uranium or radium break down in rocks and soil. Its presence is increasing as a result of climate change, and it is increasingly being found in people’s homes. When inhaled, this air pollutant releases ionizing radiation in the lungs and is seen as second only to smoking as an established cause of lung cancer.

The National Radon Action Plan of the US Environmental Protection Agency (EPA) lays out testing and mitigation guidelines based on the known role of radon in lung carcinogenesis. But radon testing and mitigation are less common than recommended, and the EPA’s action plan doesn’t cover diseases other than lung cancer.

Compared with men, women have a higher rate of stroke and, in the US, typically spend about 11% more hours per day indoors at home, which investigators note highlights a “potential role of the residential environment among other risk factors specific to women.”

Researchers examined longitudinal associations between home radon exposure and incident stroke in 158,910 women at baseline (mean age 63.2 years; 83% White) over a mean follow-up of 13.4 years. During this time, participants experienced a total of 6979 strokes.

Participants’ home addresses were linked to radon concentration data drawn from the US Geological Survey and the EPA, which recommends that average indoor radon concentrations not exceed 4 pCi/L. 

The highest radon exposure group resided in areas where average radon concentrations were < 4 pCi/L; the middle exposure group lived in regions with average concentrations of 2-4 pCi/L; and the lowest exposure group lived in areas with average concentrations < 2 pCi/L. 

The researchers adjusted for demographic, social, behavioral, and clinical characteristics.

Public Health Implications

The incidence rates of stroke per 100,000 women in the lowest, middle, and highest radon concentration areas were 333, 343, and 349, respectively.

Stroke risk was 6% higher among those in the middle exposure group (adjusted hazard ratio [aHR], 1.06; 95% CI, 0.99-1.13) and 14% higher in the highest exposure group (aHR, 1.14; 95% CI, 1.05-1.22) compared with the lowest exposure group.

Notably, stroke risk was significant even at concentrations ranging from 2 to 4 pCi/L (P = .0004) vs < 2 pCi/L, which is below the EPA›s Radon Action Level for mitigation. 

The findings remained robust in sensitivity analyses, although the associations were slightly stronger for ischemic stroke (especially cardioembolic, small-vessel occlusive, and very large artery atherosclerotic) compared with hemorrhagic stroke.

“Radon is an indoor air pollutant that can only be detected through testing that measures concentrations of the gas in homes,” Dr. Whitsel said in the release. “More studies are needed to confirm our findings. Confirmation would present an opportunity to improve public health by addressing an emerging risk factor for stroke.”

The study lacked gender and racial/ethnic diversity, so the findings may not be generalizable to other populations. 

“Replication studies of individual-level radon exposures are needed to confirm this positive radon-stroke association,” the authors write. “Confirmation would present a potential opportunity to affect public health by addressing a pervasive environmental risk factor for stroke and thereby merit reconsideration of extant radon policy.”

The study was funded by the National Institute of Environmental Health Sciences and National Heart, Lung, and Blood Institute. Dr. Whitsel and coauthors report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Men prescribed drugs to treat newly diagnosed erectile dysfunction (ED) are 18% less likely to develop Alzheimer’s disease (AD) during a 5-year follow-up period, new research shows. 

The study is the second in recent years to suggest an association between the use of phosphodiesterase type 5 inhibitors (PDE5Is) such as sildenafil (Viagra) or tadalafil (Cialis) and AD risk. The findings contradict those in a third study, reported by this news organization, that showed no link between the two. 

Although the research is interesting, outside experts noted that there is no evidence that the drugs can treat AD and urge caution when interpreting the findings. 

Investigators agree but believe that the results offer a direction for future studies and underscore the importance of investigating whether existing approved therapies can be repurposed to treat AD. 

“The positive findings from our large study in over 250,000 men is promising and can be used to enhance research capacity and knowledge, with a potential future impact on clinical use and public health policy,” senior author Ruth Brauer, PhD, of the University College London, told this news organization.

“However, before recommending PDE5I are used to reduce the risk of AD, more work is required to validate the findings of our work, particularly in a more generalizable population that includes women and men without erectile dysfunction,” she continued.

The findings were published online February 7 in Neurology.

Strong Association

The study drew on primary healthcare data from the United Kingdom and included 269,725 men (average age, 59 years) with newly diagnosed ED, 55% of whom had received prescriptions for PDE5Is. 

Participants were free from memory or cognitive issues when the study began and were followed for a median of 5.1 years. Investigators accounted for a range of potential AD risk factors, including smoking status, alcohol use, body mass index, hypertension, diabetes, depression, anxiety, and concomitant medication use.

During the study period, 749 in the PDE5I group were diagnosed with AD, corresponding to a rate of 8.1 cases per 10,000 person-years. Among those who did not take the drugs, 370 developed AD, corresponding to a rate of 9.7 cases per 10,000 person-years.

Overall, initiation of a PDE5I was associated with an 18% lower risk for AD (adjusted hazard ration [aHR], 0.82; 95% CI, 0.72-0.93) compared with those with no prescriptions. 

The association was stronger in people aged 70 years or older and those with a history of hypertension or diabetes. The greatest risk reduction was found in people with the most prescriptions during the study period. Those with 21-50 prescriptions had a 44% lower risk for AD (aHR, 0.56; 95% CI, 0.43-0.73) and those with more than 50 were 35% less likely to be diagnosed with AD (aHR, 0.65; 95% CI, 0.49-0.87).

There was no association with AD risk in individuals who received fewer than 20 prescriptions. 

Investigators also analyzed associations after introducing a 1- and 3-year lag period after cohort entry to address the latent period between AD onset and diagnosis. The primary findings held with a 1-year lag period but lost significance with the inclusion of a 3-year lag period.

In subgroup analyses, investigators found evidence of reduced AD risk in those who received prescriptions for sildenafil (aHR, 0.81; 95% CI, 0.71-0.93), but there was no evidence for reduced risk compared with nonusers in those who received tadalafil and vardenafil.

Lower AD risk was found in patients with hypertension, diabetes, and in men aged 70 years or older, but there was no association in younger men or those with no history of hypertension or diabetes. 

Although investigators controlled for a wide range of potential risk factors, Dr. Brauer noted that unmeasured confounders such as physical and sexual activity, which were not tracked and may predict PDE5I exposure, may have affected the results. 

Interpret With Caution

Commenting on the findings, Ozama Ismail, PhD, Alzheimer’s Association director of scientific programs, noted that in addition to the limitations cited by the study authors, AD diagnoses were not made with the “gold standard” testing that typically includes imaging biomarkers and postmortem assessments. 

“While this study is interesting and adds to a potential association, there is no evidence that these drugs are able to treat Alzheimer’s disease,” said Dr. Brauer, who was not part of the current study. 

“People should not use over-the-counter phosphodiesterase type 5 inhibitors for prevention of Alzheimer’s or other dementias based on this very preliminary finding. Always consult with your physician before starting or changing your medications,” he cautioned.

However, Dr. Ismael added that the study does highlight a potential new avenue for drug repurposing. 

“Repurposing of existing, already-approved treatments can be a valuable part of drug development because, through already-completed testing, we know much about their safety and side effects,” which can decrease cost and time needed for studies, he said. 

“When considering repurposing an existing drug to an Alzheimer’s treatment, however, it is often important to conduct new studies over longer periods of time and in older people that reflect the diversity of individuals living with Alzheimer’s disease,” Dr. Ismael said.

Randomized Trials Needed

Dr. Brauer agreed, offering that such a trial should also include people with mild cognitive impairment and measure the effects of PDE5Is given in predefined doses plus an acetylcholinesterase inhibitor or placebo plus an acetylcholinesterase inhibitor. 

“The primary outcome would be the change in baseline cognitive function,” she said. “This approach would provide a comprehensive understanding of the potential therapeutic benefits of PDE5I and AD.”

Studies are also needed to better understand the mechanisms by which these drugs might influence AD risk, Sevil Yasar, MD, PhD, and Lolita Nidadavolu, MD, PhD, from the Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, noted in an accompanying editorial.

The strong association between PDE5I use and AD risk in people with a history of hypertension or diabetes suggests “a potential neuroprotective effect through a vascular pathway,” they wrote.

In vitro studies on the role of inflammation and clearance of beta-amyloid could strengthen findings from studies like this one, and in vivo studies could help explain the mechanisms behind PDE5I use and lower AD risk, Dr. Yasar and Dr. Nidadavolu noted. 

“In the end, however, further observational studies exploring mechanisms will not prove a causal association,” they wrote. “A well-designed randomized controlled trial is needed before PDE5I drugs can be prescribed for AD prevention.”

The study was unfunded. The study and editorial authors and Dr. Ismail report no relevant financial conflicts. 
 

A version of this article appeared on Medscape.com.

Men prescribed drugs to treat newly diagnosed erectile dysfunction (ED) are 18% less likely to develop Alzheimer’s disease (AD) during a 5-year follow-up period, new research shows. 

The study is the second in recent years to suggest an association between the use of phosphodiesterase type 5 inhibitors (PDE5Is) such as sildenafil (Viagra) or tadalafil (Cialis) and AD risk. The findings contradict those in a third study, reported by this news organization, that showed no link between the two. 

Although the research is interesting, outside experts noted that there is no evidence that the drugs can treat AD and urge caution when interpreting the findings. 

Investigators agree but believe that the results offer a direction for future studies and underscore the importance of investigating whether existing approved therapies can be repurposed to treat AD. 

“The positive findings from our large study in over 250,000 men is promising and can be used to enhance research capacity and knowledge, with a potential future impact on clinical use and public health policy,” senior author Ruth Brauer, PhD, of the University College London, told this news organization.

“However, before recommending PDE5I are used to reduce the risk of AD, more work is required to validate the findings of our work, particularly in a more generalizable population that includes women and men without erectile dysfunction,” she continued.

The findings were published online February 7 in Neurology.

Strong Association

The study drew on primary healthcare data from the United Kingdom and included 269,725 men (average age, 59 years) with newly diagnosed ED, 55% of whom had received prescriptions for PDE5Is. 

Participants were free from memory or cognitive issues when the study began and were followed for a median of 5.1 years. Investigators accounted for a range of potential AD risk factors, including smoking status, alcohol use, body mass index, hypertension, diabetes, depression, anxiety, and concomitant medication use.

During the study period, 749 in the PDE5I group were diagnosed with AD, corresponding to a rate of 8.1 cases per 10,000 person-years. Among those who did not take the drugs, 370 developed AD, corresponding to a rate of 9.7 cases per 10,000 person-years.

Overall, initiation of a PDE5I was associated with an 18% lower risk for AD (adjusted hazard ration [aHR], 0.82; 95% CI, 0.72-0.93) compared with those with no prescriptions. 

The association was stronger in people aged 70 years or older and those with a history of hypertension or diabetes. The greatest risk reduction was found in people with the most prescriptions during the study period. Those with 21-50 prescriptions had a 44% lower risk for AD (aHR, 0.56; 95% CI, 0.43-0.73) and those with more than 50 were 35% less likely to be diagnosed with AD (aHR, 0.65; 95% CI, 0.49-0.87).

There was no association with AD risk in individuals who received fewer than 20 prescriptions. 

Investigators also analyzed associations after introducing a 1- and 3-year lag period after cohort entry to address the latent period between AD onset and diagnosis. The primary findings held with a 1-year lag period but lost significance with the inclusion of a 3-year lag period.

In subgroup analyses, investigators found evidence of reduced AD risk in those who received prescriptions for sildenafil (aHR, 0.81; 95% CI, 0.71-0.93), but there was no evidence for reduced risk compared with nonusers in those who received tadalafil and vardenafil.

Lower AD risk was found in patients with hypertension, diabetes, and in men aged 70 years or older, but there was no association in younger men or those with no history of hypertension or diabetes. 

Although investigators controlled for a wide range of potential risk factors, Dr. Brauer noted that unmeasured confounders such as physical and sexual activity, which were not tracked and may predict PDE5I exposure, may have affected the results. 

Interpret With Caution

Commenting on the findings, Ozama Ismail, PhD, Alzheimer’s Association director of scientific programs, noted that in addition to the limitations cited by the study authors, AD diagnoses were not made with the “gold standard” testing that typically includes imaging biomarkers and postmortem assessments. 

“While this study is interesting and adds to a potential association, there is no evidence that these drugs are able to treat Alzheimer’s disease,” said Dr. Brauer, who was not part of the current study. 

“People should not use over-the-counter phosphodiesterase type 5 inhibitors for prevention of Alzheimer’s or other dementias based on this very preliminary finding. Always consult with your physician before starting or changing your medications,” he cautioned.

However, Dr. Ismael added that the study does highlight a potential new avenue for drug repurposing. 

“Repurposing of existing, already-approved treatments can be a valuable part of drug development because, through already-completed testing, we know much about their safety and side effects,” which can decrease cost and time needed for studies, he said. 

“When considering repurposing an existing drug to an Alzheimer’s treatment, however, it is often important to conduct new studies over longer periods of time and in older people that reflect the diversity of individuals living with Alzheimer’s disease,” Dr. Ismael said.

Randomized Trials Needed

Dr. Brauer agreed, offering that such a trial should also include people with mild cognitive impairment and measure the effects of PDE5Is given in predefined doses plus an acetylcholinesterase inhibitor or placebo plus an acetylcholinesterase inhibitor. 

“The primary outcome would be the change in baseline cognitive function,” she said. “This approach would provide a comprehensive understanding of the potential therapeutic benefits of PDE5I and AD.”

Studies are also needed to better understand the mechanisms by which these drugs might influence AD risk, Sevil Yasar, MD, PhD, and Lolita Nidadavolu, MD, PhD, from the Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, noted in an accompanying editorial.

The strong association between PDE5I use and AD risk in people with a history of hypertension or diabetes suggests “a potential neuroprotective effect through a vascular pathway,” they wrote.

In vitro studies on the role of inflammation and clearance of beta-amyloid could strengthen findings from studies like this one, and in vivo studies could help explain the mechanisms behind PDE5I use and lower AD risk, Dr. Yasar and Dr. Nidadavolu noted. 

“In the end, however, further observational studies exploring mechanisms will not prove a causal association,” they wrote. “A well-designed randomized controlled trial is needed before PDE5I drugs can be prescribed for AD prevention.”

The study was unfunded. The study and editorial authors and Dr. Ismail report no relevant financial conflicts. 
 

A version of this article appeared on Medscape.com.

Men prescribed drugs to treat newly diagnosed erectile dysfunction (ED) are 18% less likely to develop Alzheimer’s disease (AD) during a 5-year follow-up period, new research shows. 

The study is the second in recent years to suggest an association between the use of phosphodiesterase type 5 inhibitors (PDE5Is) such as sildenafil (Viagra) or tadalafil (Cialis) and AD risk. The findings contradict those in a third study, reported by this news organization, that showed no link between the two. 

Although the research is interesting, outside experts noted that there is no evidence that the drugs can treat AD and urge caution when interpreting the findings. 

Investigators agree but believe that the results offer a direction for future studies and underscore the importance of investigating whether existing approved therapies can be repurposed to treat AD. 

“The positive findings from our large study in over 250,000 men is promising and can be used to enhance research capacity and knowledge, with a potential future impact on clinical use and public health policy,” senior author Ruth Brauer, PhD, of the University College London, told this news organization.

“However, before recommending PDE5I are used to reduce the risk of AD, more work is required to validate the findings of our work, particularly in a more generalizable population that includes women and men without erectile dysfunction,” she continued.

The findings were published online February 7 in Neurology.

Strong Association

The study drew on primary healthcare data from the United Kingdom and included 269,725 men (average age, 59 years) with newly diagnosed ED, 55% of whom had received prescriptions for PDE5Is. 

Participants were free from memory or cognitive issues when the study began and were followed for a median of 5.1 years. Investigators accounted for a range of potential AD risk factors, including smoking status, alcohol use, body mass index, hypertension, diabetes, depression, anxiety, and concomitant medication use.

During the study period, 749 in the PDE5I group were diagnosed with AD, corresponding to a rate of 8.1 cases per 10,000 person-years. Among those who did not take the drugs, 370 developed AD, corresponding to a rate of 9.7 cases per 10,000 person-years.

Overall, initiation of a PDE5I was associated with an 18% lower risk for AD (adjusted hazard ration [aHR], 0.82; 95% CI, 0.72-0.93) compared with those with no prescriptions. 

The association was stronger in people aged 70 years or older and those with a history of hypertension or diabetes. The greatest risk reduction was found in people with the most prescriptions during the study period. Those with 21-50 prescriptions had a 44% lower risk for AD (aHR, 0.56; 95% CI, 0.43-0.73) and those with more than 50 were 35% less likely to be diagnosed with AD (aHR, 0.65; 95% CI, 0.49-0.87).

There was no association with AD risk in individuals who received fewer than 20 prescriptions. 

Investigators also analyzed associations after introducing a 1- and 3-year lag period after cohort entry to address the latent period between AD onset and diagnosis. The primary findings held with a 1-year lag period but lost significance with the inclusion of a 3-year lag period.

In subgroup analyses, investigators found evidence of reduced AD risk in those who received prescriptions for sildenafil (aHR, 0.81; 95% CI, 0.71-0.93), but there was no evidence for reduced risk compared with nonusers in those who received tadalafil and vardenafil.

Lower AD risk was found in patients with hypertension, diabetes, and in men aged 70 years or older, but there was no association in younger men or those with no history of hypertension or diabetes. 

Although investigators controlled for a wide range of potential risk factors, Dr. Brauer noted that unmeasured confounders such as physical and sexual activity, which were not tracked and may predict PDE5I exposure, may have affected the results. 

Interpret With Caution

Commenting on the findings, Ozama Ismail, PhD, Alzheimer’s Association director of scientific programs, noted that in addition to the limitations cited by the study authors, AD diagnoses were not made with the “gold standard” testing that typically includes imaging biomarkers and postmortem assessments. 

“While this study is interesting and adds to a potential association, there is no evidence that these drugs are able to treat Alzheimer’s disease,” said Dr. Brauer, who was not part of the current study. 

“People should not use over-the-counter phosphodiesterase type 5 inhibitors for prevention of Alzheimer’s or other dementias based on this very preliminary finding. Always consult with your physician before starting or changing your medications,” he cautioned.

However, Dr. Ismael added that the study does highlight a potential new avenue for drug repurposing. 

“Repurposing of existing, already-approved treatments can be a valuable part of drug development because, through already-completed testing, we know much about their safety and side effects,” which can decrease cost and time needed for studies, he said. 

“When considering repurposing an existing drug to an Alzheimer’s treatment, however, it is often important to conduct new studies over longer periods of time and in older people that reflect the diversity of individuals living with Alzheimer’s disease,” Dr. Ismael said.

Randomized Trials Needed

Dr. Brauer agreed, offering that such a trial should also include people with mild cognitive impairment and measure the effects of PDE5Is given in predefined doses plus an acetylcholinesterase inhibitor or placebo plus an acetylcholinesterase inhibitor. 

“The primary outcome would be the change in baseline cognitive function,” she said. “This approach would provide a comprehensive understanding of the potential therapeutic benefits of PDE5I and AD.”

Studies are also needed to better understand the mechanisms by which these drugs might influence AD risk, Sevil Yasar, MD, PhD, and Lolita Nidadavolu, MD, PhD, from the Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, noted in an accompanying editorial.

The strong association between PDE5I use and AD risk in people with a history of hypertension or diabetes suggests “a potential neuroprotective effect through a vascular pathway,” they wrote.

In vitro studies on the role of inflammation and clearance of beta-amyloid could strengthen findings from studies like this one, and in vivo studies could help explain the mechanisms behind PDE5I use and lower AD risk, Dr. Yasar and Dr. Nidadavolu noted. 

“In the end, however, further observational studies exploring mechanisms will not prove a causal association,” they wrote. “A well-designed randomized controlled trial is needed before PDE5I drugs can be prescribed for AD prevention.”

The study was unfunded. The study and editorial authors and Dr. Ismail report no relevant financial conflicts. 
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has cleared NM-101 (Terran Biosciences), a cloud-based software platform to analyze neuromelanin-sensitive MRI scans, which could aid in the diagnosis of neurodegenerative diseases. 

Research has suggested that neuromelanin is a potential biomarker for neurologic disorders such as Parkinson’s disease.

A recent meta-analysis of 12 neuromelanin MRI studies with 403 patients with Parkinson’s disease and 298 control participants found that neuromelanin MRI had “favorable” diagnostic performance in discriminating patients with Parkinson’s disease from healthy controls.

Until now, there were no FDA-approved devices capable of providing clinicians with analysis of neuromelanin MRI due to a lack of automation and standardization. NM-101 contains algorithms that enable fully automated analysis and the cross-scanner harmonization of neuromelanin MRI scans, the company explains in a news release.

NM-101 is designed to “seamlessly” integrate into existing workflows at hospitals and imaging centers, the company says. 

The platform allows clinicians to send neuromelanin MRI images to Terran directly through the hospital picture archiving and communication system and receive results in less than 1 hour. 

When interpreted by a neuroradiologist, NM-101 could provide information that may be helpful in determining neuromelanin association as an adjunct to diagnosis.

“We believe this technology could become very important in the clinical workflow of patients with neurological and psychiatric disorders,” Terran Biosciences Founder and CEO Sam Clark, MD, PhD, said in the release. 

Neuromelanin MRI has the potential to become “part of the standard of care for the workup of all patients suspected of Parkinson’s and related diseases,” David Sulzer, PhD, professor of neurobiology at Columbia University Vagelos College of Physicians and Surgeons, New York, and co-author of multiple studies using neuromelanin MRI, commented in the news release.

“It’s great to see neuromelanin MRI become more accessible in clinical settings. We hope this opens the door for the adoption of neuromelanin MRI into the clinical workflow for patients with neuropsychiatric disorders,” added Guillermo Horga, MD, PhD, associate professor of psychiatry at Columbia University Vagelos College of Physicians and Surgeons.

Terran Biosciences has an exclusive license to the CNS biomarker software platform and related patents co-owned by Columbia University and Research Foundation for Mental Hygiene. Dr. Horga will receive a portion of the royalties paid to Columbia University for sales of the product.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has cleared NM-101 (Terran Biosciences), a cloud-based software platform to analyze neuromelanin-sensitive MRI scans, which could aid in the diagnosis of neurodegenerative diseases. 

Research has suggested that neuromelanin is a potential biomarker for neurologic disorders such as Parkinson’s disease.

A recent meta-analysis of 12 neuromelanin MRI studies with 403 patients with Parkinson’s disease and 298 control participants found that neuromelanin MRI had “favorable” diagnostic performance in discriminating patients with Parkinson’s disease from healthy controls.

Until now, there were no FDA-approved devices capable of providing clinicians with analysis of neuromelanin MRI due to a lack of automation and standardization. NM-101 contains algorithms that enable fully automated analysis and the cross-scanner harmonization of neuromelanin MRI scans, the company explains in a news release.

NM-101 is designed to “seamlessly” integrate into existing workflows at hospitals and imaging centers, the company says. 

The platform allows clinicians to send neuromelanin MRI images to Terran directly through the hospital picture archiving and communication system and receive results in less than 1 hour. 

When interpreted by a neuroradiologist, NM-101 could provide information that may be helpful in determining neuromelanin association as an adjunct to diagnosis.

“We believe this technology could become very important in the clinical workflow of patients with neurological and psychiatric disorders,” Terran Biosciences Founder and CEO Sam Clark, MD, PhD, said in the release. 

Neuromelanin MRI has the potential to become “part of the standard of care for the workup of all patients suspected of Parkinson’s and related diseases,” David Sulzer, PhD, professor of neurobiology at Columbia University Vagelos College of Physicians and Surgeons, New York, and co-author of multiple studies using neuromelanin MRI, commented in the news release.

“It’s great to see neuromelanin MRI become more accessible in clinical settings. We hope this opens the door for the adoption of neuromelanin MRI into the clinical workflow for patients with neuropsychiatric disorders,” added Guillermo Horga, MD, PhD, associate professor of psychiatry at Columbia University Vagelos College of Physicians and Surgeons.

Terran Biosciences has an exclusive license to the CNS biomarker software platform and related patents co-owned by Columbia University and Research Foundation for Mental Hygiene. Dr. Horga will receive a portion of the royalties paid to Columbia University for sales of the product.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has cleared NM-101 (Terran Biosciences), a cloud-based software platform to analyze neuromelanin-sensitive MRI scans, which could aid in the diagnosis of neurodegenerative diseases. 

Research has suggested that neuromelanin is a potential biomarker for neurologic disorders such as Parkinson’s disease.

A recent meta-analysis of 12 neuromelanin MRI studies with 403 patients with Parkinson’s disease and 298 control participants found that neuromelanin MRI had “favorable” diagnostic performance in discriminating patients with Parkinson’s disease from healthy controls.

Until now, there were no FDA-approved devices capable of providing clinicians with analysis of neuromelanin MRI due to a lack of automation and standardization. NM-101 contains algorithms that enable fully automated analysis and the cross-scanner harmonization of neuromelanin MRI scans, the company explains in a news release.

NM-101 is designed to “seamlessly” integrate into existing workflows at hospitals and imaging centers, the company says. 

The platform allows clinicians to send neuromelanin MRI images to Terran directly through the hospital picture archiving and communication system and receive results in less than 1 hour. 

When interpreted by a neuroradiologist, NM-101 could provide information that may be helpful in determining neuromelanin association as an adjunct to diagnosis.

“We believe this technology could become very important in the clinical workflow of patients with neurological and psychiatric disorders,” Terran Biosciences Founder and CEO Sam Clark, MD, PhD, said in the release. 

Neuromelanin MRI has the potential to become “part of the standard of care for the workup of all patients suspected of Parkinson’s and related diseases,” David Sulzer, PhD, professor of neurobiology at Columbia University Vagelos College of Physicians and Surgeons, New York, and co-author of multiple studies using neuromelanin MRI, commented in the news release.

“It’s great to see neuromelanin MRI become more accessible in clinical settings. We hope this opens the door for the adoption of neuromelanin MRI into the clinical workflow for patients with neuropsychiatric disorders,” added Guillermo Horga, MD, PhD, associate professor of psychiatry at Columbia University Vagelos College of Physicians and Surgeons.

Terran Biosciences has an exclusive license to the CNS biomarker software platform and related patents co-owned by Columbia University and Research Foundation for Mental Hygiene. Dr. Horga will receive a portion of the royalties paid to Columbia University for sales of the product.

A version of this article appeared on Medscape.com.

Comorbidities may play a large role in driving poor pregnancy outcomes in pregnant people with certain immune-mediated inflammatory diseases (IMIDs).

In a new study of 12 individual IMIDs, people with rheumatoid arthritis (RA) or inflammatory bowel disease (IBD) did not have signficantly increased risk for preterm birth (PTB) or low birth weight (LBW), compared with people who did not have an IMID, after adjusting for additional chronic conditions and other confounding factors.

The study was published online on February 1 in eClinicalMedicine.

While many studies have explored the relationships between pregnancy outcomes and IMIDs, “the impact of comorbidities on the relation between IMIDs and pregnancy course is insufficiently examined,” the authors wrote. These previous studies also tended to have a small sample size.
 

Pregnancy Outcome Risks Varied Between IMIDs

To remedy this, researchers used electronic health record data from Providence St Joseph Health — a multistate integrated healthcare system — to identify more than 365,000 pregnant people with live births between January 1, 2013, and December 31, 2022. The cohort included more than 5700 people with at least one of 12 IMIDs: Psoriasis, IBD, RA, spondyloarthritis (SpA), multiple sclerosis, systemic lupus erythematosus (SLE), psoriatic arthritis (PsA), antiphospholipid syndrome (APS), Sjögren syndrome (SjS), vasculitis, sarcoidosis, and systemic sclerosis. The study included only live births with a gestational age of 20 weeks or greater.

Researchers compared maternal-fetal health outcomes between the two groups, controlling for comorbidities including diabetes, cardiovascular disease, chronic kidney disease, obesity, and depression. They also accounted for confounding variables including race, age, smoking status, and socioeconomic status.

In total, 83% of people in the IMID group had no immunomodulatory medication prescriptions during their pregnancy. Of the 17% taking medication, 48%-70% continued taking their medication until delivery. Most patients were White, comprising 62.9% of the non-IMID group and 73.1% of the IMID group.

After adjusting for comorbidities, patients with any of the 12 IMIDs had a 10%-20% higher risk for PTB, LBW, small for gestation age (SGA), and cesarean section than did comparators.

But these risks varied between IMIDs. Patients with RA and IBD did not have an increased risk for PTB or LBW. However, when researchers did not control for comorbidities, pregnancy risks were higher and showed statistical significance in these two groups.

“This suggests that for RA and IBD, comorbidities may be a more important factor for adverse outcomes than the underlying autoimmune disease,” senior author Jennifer Hadlock, MD, an associate professor and director of medical data science at the Institute for Systems Biology in Seattle, Washington, said in a video accompanying a press release.

Overall, the analysis found that women with IMIDs were approximately two to three times more likely to have chronic comorbidities than the control group.

Like previous studies, there was a strong association between SLE and APS and poor pregnancy outcomes, even after controlling for confounding factors. Patients with SpA had a 50% increased risk for PTB, while those with SLE and APS had more than a twofold higher risk. Patients with SLE were 90% more likely than comparators to deliver babies with an SGA condition, while RA patients had a 30% higher risk. SLE was the only condition with an increased risk for LBW (relative risk, 3.5). IBD, RA, PsA, SpA, SLE, APS, and SjS were all associated with a higher likelihood of delivery via cesarean section.

“The findings of this study reveal that the associations between IMIDs and adverse pregnancy outcomes are influenced by the specific type of IMIDs and the presence of comorbidities,” the authors wrote.
 

A Large Study, But How Representative Is It?

Asked to comment on the study, Catherine Sims, MD, a rheumatologist at Duke University Medical Center in Durham, North Carolina, noted that the analysis was much larger than many reproductive rheumatology studies, and “their statistics were phenomenal.”

She agreed that “not all autoimmune diseases are created equal when it comes to pregnancy-associated risks.” However, she added that this study’s patient population may not be totally representative of pregnant people with IMIDs or autoimmune diseases.

“We’re making generalizations about autoimmune diseases based on this demographic of White women who are not taking immunosuppression,” she said.

“We know that race and ethnicity play a huge role in pregnancy outcomes, and Black women have higher maternal and fetal morbidity and mortality, which is likely related to systemic racism and biases in the medical system,” she added. “While the study did control for sociodemographic factors, the population studied is not diverse.”

Only 17% of people with IMID in the cohort were on immunosuppressive medication, which could suggest low disease activity in the study population, Dr. Sims said. If the population generally had well-controlled disease, that could have positioned them for better pregnancy outcomes.

The authors noted that their analysis did not have information on IMID disease activity or severity — one of the limitations of the study.

However, the authors argued that the observed low prescription rate during the study may have increased poor pregnancy outcomes.

“Although this reflects real-world care in the population studied, results from this study may show higher risk than might be achieved with recommended care guidelines,” they wrote.

Ultimately, the authors argued that these findings show how co-occurring health conditions can affect pregnancy outcomes in autoimmune diseases, particularly for RA and IBD.

“There is a need to take comorbidities into consideration for guidelines for patients with inflammatory bowel disease and rheumatoid arthritis and when designing future research to investigate maternal health in patients with IMIDs,” they wrote.

The study was funded by the National Institutes of Health. Dr. Sims declared no relevant financial relationships. Dr. Hadlock has received research funding (paid to the institute) from Pfizer, Novartis, Janssen, Bristol-Myers Squibb, and Gilead.

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

Comorbidities may play a large role in driving poor pregnancy outcomes in pregnant people with certain immune-mediated inflammatory diseases (IMIDs).

In a new study of 12 individual IMIDs, people with rheumatoid arthritis (RA) or inflammatory bowel disease (IBD) did not have signficantly increased risk for preterm birth (PTB) or low birth weight (LBW), compared with people who did not have an IMID, after adjusting for additional chronic conditions and other confounding factors.

The study was published online on February 1 in eClinicalMedicine.

While many studies have explored the relationships between pregnancy outcomes and IMIDs, “the impact of comorbidities on the relation between IMIDs and pregnancy course is insufficiently examined,” the authors wrote. These previous studies also tended to have a small sample size.
 

Pregnancy Outcome Risks Varied Between IMIDs

To remedy this, researchers used electronic health record data from Providence St Joseph Health — a multistate integrated healthcare system — to identify more than 365,000 pregnant people with live births between January 1, 2013, and December 31, 2022. The cohort included more than 5700 people with at least one of 12 IMIDs: Psoriasis, IBD, RA, spondyloarthritis (SpA), multiple sclerosis, systemic lupus erythematosus (SLE), psoriatic arthritis (PsA), antiphospholipid syndrome (APS), Sjögren syndrome (SjS), vasculitis, sarcoidosis, and systemic sclerosis. The study included only live births with a gestational age of 20 weeks or greater.

Researchers compared maternal-fetal health outcomes between the two groups, controlling for comorbidities including diabetes, cardiovascular disease, chronic kidney disease, obesity, and depression. They also accounted for confounding variables including race, age, smoking status, and socioeconomic status.

In total, 83% of people in the IMID group had no immunomodulatory medication prescriptions during their pregnancy. Of the 17% taking medication, 48%-70% continued taking their medication until delivery. Most patients were White, comprising 62.9% of the non-IMID group and 73.1% of the IMID group.

After adjusting for comorbidities, patients with any of the 12 IMIDs had a 10%-20% higher risk for PTB, LBW, small for gestation age (SGA), and cesarean section than did comparators.

But these risks varied between IMIDs. Patients with RA and IBD did not have an increased risk for PTB or LBW. However, when researchers did not control for comorbidities, pregnancy risks were higher and showed statistical significance in these two groups.

“This suggests that for RA and IBD, comorbidities may be a more important factor for adverse outcomes than the underlying autoimmune disease,” senior author Jennifer Hadlock, MD, an associate professor and director of medical data science at the Institute for Systems Biology in Seattle, Washington, said in a video accompanying a press release.

Overall, the analysis found that women with IMIDs were approximately two to three times more likely to have chronic comorbidities than the control group.

Like previous studies, there was a strong association between SLE and APS and poor pregnancy outcomes, even after controlling for confounding factors. Patients with SpA had a 50% increased risk for PTB, while those with SLE and APS had more than a twofold higher risk. Patients with SLE were 90% more likely than comparators to deliver babies with an SGA condition, while RA patients had a 30% higher risk. SLE was the only condition with an increased risk for LBW (relative risk, 3.5). IBD, RA, PsA, SpA, SLE, APS, and SjS were all associated with a higher likelihood of delivery via cesarean section.

“The findings of this study reveal that the associations between IMIDs and adverse pregnancy outcomes are influenced by the specific type of IMIDs and the presence of comorbidities,” the authors wrote.
 

A Large Study, But How Representative Is It?

Asked to comment on the study, Catherine Sims, MD, a rheumatologist at Duke University Medical Center in Durham, North Carolina, noted that the analysis was much larger than many reproductive rheumatology studies, and “their statistics were phenomenal.”

She agreed that “not all autoimmune diseases are created equal when it comes to pregnancy-associated risks.” However, she added that this study’s patient population may not be totally representative of pregnant people with IMIDs or autoimmune diseases.

“We’re making generalizations about autoimmune diseases based on this demographic of White women who are not taking immunosuppression,” she said.

“We know that race and ethnicity play a huge role in pregnancy outcomes, and Black women have higher maternal and fetal morbidity and mortality, which is likely related to systemic racism and biases in the medical system,” she added. “While the study did control for sociodemographic factors, the population studied is not diverse.”

Only 17% of people with IMID in the cohort were on immunosuppressive medication, which could suggest low disease activity in the study population, Dr. Sims said. If the population generally had well-controlled disease, that could have positioned them for better pregnancy outcomes.

The authors noted that their analysis did not have information on IMID disease activity or severity — one of the limitations of the study.

However, the authors argued that the observed low prescription rate during the study may have increased poor pregnancy outcomes.

“Although this reflects real-world care in the population studied, results from this study may show higher risk than might be achieved with recommended care guidelines,” they wrote.

Ultimately, the authors argued that these findings show how co-occurring health conditions can affect pregnancy outcomes in autoimmune diseases, particularly for RA and IBD.

“There is a need to take comorbidities into consideration for guidelines for patients with inflammatory bowel disease and rheumatoid arthritis and when designing future research to investigate maternal health in patients with IMIDs,” they wrote.

The study was funded by the National Institutes of Health. Dr. Sims declared no relevant financial relationships. Dr. Hadlock has received research funding (paid to the institute) from Pfizer, Novartis, Janssen, Bristol-Myers Squibb, and Gilead.

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

Comorbidities may play a large role in driving poor pregnancy outcomes in pregnant people with certain immune-mediated inflammatory diseases (IMIDs).

In a new study of 12 individual IMIDs, people with rheumatoid arthritis (RA) or inflammatory bowel disease (IBD) did not have signficantly increased risk for preterm birth (PTB) or low birth weight (LBW), compared with people who did not have an IMID, after adjusting for additional chronic conditions and other confounding factors.

The study was published online on February 1 in eClinicalMedicine.

While many studies have explored the relationships between pregnancy outcomes and IMIDs, “the impact of comorbidities on the relation between IMIDs and pregnancy course is insufficiently examined,” the authors wrote. These previous studies also tended to have a small sample size.
 

Pregnancy Outcome Risks Varied Between IMIDs

To remedy this, researchers used electronic health record data from Providence St Joseph Health — a multistate integrated healthcare system — to identify more than 365,000 pregnant people with live births between January 1, 2013, and December 31, 2022. The cohort included more than 5700 people with at least one of 12 IMIDs: Psoriasis, IBD, RA, spondyloarthritis (SpA), multiple sclerosis, systemic lupus erythematosus (SLE), psoriatic arthritis (PsA), antiphospholipid syndrome (APS), Sjögren syndrome (SjS), vasculitis, sarcoidosis, and systemic sclerosis. The study included only live births with a gestational age of 20 weeks or greater.

Researchers compared maternal-fetal health outcomes between the two groups, controlling for comorbidities including diabetes, cardiovascular disease, chronic kidney disease, obesity, and depression. They also accounted for confounding variables including race, age, smoking status, and socioeconomic status.

In total, 83% of people in the IMID group had no immunomodulatory medication prescriptions during their pregnancy. Of the 17% taking medication, 48%-70% continued taking their medication until delivery. Most patients were White, comprising 62.9% of the non-IMID group and 73.1% of the IMID group.

After adjusting for comorbidities, patients with any of the 12 IMIDs had a 10%-20% higher risk for PTB, LBW, small for gestation age (SGA), and cesarean section than did comparators.

But these risks varied between IMIDs. Patients with RA and IBD did not have an increased risk for PTB or LBW. However, when researchers did not control for comorbidities, pregnancy risks were higher and showed statistical significance in these two groups.

“This suggests that for RA and IBD, comorbidities may be a more important factor for adverse outcomes than the underlying autoimmune disease,” senior author Jennifer Hadlock, MD, an associate professor and director of medical data science at the Institute for Systems Biology in Seattle, Washington, said in a video accompanying a press release.

Overall, the analysis found that women with IMIDs were approximately two to three times more likely to have chronic comorbidities than the control group.

Like previous studies, there was a strong association between SLE and APS and poor pregnancy outcomes, even after controlling for confounding factors. Patients with SpA had a 50% increased risk for PTB, while those with SLE and APS had more than a twofold higher risk. Patients with SLE were 90% more likely than comparators to deliver babies with an SGA condition, while RA patients had a 30% higher risk. SLE was the only condition with an increased risk for LBW (relative risk, 3.5). IBD, RA, PsA, SpA, SLE, APS, and SjS were all associated with a higher likelihood of delivery via cesarean section.

“The findings of this study reveal that the associations between IMIDs and adverse pregnancy outcomes are influenced by the specific type of IMIDs and the presence of comorbidities,” the authors wrote.
 

A Large Study, But How Representative Is It?

Asked to comment on the study, Catherine Sims, MD, a rheumatologist at Duke University Medical Center in Durham, North Carolina, noted that the analysis was much larger than many reproductive rheumatology studies, and “their statistics were phenomenal.”

She agreed that “not all autoimmune diseases are created equal when it comes to pregnancy-associated risks.” However, she added that this study’s patient population may not be totally representative of pregnant people with IMIDs or autoimmune diseases.

“We’re making generalizations about autoimmune diseases based on this demographic of White women who are not taking immunosuppression,” she said.

“We know that race and ethnicity play a huge role in pregnancy outcomes, and Black women have higher maternal and fetal morbidity and mortality, which is likely related to systemic racism and biases in the medical system,” she added. “While the study did control for sociodemographic factors, the population studied is not diverse.”

Only 17% of people with IMID in the cohort were on immunosuppressive medication, which could suggest low disease activity in the study population, Dr. Sims said. If the population generally had well-controlled disease, that could have positioned them for better pregnancy outcomes.

The authors noted that their analysis did not have information on IMID disease activity or severity — one of the limitations of the study.

However, the authors argued that the observed low prescription rate during the study may have increased poor pregnancy outcomes.

“Although this reflects real-world care in the population studied, results from this study may show higher risk than might be achieved with recommended care guidelines,” they wrote.

Ultimately, the authors argued that these findings show how co-occurring health conditions can affect pregnancy outcomes in autoimmune diseases, particularly for RA and IBD.

“There is a need to take comorbidities into consideration for guidelines for patients with inflammatory bowel disease and rheumatoid arthritis and when designing future research to investigate maternal health in patients with IMIDs,” they wrote.

The study was funded by the National Institutes of Health. Dr. Sims declared no relevant financial relationships. Dr. Hadlock has received research funding (paid to the institute) from Pfizer, Novartis, Janssen, Bristol-Myers Squibb, and Gilead.

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