Neurology

‘Grainy’ or ‘pixelated’ vision can be an alarming symptom for patients. The phenomenon is called visual snow, and although it was first described only recently, it is fairly common.

“This is a symptom of vision where patients describe numerous flickering dots throughout their vision. Sometimes they’ll use the term grainy or pixelated vision. Many times there’s a dynamic moving component to this. Many patients will describe this as like a TV static overlay on their vision,” Carrie Robertson, MD, said during a presentation on the topic at the 2021 Scottsdale Headache Symposium. Dr. Robertson is a neurologist at the Mayo Clinic in Rochester, Minn.

“It turns out that a little over 3% of us probably see this in our vision. So even if you haven’t seen this in the clinic yet, it’s likely that you will in the future,” said Dr. Robertson.

The first report describing visual snow appeared in 1995, among migraine patients. As of 2014 there were only 10 cases described in the literature. Although the condition was initially thought of as an unusual feature of migraine, a 2014 combined chart review and survey found that 15 of 22 patients had additional visual symptoms, such as photophobia or difficulty with night vision. Twenty of the 22 patients had comorbid migraine. Other symptoms include visual ghosts that persist after looking away from an object, as well as a higher frequency of experiencing floaters.

Symptoms aren’t restricted to the visual domain. Migraine, tinnitus, dizziness, and impaired concentration also occur.

The condition is more common than many suspect. “We used to think it was very rare. Now we assume that this was just under recognized,” said Dr. Robertson. One survey in the United Kingdom found that 3.7% of respondents reported visual snow, and 2.2% met the criteria for the syndrome.
 

A common and typically benign problem

It is a common clinical problem, according to Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program. “Almost every week I personally see somebody and then in our group, we have a whole host of them,” he said.

“When you see these patients in clinic, it’s important to remember that this is a heterogeneous disorder,” said Dr. Robertson. “Some patients will say, ‘Oh yeah, I’ve seen visual snow for as long as I can remember, I didn’t even know it was abnormal.’ Some will describe a family history of visual snow. Others will show up in clinic panicked because their visual snow just started or sometimes it’ll start after a triggering events like a head injury or hallucinogen use, and they’re worried that they’re going to go blind.”

It’s important to rule out other potential causes. Dr. Robertson’s group examined 248 cases of visual snow and found that 89 had a comorbidity that explained the condition. Issues within the retina, cornea, and the optical nerve can cause visual snow, which makes it critical that patients be seen by an ophthalmologist.

Some patients reported improvement when they stopped a new medication. “I always ask if there was a specific medicine that they started at the onset of their symptoms,” said Dr. Robertson. Other rare conditions associated with visual snow include idiopathic intracranial hypertension, posterior cortical atrophy, and even the Heidenhain variant of Creutzfeldt-Jakob disease.

In the absence of a secondary cause, and the if condition doesn’t worsen, physicians should reassure patients that the condition is typically benign. “Many of these patients are panicked that they’re going to lose their vision, and that’s what brings them to your office. It’s important to stress that visual snow is real, that you believe them, that they’re seeing what they say that they’re seeing. It’s not a migraine aura, but it’s typically benign. I like to give the analogy that it’s similar to tinnitus because I think that that’s helpful for patients to put it in that category of benign but very annoying,” said Dr. Robertson.
 

Limited treatment options

Unfortunately, there is little evidence on medications to treat the problem. According to Dr. Robertson, the best available evidence – from case reports – is for lamotrigine. Nearly 20% of patients achieve a partial response, and complete responses are rare.

Clinical trials are a possibility, but patients should be made aware that medications have the potential to worsen visual snow.

Nonpharmaceutical approaches include visual and mental distraction, along with manipulation of lighting at work and at home. Stress reduction may help, and Dr. Robertson may send patients with dizziness for visual vestibular therapy to work on visual motion desensitization exercises.

There are visual snow relief videos available on YouTube, which may provide temporary relief. “It’s probably similar to white noise therapy for tinnitus,” said Dr. Robertson.

Colored glass lenses may be helpful. “I’m having the best success at this point with FL-41 lenses. Some prefer amber, and others prefer the rose-tinted, just like migraine. I usually start with that,” said Dr. Robertson. Yellow lenses may help with nyctalopia.

She recommends that patients avoid consuming too much caffeine, and that they avoid stimulants, especially attention-deficit disorder (ADD) medications. “I’ve had a lot of patients worsen with ADD medication,” said Dr. Robertson. She also warns patients away from marijuana and hallucinogens.

There is a large community available for patients with visual snow, including more than 60 Facebook groups, and many YouTube videos of patients describing their experiences. There is even a visual snow simulator that neurologists can show patients to confirm what they are seeing. “It’s very validating for the patient,” said Dr. Robertson.

Dr. Charles noted the relatively few treatment options and poor understanding of the mechanisms behind the condition. “It’s incredibly frustrating that we have to tell them that we have so little understanding of basic mechanisms, and no really clear therapeutic strategy that we can apply across all patients and expect results,” said Dr. Charles.

The heightened interest in the condition does represent some hope. “It’s very much reassuring to people that, number one, we’re starting to understand it – but number two, that they’re not crazy. It’s very much validating to hear that it’s now a topic of much more rigorous investigation,” said Dr. Charles.

Dr. Robertson and Dr. Charles have no relevant financial disclosures.

‘Grainy’ or ‘pixelated’ vision can be an alarming symptom for patients. The phenomenon is called visual snow, and although it was first described only recently, it is fairly common.

“This is a symptom of vision where patients describe numerous flickering dots throughout their vision. Sometimes they’ll use the term grainy or pixelated vision. Many times there’s a dynamic moving component to this. Many patients will describe this as like a TV static overlay on their vision,” Carrie Robertson, MD, said during a presentation on the topic at the 2021 Scottsdale Headache Symposium. Dr. Robertson is a neurologist at the Mayo Clinic in Rochester, Minn.

“It turns out that a little over 3% of us probably see this in our vision. So even if you haven’t seen this in the clinic yet, it’s likely that you will in the future,” said Dr. Robertson.

The first report describing visual snow appeared in 1995, among migraine patients. As of 2014 there were only 10 cases described in the literature. Although the condition was initially thought of as an unusual feature of migraine, a 2014 combined chart review and survey found that 15 of 22 patients had additional visual symptoms, such as photophobia or difficulty with night vision. Twenty of the 22 patients had comorbid migraine. Other symptoms include visual ghosts that persist after looking away from an object, as well as a higher frequency of experiencing floaters.

Symptoms aren’t restricted to the visual domain. Migraine, tinnitus, dizziness, and impaired concentration also occur.

The condition is more common than many suspect. “We used to think it was very rare. Now we assume that this was just under recognized,” said Dr. Robertson. One survey in the United Kingdom found that 3.7% of respondents reported visual snow, and 2.2% met the criteria for the syndrome.
 

A common and typically benign problem

It is a common clinical problem, according to Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program. “Almost every week I personally see somebody and then in our group, we have a whole host of them,” he said.

“When you see these patients in clinic, it’s important to remember that this is a heterogeneous disorder,” said Dr. Robertson. “Some patients will say, ‘Oh yeah, I’ve seen visual snow for as long as I can remember, I didn’t even know it was abnormal.’ Some will describe a family history of visual snow. Others will show up in clinic panicked because their visual snow just started or sometimes it’ll start after a triggering events like a head injury or hallucinogen use, and they’re worried that they’re going to go blind.”

It’s important to rule out other potential causes. Dr. Robertson’s group examined 248 cases of visual snow and found that 89 had a comorbidity that explained the condition. Issues within the retina, cornea, and the optical nerve can cause visual snow, which makes it critical that patients be seen by an ophthalmologist.

Some patients reported improvement when they stopped a new medication. “I always ask if there was a specific medicine that they started at the onset of their symptoms,” said Dr. Robertson. Other rare conditions associated with visual snow include idiopathic intracranial hypertension, posterior cortical atrophy, and even the Heidenhain variant of Creutzfeldt-Jakob disease.

In the absence of a secondary cause, and the if condition doesn’t worsen, physicians should reassure patients that the condition is typically benign. “Many of these patients are panicked that they’re going to lose their vision, and that’s what brings them to your office. It’s important to stress that visual snow is real, that you believe them, that they’re seeing what they say that they’re seeing. It’s not a migraine aura, but it’s typically benign. I like to give the analogy that it’s similar to tinnitus because I think that that’s helpful for patients to put it in that category of benign but very annoying,” said Dr. Robertson.
 

Limited treatment options

Unfortunately, there is little evidence on medications to treat the problem. According to Dr. Robertson, the best available evidence – from case reports – is for lamotrigine. Nearly 20% of patients achieve a partial response, and complete responses are rare.

Clinical trials are a possibility, but patients should be made aware that medications have the potential to worsen visual snow.

Nonpharmaceutical approaches include visual and mental distraction, along with manipulation of lighting at work and at home. Stress reduction may help, and Dr. Robertson may send patients with dizziness for visual vestibular therapy to work on visual motion desensitization exercises.

There are visual snow relief videos available on YouTube, which may provide temporary relief. “It’s probably similar to white noise therapy for tinnitus,” said Dr. Robertson.

Colored glass lenses may be helpful. “I’m having the best success at this point with FL-41 lenses. Some prefer amber, and others prefer the rose-tinted, just like migraine. I usually start with that,” said Dr. Robertson. Yellow lenses may help with nyctalopia.

She recommends that patients avoid consuming too much caffeine, and that they avoid stimulants, especially attention-deficit disorder (ADD) medications. “I’ve had a lot of patients worsen with ADD medication,” said Dr. Robertson. She also warns patients away from marijuana and hallucinogens.

There is a large community available for patients with visual snow, including more than 60 Facebook groups, and many YouTube videos of patients describing their experiences. There is even a visual snow simulator that neurologists can show patients to confirm what they are seeing. “It’s very validating for the patient,” said Dr. Robertson.

Dr. Charles noted the relatively few treatment options and poor understanding of the mechanisms behind the condition. “It’s incredibly frustrating that we have to tell them that we have so little understanding of basic mechanisms, and no really clear therapeutic strategy that we can apply across all patients and expect results,” said Dr. Charles.

The heightened interest in the condition does represent some hope. “It’s very much reassuring to people that, number one, we’re starting to understand it – but number two, that they’re not crazy. It’s very much validating to hear that it’s now a topic of much more rigorous investigation,” said Dr. Charles.

Dr. Robertson and Dr. Charles have no relevant financial disclosures.

‘Grainy’ or ‘pixelated’ vision can be an alarming symptom for patients. The phenomenon is called visual snow, and although it was first described only recently, it is fairly common.

“This is a symptom of vision where patients describe numerous flickering dots throughout their vision. Sometimes they’ll use the term grainy or pixelated vision. Many times there’s a dynamic moving component to this. Many patients will describe this as like a TV static overlay on their vision,” Carrie Robertson, MD, said during a presentation on the topic at the 2021 Scottsdale Headache Symposium. Dr. Robertson is a neurologist at the Mayo Clinic in Rochester, Minn.

“It turns out that a little over 3% of us probably see this in our vision. So even if you haven’t seen this in the clinic yet, it’s likely that you will in the future,” said Dr. Robertson.

The first report describing visual snow appeared in 1995, among migraine patients. As of 2014 there were only 10 cases described in the literature. Although the condition was initially thought of as an unusual feature of migraine, a 2014 combined chart review and survey found that 15 of 22 patients had additional visual symptoms, such as photophobia or difficulty with night vision. Twenty of the 22 patients had comorbid migraine. Other symptoms include visual ghosts that persist after looking away from an object, as well as a higher frequency of experiencing floaters.

Symptoms aren’t restricted to the visual domain. Migraine, tinnitus, dizziness, and impaired concentration also occur.

The condition is more common than many suspect. “We used to think it was very rare. Now we assume that this was just under recognized,” said Dr. Robertson. One survey in the United Kingdom found that 3.7% of respondents reported visual snow, and 2.2% met the criteria for the syndrome.
 

A common and typically benign problem

It is a common clinical problem, according to Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program. “Almost every week I personally see somebody and then in our group, we have a whole host of them,” he said.

“When you see these patients in clinic, it’s important to remember that this is a heterogeneous disorder,” said Dr. Robertson. “Some patients will say, ‘Oh yeah, I’ve seen visual snow for as long as I can remember, I didn’t even know it was abnormal.’ Some will describe a family history of visual snow. Others will show up in clinic panicked because their visual snow just started or sometimes it’ll start after a triggering events like a head injury or hallucinogen use, and they’re worried that they’re going to go blind.”

It’s important to rule out other potential causes. Dr. Robertson’s group examined 248 cases of visual snow and found that 89 had a comorbidity that explained the condition. Issues within the retina, cornea, and the optical nerve can cause visual snow, which makes it critical that patients be seen by an ophthalmologist.

Some patients reported improvement when they stopped a new medication. “I always ask if there was a specific medicine that they started at the onset of their symptoms,” said Dr. Robertson. Other rare conditions associated with visual snow include idiopathic intracranial hypertension, posterior cortical atrophy, and even the Heidenhain variant of Creutzfeldt-Jakob disease.

In the absence of a secondary cause, and the if condition doesn’t worsen, physicians should reassure patients that the condition is typically benign. “Many of these patients are panicked that they’re going to lose their vision, and that’s what brings them to your office. It’s important to stress that visual snow is real, that you believe them, that they’re seeing what they say that they’re seeing. It’s not a migraine aura, but it’s typically benign. I like to give the analogy that it’s similar to tinnitus because I think that that’s helpful for patients to put it in that category of benign but very annoying,” said Dr. Robertson.
 

Limited treatment options

Unfortunately, there is little evidence on medications to treat the problem. According to Dr. Robertson, the best available evidence – from case reports – is for lamotrigine. Nearly 20% of patients achieve a partial response, and complete responses are rare.

Clinical trials are a possibility, but patients should be made aware that medications have the potential to worsen visual snow.

Nonpharmaceutical approaches include visual and mental distraction, along with manipulation of lighting at work and at home. Stress reduction may help, and Dr. Robertson may send patients with dizziness for visual vestibular therapy to work on visual motion desensitization exercises.

There are visual snow relief videos available on YouTube, which may provide temporary relief. “It’s probably similar to white noise therapy for tinnitus,” said Dr. Robertson.

Colored glass lenses may be helpful. “I’m having the best success at this point with FL-41 lenses. Some prefer amber, and others prefer the rose-tinted, just like migraine. I usually start with that,” said Dr. Robertson. Yellow lenses may help with nyctalopia.

She recommends that patients avoid consuming too much caffeine, and that they avoid stimulants, especially attention-deficit disorder (ADD) medications. “I’ve had a lot of patients worsen with ADD medication,” said Dr. Robertson. She also warns patients away from marijuana and hallucinogens.

There is a large community available for patients with visual snow, including more than 60 Facebook groups, and many YouTube videos of patients describing their experiences. There is even a visual snow simulator that neurologists can show patients to confirm what they are seeing. “It’s very validating for the patient,” said Dr. Robertson.

Dr. Charles noted the relatively few treatment options and poor understanding of the mechanisms behind the condition. “It’s incredibly frustrating that we have to tell them that we have so little understanding of basic mechanisms, and no really clear therapeutic strategy that we can apply across all patients and expect results,” said Dr. Charles.

The heightened interest in the condition does represent some hope. “It’s very much reassuring to people that, number one, we’re starting to understand it – but number two, that they’re not crazy. It’s very much validating to hear that it’s now a topic of much more rigorous investigation,” said Dr. Charles.

Dr. Robertson and Dr. Charles have no relevant financial disclosures.

A new blood test that identifies a variant of the protein P53 appears to predict Alzheimer’s disease (AD) progression up to 6 years in advance of a clinical diagnosis, early research suggests.

Analysis of two studies showed the test (AlzoSure Predict), which uses less than 1 ml of blood, had numerous benefits compared with other blood tests that track AD pathology.

“We believe this has the potential to radically improve early stratification and identification of patients for trials 6 years in advance of a diagnosis, which can potentially enable more rapid and efficient approvals of therapies,” Paul Kinnon, CEO of Diadem, the test’s manufacturer, said in an interview.

The findings were presented at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
 

Positive “discovery” results

P53, which is present in both the brain and elsewhere in the body, “is one of the most targeted proteins” for drug development in cancer and other conditions, said Mr. Kinnon.

The current blood test measures a derivative of P53 (U-p53AZ). Previous research suggests this derivative, which affects amyloid and oxidative stress, is also implicated in AD pathogenesis.

Researchers used blood samples from patients aged 60 years and older from the Australia Imaging, Biomarkers, and Lifestyles (AIBL) study who had various levels of cognitive function.

They analyzed samples at multiple timepoints over a 10-year period, “so we know when the marker is most accurate at predicting decline,” Mr. Kinnon said.

The first of two studies was considered a “discovery” study and included blood samples from 224 patients.

Results showed the test predicted decline from mild cognitive impairment (MCI) to AD at the end of 6 years, with an area under the curve (AUC) greater than 90%.

These results are “massive,” said Mr. Kinnon. “It’s the most accurate test I’ve seen anywhere for predicting decline of a patient.”

The test can also accurately classify a patient’s stage of cognition, he added. “Not only does it allow us to predict 6 years in advance, it also tells us if the patient has SMC [subjective memory complaints], MCI, or AD with a 95% certainty,” Mr. Kinnon said.

He noted that test sensitivity was higher than results found from traditional methods that are currently being used. The positive predictive value (PPV) and negative predictive value (NPV), which were at 90% or more, were “absolutely fantastic,” said Mr. Kinnon.
 

“Better than expected” results

In the second “validation” study, investigators examined samples from a completely different group of 482 patients. The “very compelling” results showed AUCs over 90%, PPVs over 90%, and “very high” NPVs, Mr. Kinnon said.

“These are great data, better than we expected,” he added.

However, he noted the test is “very specific” for decline to AD and not to other dementias.

In addition, Mr. Kinnon noted the test does not monitor levels of amyloid beta or tau, which accumulate at a later stage of AD. “Amyloid and tau tell you you’ve got it. We’re there way before those concentrations become detectable,” he said.

Identifying patients who will progress to AD years before they have symptoms gives them time to make medical decisions. These patients may also try treatments at an earlier stage of the disease, when these therapies are most likely to be helpful, said Mr. Kinnon.

In addition, using the test could speed up the approval of prospective drug treatments for AD. Currently, pharmaceutical companies enroll thousands of patients into a clinical study “and they don’t know which ones will have AD,” Mr. Kinnon noted.

“This test tells you these are the ones who are going to progress and should go into the study, and these are the ones that aren’t. So it makes the studies statistically relevant and accurate,” he said.

Investigators can also use the test to monitor patients during a study instead of relying on expensive PET scans and painful and costly spinal fluid taps, he added.

Previous surveys and market research have shown that neurologists and general practitioners “want a blood test to screen patients early, to help educate and inform patients,” said Mr. Kinnon.

Further results that will include biobank data on more than 1,000 patients in the United States and Europe are due for completion toward the end of this year.

The company is currently in negotiations to bring the product to North America, Europe, and elsewhere. “Our goal is to have it on the market by the middle of next year in multiple regions,” Mr. Kinnon said.
 

Encouraging, preliminary

Commenting on the findings, Percy Griffin, PhD, MSc, director of scientific engagement at the Alzheimer’s Association, said “it’s exciting” to see development of novel ways for detecting or predicting AD.

“There is an urgent need for simple, inexpensive, noninvasive, and accessible early detection tools for Alzheimer’s, such as a blood test,” he said.

However, Dr. Griffin cautioned the test is still in the early stages of development and has not been tested extensively in large, diverse clinical trials.

In addition, although the test predicts whether a person will progress, it does not predict when the person will progress, he added.

“These preliminary results are encouraging, but further validation is needed before this test can be implemented widely,” he said.

Technologies that facilitate the early detection and intervention before significant loss of brain cells from AD “would be game-changing” for individuals, families, and the healthcare system, Dr. Griffin concluded.

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

A new blood test that identifies a variant of the protein P53 appears to predict Alzheimer’s disease (AD) progression up to 6 years in advance of a clinical diagnosis, early research suggests.

Analysis of two studies showed the test (AlzoSure Predict), which uses less than 1 ml of blood, had numerous benefits compared with other blood tests that track AD pathology.

“We believe this has the potential to radically improve early stratification and identification of patients for trials 6 years in advance of a diagnosis, which can potentially enable more rapid and efficient approvals of therapies,” Paul Kinnon, CEO of Diadem, the test’s manufacturer, said in an interview.

The findings were presented at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
 

Positive “discovery” results

P53, which is present in both the brain and elsewhere in the body, “is one of the most targeted proteins” for drug development in cancer and other conditions, said Mr. Kinnon.

The current blood test measures a derivative of P53 (U-p53AZ). Previous research suggests this derivative, which affects amyloid and oxidative stress, is also implicated in AD pathogenesis.

Researchers used blood samples from patients aged 60 years and older from the Australia Imaging, Biomarkers, and Lifestyles (AIBL) study who had various levels of cognitive function.

They analyzed samples at multiple timepoints over a 10-year period, “so we know when the marker is most accurate at predicting decline,” Mr. Kinnon said.

The first of two studies was considered a “discovery” study and included blood samples from 224 patients.

Results showed the test predicted decline from mild cognitive impairment (MCI) to AD at the end of 6 years, with an area under the curve (AUC) greater than 90%.

These results are “massive,” said Mr. Kinnon. “It’s the most accurate test I’ve seen anywhere for predicting decline of a patient.”

The test can also accurately classify a patient’s stage of cognition, he added. “Not only does it allow us to predict 6 years in advance, it also tells us if the patient has SMC [subjective memory complaints], MCI, or AD with a 95% certainty,” Mr. Kinnon said.

He noted that test sensitivity was higher than results found from traditional methods that are currently being used. The positive predictive value (PPV) and negative predictive value (NPV), which were at 90% or more, were “absolutely fantastic,” said Mr. Kinnon.
 

“Better than expected” results

In the second “validation” study, investigators examined samples from a completely different group of 482 patients. The “very compelling” results showed AUCs over 90%, PPVs over 90%, and “very high” NPVs, Mr. Kinnon said.

“These are great data, better than we expected,” he added.

However, he noted the test is “very specific” for decline to AD and not to other dementias.

In addition, Mr. Kinnon noted the test does not monitor levels of amyloid beta or tau, which accumulate at a later stage of AD. “Amyloid and tau tell you you’ve got it. We’re there way before those concentrations become detectable,” he said.

Identifying patients who will progress to AD years before they have symptoms gives them time to make medical decisions. These patients may also try treatments at an earlier stage of the disease, when these therapies are most likely to be helpful, said Mr. Kinnon.

In addition, using the test could speed up the approval of prospective drug treatments for AD. Currently, pharmaceutical companies enroll thousands of patients into a clinical study “and they don’t know which ones will have AD,” Mr. Kinnon noted.

“This test tells you these are the ones who are going to progress and should go into the study, and these are the ones that aren’t. So it makes the studies statistically relevant and accurate,” he said.

Investigators can also use the test to monitor patients during a study instead of relying on expensive PET scans and painful and costly spinal fluid taps, he added.

Previous surveys and market research have shown that neurologists and general practitioners “want a blood test to screen patients early, to help educate and inform patients,” said Mr. Kinnon.

Further results that will include biobank data on more than 1,000 patients in the United States and Europe are due for completion toward the end of this year.

The company is currently in negotiations to bring the product to North America, Europe, and elsewhere. “Our goal is to have it on the market by the middle of next year in multiple regions,” Mr. Kinnon said.
 

Encouraging, preliminary

Commenting on the findings, Percy Griffin, PhD, MSc, director of scientific engagement at the Alzheimer’s Association, said “it’s exciting” to see development of novel ways for detecting or predicting AD.

“There is an urgent need for simple, inexpensive, noninvasive, and accessible early detection tools for Alzheimer’s, such as a blood test,” he said.

However, Dr. Griffin cautioned the test is still in the early stages of development and has not been tested extensively in large, diverse clinical trials.

In addition, although the test predicts whether a person will progress, it does not predict when the person will progress, he added.

“These preliminary results are encouraging, but further validation is needed before this test can be implemented widely,” he said.

Technologies that facilitate the early detection and intervention before significant loss of brain cells from AD “would be game-changing” for individuals, families, and the healthcare system, Dr. Griffin concluded.

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

A new blood test that identifies a variant of the protein P53 appears to predict Alzheimer’s disease (AD) progression up to 6 years in advance of a clinical diagnosis, early research suggests.

Analysis of two studies showed the test (AlzoSure Predict), which uses less than 1 ml of blood, had numerous benefits compared with other blood tests that track AD pathology.

“We believe this has the potential to radically improve early stratification and identification of patients for trials 6 years in advance of a diagnosis, which can potentially enable more rapid and efficient approvals of therapies,” Paul Kinnon, CEO of Diadem, the test’s manufacturer, said in an interview.

The findings were presented at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
 

Positive “discovery” results

P53, which is present in both the brain and elsewhere in the body, “is one of the most targeted proteins” for drug development in cancer and other conditions, said Mr. Kinnon.

The current blood test measures a derivative of P53 (U-p53AZ). Previous research suggests this derivative, which affects amyloid and oxidative stress, is also implicated in AD pathogenesis.

Researchers used blood samples from patients aged 60 years and older from the Australia Imaging, Biomarkers, and Lifestyles (AIBL) study who had various levels of cognitive function.

They analyzed samples at multiple timepoints over a 10-year period, “so we know when the marker is most accurate at predicting decline,” Mr. Kinnon said.

The first of two studies was considered a “discovery” study and included blood samples from 224 patients.

Results showed the test predicted decline from mild cognitive impairment (MCI) to AD at the end of 6 years, with an area under the curve (AUC) greater than 90%.

These results are “massive,” said Mr. Kinnon. “It’s the most accurate test I’ve seen anywhere for predicting decline of a patient.”

The test can also accurately classify a patient’s stage of cognition, he added. “Not only does it allow us to predict 6 years in advance, it also tells us if the patient has SMC [subjective memory complaints], MCI, or AD with a 95% certainty,” Mr. Kinnon said.

He noted that test sensitivity was higher than results found from traditional methods that are currently being used. The positive predictive value (PPV) and negative predictive value (NPV), which were at 90% or more, were “absolutely fantastic,” said Mr. Kinnon.
 

“Better than expected” results

In the second “validation” study, investigators examined samples from a completely different group of 482 patients. The “very compelling” results showed AUCs over 90%, PPVs over 90%, and “very high” NPVs, Mr. Kinnon said.

“These are great data, better than we expected,” he added.

However, he noted the test is “very specific” for decline to AD and not to other dementias.

In addition, Mr. Kinnon noted the test does not monitor levels of amyloid beta or tau, which accumulate at a later stage of AD. “Amyloid and tau tell you you’ve got it. We’re there way before those concentrations become detectable,” he said.

Identifying patients who will progress to AD years before they have symptoms gives them time to make medical decisions. These patients may also try treatments at an earlier stage of the disease, when these therapies are most likely to be helpful, said Mr. Kinnon.

In addition, using the test could speed up the approval of prospective drug treatments for AD. Currently, pharmaceutical companies enroll thousands of patients into a clinical study “and they don’t know which ones will have AD,” Mr. Kinnon noted.

“This test tells you these are the ones who are going to progress and should go into the study, and these are the ones that aren’t. So it makes the studies statistically relevant and accurate,” he said.

Investigators can also use the test to monitor patients during a study instead of relying on expensive PET scans and painful and costly spinal fluid taps, he added.

Previous surveys and market research have shown that neurologists and general practitioners “want a blood test to screen patients early, to help educate and inform patients,” said Mr. Kinnon.

Further results that will include biobank data on more than 1,000 patients in the United States and Europe are due for completion toward the end of this year.

The company is currently in negotiations to bring the product to North America, Europe, and elsewhere. “Our goal is to have it on the market by the middle of next year in multiple regions,” Mr. Kinnon said.
 

Encouraging, preliminary

Commenting on the findings, Percy Griffin, PhD, MSc, director of scientific engagement at the Alzheimer’s Association, said “it’s exciting” to see development of novel ways for detecting or predicting AD.

“There is an urgent need for simple, inexpensive, noninvasive, and accessible early detection tools for Alzheimer’s, such as a blood test,” he said.

However, Dr. Griffin cautioned the test is still in the early stages of development and has not been tested extensively in large, diverse clinical trials.

In addition, although the test predicts whether a person will progress, it does not predict when the person will progress, he added.

“These preliminary results are encouraging, but further validation is needed before this test can be implemented widely,” he said.

Technologies that facilitate the early detection and intervention before significant loss of brain cells from AD “would be game-changing” for individuals, families, and the healthcare system, Dr. Griffin concluded.

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

A newly released position statement from the American Academy of Neurology (AAN) provides guidance to neurologists about counseling  patients with Alzheimer’s disease and their families about the controversial drug aducanumab (Aduhelm).

The statement includes ethical considerations and recommendations for informed consent, and the AAN notes that neurologists should ensure that patients understand all of the issues and uncertainties surrounding the use of aducanumab.

“Neurologists and other clinicians want to provide the best care to patients and families, particularly for a disease that is as challenging as Alzheimer’s. We hope that this statement can be a guide for clinicians in communicating with patients and families in order to carefully consider decisions about the use of aducanumab,” said lead author Winston Chiong, MD, PhD, University of California San Francisco Memory and Aging Center, and a member of the AAN’s Ethics, Law, and Humanities Committee.

The statement was published online Nov. 17 in Neurology.
 

Open, honest communication

The Food and Drug Administration approved the antiamyloid agent aducanumab based on two studies that were both stopped prematurely for futility. In subsequent post hoc analyses of the available data, one of those studies indicated a statistically significant, albeit small, benefit with high-dose aducanumab, while the other study continued to show no benefit.

The clinical importance of the small statistical benefit in the single trial for daily function is unclear, and aducanumab was also associated with brain inflammation and brain bleeds in more than one-third of patients who received the FDA-approved dose, which requires regular brain MRI monitoring.

All of this should be communicated to patients, the AAN advises.

Patients should know that while aducanumab reduces beta-amyloid plaques in the brain that are markers of Alzheimer’s disease, it remains unclear whether this provides any meaningful benefit.

The AAN adds that it is equally important to tell patients and families that aducanumab does not restore cognitive function and that there is insufficient data to offer it to people with moderate or advanced dementia or to those without evidence of beta-amyloid plaques.

It’s important to note that very few participants in the aducanumab trials were Hispanic, Black, or Indigenous. 

“Informed consent conversations with patients of populations underrepresented in clinical trials should include disclosure about the absence of safety and efficacy data in these groups,” the authors noted.
 

‘New territory’ for neurologists

“There are two aspects of aducanumab that are relatively new territory for us as neurologists,” Dr. Chiong said. One is the controversy about the evidence for the drug. “In the statement, we’ve tried to help clinicians communicate the uncertainty over aducanumab’s risks and potential benefits,” Dr. Chiong said. The other is the high cost of the drug and how it will be covered.

Aducanumab has a price tag of $56,000 per year, which does not include the cost of infusing the drug, required repeat imaging, and medical management.

The AAN estimates annual costs of prescribing aducanumab may top $100,000 per year. With Medicare generally covering 80%, patients and families must be told that the full costs of treatment may not be covered.

“Regarding cost, we probably don’t think often enough about what prescribing a drug means for an individual patient’s finances and for the health system,” said Dr. Chiong. “In particular, when patients are in Medicare we might assume their health care costs will be sufficiently covered, but because aducanumab is so expensive its use is likely to impose very significant costs on individual patients as well as to the Medicare program,” Dr. Chiong said.

“It is understandable why a new drug for Alzheimer’s disease generates so much interest, because while its approval has been controversial, it still offers a glimmer of hope to patients and their families,” AAN President Orly Avitzur, MD, said in a news release. “By using ethical principles to create this position statement, the American Academy of Neurology aims to help neurologists and other physicians transparently counsel patients and their families with a goal of providing the highest quality patient-centered care,” Dr. Avitzur said.

This statement was approved by the Ethics, Law, and Humanities Committee, a joint committee of the AAN, American Neurological Association, and Child Neurology Society.

This research had no targeted funding. Dr. Chiong has received personal compensation for serving on the Neuroethics Working Group of the National Institutes of Health BRAIN Initiative, and his institution has received research support from the National Institutes of Health. A complete list of author disclosures is available with the original article.

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

A newly released position statement from the American Academy of Neurology (AAN) provides guidance to neurologists about counseling  patients with Alzheimer’s disease and their families about the controversial drug aducanumab (Aduhelm).

The statement includes ethical considerations and recommendations for informed consent, and the AAN notes that neurologists should ensure that patients understand all of the issues and uncertainties surrounding the use of aducanumab.

“Neurologists and other clinicians want to provide the best care to patients and families, particularly for a disease that is as challenging as Alzheimer’s. We hope that this statement can be a guide for clinicians in communicating with patients and families in order to carefully consider decisions about the use of aducanumab,” said lead author Winston Chiong, MD, PhD, University of California San Francisco Memory and Aging Center, and a member of the AAN’s Ethics, Law, and Humanities Committee.

The statement was published online Nov. 17 in Neurology.
 

Open, honest communication

The Food and Drug Administration approved the antiamyloid agent aducanumab based on two studies that were both stopped prematurely for futility. In subsequent post hoc analyses of the available data, one of those studies indicated a statistically significant, albeit small, benefit with high-dose aducanumab, while the other study continued to show no benefit.

The clinical importance of the small statistical benefit in the single trial for daily function is unclear, and aducanumab was also associated with brain inflammation and brain bleeds in more than one-third of patients who received the FDA-approved dose, which requires regular brain MRI monitoring.

All of this should be communicated to patients, the AAN advises.

Patients should know that while aducanumab reduces beta-amyloid plaques in the brain that are markers of Alzheimer’s disease, it remains unclear whether this provides any meaningful benefit.

The AAN adds that it is equally important to tell patients and families that aducanumab does not restore cognitive function and that there is insufficient data to offer it to people with moderate or advanced dementia or to those without evidence of beta-amyloid plaques.

It’s important to note that very few participants in the aducanumab trials were Hispanic, Black, or Indigenous. 

“Informed consent conversations with patients of populations underrepresented in clinical trials should include disclosure about the absence of safety and efficacy data in these groups,” the authors noted.
 

‘New territory’ for neurologists

“There are two aspects of aducanumab that are relatively new territory for us as neurologists,” Dr. Chiong said. One is the controversy about the evidence for the drug. “In the statement, we’ve tried to help clinicians communicate the uncertainty over aducanumab’s risks and potential benefits,” Dr. Chiong said. The other is the high cost of the drug and how it will be covered.

Aducanumab has a price tag of $56,000 per year, which does not include the cost of infusing the drug, required repeat imaging, and medical management.

The AAN estimates annual costs of prescribing aducanumab may top $100,000 per year. With Medicare generally covering 80%, patients and families must be told that the full costs of treatment may not be covered.

“Regarding cost, we probably don’t think often enough about what prescribing a drug means for an individual patient’s finances and for the health system,” said Dr. Chiong. “In particular, when patients are in Medicare we might assume their health care costs will be sufficiently covered, but because aducanumab is so expensive its use is likely to impose very significant costs on individual patients as well as to the Medicare program,” Dr. Chiong said.

“It is understandable why a new drug for Alzheimer’s disease generates so much interest, because while its approval has been controversial, it still offers a glimmer of hope to patients and their families,” AAN President Orly Avitzur, MD, said in a news release. “By using ethical principles to create this position statement, the American Academy of Neurology aims to help neurologists and other physicians transparently counsel patients and their families with a goal of providing the highest quality patient-centered care,” Dr. Avitzur said.

This statement was approved by the Ethics, Law, and Humanities Committee, a joint committee of the AAN, American Neurological Association, and Child Neurology Society.

This research had no targeted funding. Dr. Chiong has received personal compensation for serving on the Neuroethics Working Group of the National Institutes of Health BRAIN Initiative, and his institution has received research support from the National Institutes of Health. A complete list of author disclosures is available with the original article.

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

A newly released position statement from the American Academy of Neurology (AAN) provides guidance to neurologists about counseling  patients with Alzheimer’s disease and their families about the controversial drug aducanumab (Aduhelm).

The statement includes ethical considerations and recommendations for informed consent, and the AAN notes that neurologists should ensure that patients understand all of the issues and uncertainties surrounding the use of aducanumab.

“Neurologists and other clinicians want to provide the best care to patients and families, particularly for a disease that is as challenging as Alzheimer’s. We hope that this statement can be a guide for clinicians in communicating with patients and families in order to carefully consider decisions about the use of aducanumab,” said lead author Winston Chiong, MD, PhD, University of California San Francisco Memory and Aging Center, and a member of the AAN’s Ethics, Law, and Humanities Committee.

The statement was published online Nov. 17 in Neurology.
 

Open, honest communication

The Food and Drug Administration approved the antiamyloid agent aducanumab based on two studies that were both stopped prematurely for futility. In subsequent post hoc analyses of the available data, one of those studies indicated a statistically significant, albeit small, benefit with high-dose aducanumab, while the other study continued to show no benefit.

The clinical importance of the small statistical benefit in the single trial for daily function is unclear, and aducanumab was also associated with brain inflammation and brain bleeds in more than one-third of patients who received the FDA-approved dose, which requires regular brain MRI monitoring.

All of this should be communicated to patients, the AAN advises.

Patients should know that while aducanumab reduces beta-amyloid plaques in the brain that are markers of Alzheimer’s disease, it remains unclear whether this provides any meaningful benefit.

The AAN adds that it is equally important to tell patients and families that aducanumab does not restore cognitive function and that there is insufficient data to offer it to people with moderate or advanced dementia or to those without evidence of beta-amyloid plaques.

It’s important to note that very few participants in the aducanumab trials were Hispanic, Black, or Indigenous. 

“Informed consent conversations with patients of populations underrepresented in clinical trials should include disclosure about the absence of safety and efficacy data in these groups,” the authors noted.
 

‘New territory’ for neurologists

“There are two aspects of aducanumab that are relatively new territory for us as neurologists,” Dr. Chiong said. One is the controversy about the evidence for the drug. “In the statement, we’ve tried to help clinicians communicate the uncertainty over aducanumab’s risks and potential benefits,” Dr. Chiong said. The other is the high cost of the drug and how it will be covered.

Aducanumab has a price tag of $56,000 per year, which does not include the cost of infusing the drug, required repeat imaging, and medical management.

The AAN estimates annual costs of prescribing aducanumab may top $100,000 per year. With Medicare generally covering 80%, patients and families must be told that the full costs of treatment may not be covered.

“Regarding cost, we probably don’t think often enough about what prescribing a drug means for an individual patient’s finances and for the health system,” said Dr. Chiong. “In particular, when patients are in Medicare we might assume their health care costs will be sufficiently covered, but because aducanumab is so expensive its use is likely to impose very significant costs on individual patients as well as to the Medicare program,” Dr. Chiong said.

“It is understandable why a new drug for Alzheimer’s disease generates so much interest, because while its approval has been controversial, it still offers a glimmer of hope to patients and their families,” AAN President Orly Avitzur, MD, said in a news release. “By using ethical principles to create this position statement, the American Academy of Neurology aims to help neurologists and other physicians transparently counsel patients and their families with a goal of providing the highest quality patient-centered care,” Dr. Avitzur said.

This statement was approved by the Ethics, Law, and Humanities Committee, a joint committee of the AAN, American Neurological Association, and Child Neurology Society.

This research had no targeted funding. Dr. Chiong has received personal compensation for serving on the Neuroethics Working Group of the National Institutes of Health BRAIN Initiative, and his institution has received research support from the National Institutes of Health. A complete list of author disclosures is available with the original article.

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

Short-acting opioids may complement methadone and buprenorphine for opioid withdrawal symptoms in U.S. hospitals, say authors of an opinion piece calling for rethinking current strategies for opioid withdrawal in this country.

The commentary by Robert A. Kleinman, MD, with the Centre for Addiction and Mental Health, and department of psychiatry, University of Toronto, and Sarah E. Wakeman, MD, with the division of general internal medicine at Massachusetts General Hospital, and Harvard Medical School, Boston, was published in Annals of Internal Medicine.

Currently, short-acting opioids are not recommended in the United States for opioid withdrawal symptoms (OWS) management in the hospital, the authors wrote. Instead, withdrawal symptoms are typically treated, followed by methadone or buprenorphine or nonopioid medications, but many patients don’t get enough relief. Undertreated withdrawal can result in patients leaving the hospital against medical advice, which is linked with higher risk of death.

Addiction specialist Elisabeth Poorman, MD, of the University of Illinois Chicago, said in an interview that she agrees it’s time to start shifting the thinking on using short-acting opioids for OWS in hospitals. Use varies greatly by hospital and by clinician, she said.

“It’s time to let evidence guide us and to be flexible,” Dr. Poorman said.

The commentary authors noted that with methadone, patients must wait several hours for maximal symptom reduction, and the full benefits of methadone treatment are not realized until days after initiation.

Rapid initiation of methadone may be feasible in hospitals and has been proposed as an option, but further study is necessary before widespread use, the authors wrote.
 

Short-acting opioids may address limitations of other opioids

Lofexidine, an alpha-2-adrenergic agonist, is the only drug approved by the Food and Drug Administration specifically for OWS.

“However,” the authors said, “more than half of patients with OWS treated with lofexidine in phase 3 efficacy trials dropped out by day five. Clonidine, another alpha-2-agonist used off label to treat OWS, has similar effects to those of lofexidine. “

Therefore, short-acting opioids may complement methadone and buprenorphine in treating OWS in the hospital by addressing their limitations, the authors wrote.

Dr. Kleinman and Dr. Wakeman also say short-acting opioids may help with starting buprenorphine for patients exposed to fentanyl, because short-acting opioids can relieve withdrawal symptoms while fentanyl is metabolized and excreted.

Supplementation with short-acting opioids within the hospital can relieve withdrawal symptoms and help keep patients comfortable while methadone is titrated to more effective doses for long-term treatment, they wrote.

With short-acting opioids, patients may become more engaged in their care with, for example, a tamper-proof, patient-controlled analgesia pump, which would allow them to have more autonomy in administration of opioids to relieve pain and withdrawal symptoms, the authors wrote.

Dr. Kleinman and Dr. Wakeman noted that many patients who inject drugs already consume short-acting illicit drugs in the hospital, typically in washrooms and smoking areas, so supervised use of short-acting opioids helps eliminate the risk for unwitnessed overdoses.

Barriers to short-acting opioid use

Despite use of short-acting opioids internationally, barriers in the United States include limited prospective, randomized, controlled research on their benefits. There is limited institutional support for such approaches, and concerns and stigma around providing opioids to patients with OUD.

“[M]any institutions have insufficient numbers of providers who are both confident and competent with standard buprenorphine and methadone initiation approaches, a prerequisite before adopting more complex regimens,” the authors wrote.

Short-acting, full-agonist opioids, as a complement to methadone or buprenorphine, is already recommended for inpatients with OUD who are experiencing acute pain.

But the authors argue it should be an option when pain is not present, but methadone or buprenorphine have not provided enough OWS relief.
 

When short-acting opioids are helpful, according to outside expert

Dr. Poorman agrees and says she has found short-acting opioids simple to use in the hospital and very helpful in two situations.

One is when patients are very clear that they don’t want any medication for opioid use disorder, but they do want to be treated for their acute medical issue.

“I thought that was a fantastic tool to have to demonstrate we’re listening to them and weren’t trying to impose something on them and left the door open to come back when they did want treatment, which many of them did,” Dr. Poorman said.

The second situation is when the patient is uncertain about options but very afraid of precipitated withdrawal from buprenorphine.

She said she then found it easy to switch from those medications to buprenorphine and methadone.

Dr. Poorman described a situation she encountered previously where the patient was injecting heroin several times a day for 30-40 years. He was very clear he wasn’t going to stop injecting heroin, but he needed medical attention. He was willing to get medical attention, but he told his doctor he didn’t want to be uncomfortable while in the hospital.

It was very hard for his doctor to accept relieving his symptoms of withdrawal as part of her job, because she felt as though she was condoning his drug use, Dr. Poorman explained.

But Dr. Poorman said it’s not realistic to think that someone who clearly does not want to stop using is going to stop using because a doctor made that person go through painful withdrawal “that they’ve structured their whole life around avoiding.”
 

Take-home message

“We need to understand that addiction is very complex. A lot of times people come to us distressed, and it’s a great time to engage them in care but engaging them in care doesn’t mean imposing discomfort or pain on them,” Dr. Poorman noted. Instead, it means “listening to them, helping them be comfortable in a really stressful situation and then letting them know we are always there for them wherever they are on their disease process or recovery journey so that they can come back to us.”

Dr. Wakeman previously served on clinical advisory board for Celero Systems and receives textbook royalties from Springer and author payment from UpToDate. Dr. Kleinman and Dr. Poorman declared no relevant financial relationships.

Short-acting opioids may complement methadone and buprenorphine for opioid withdrawal symptoms in U.S. hospitals, say authors of an opinion piece calling for rethinking current strategies for opioid withdrawal in this country.

The commentary by Robert A. Kleinman, MD, with the Centre for Addiction and Mental Health, and department of psychiatry, University of Toronto, and Sarah E. Wakeman, MD, with the division of general internal medicine at Massachusetts General Hospital, and Harvard Medical School, Boston, was published in Annals of Internal Medicine.

Currently, short-acting opioids are not recommended in the United States for opioid withdrawal symptoms (OWS) management in the hospital, the authors wrote. Instead, withdrawal symptoms are typically treated, followed by methadone or buprenorphine or nonopioid medications, but many patients don’t get enough relief. Undertreated withdrawal can result in patients leaving the hospital against medical advice, which is linked with higher risk of death.

Addiction specialist Elisabeth Poorman, MD, of the University of Illinois Chicago, said in an interview that she agrees it’s time to start shifting the thinking on using short-acting opioids for OWS in hospitals. Use varies greatly by hospital and by clinician, she said.

“It’s time to let evidence guide us and to be flexible,” Dr. Poorman said.

The commentary authors noted that with methadone, patients must wait several hours for maximal symptom reduction, and the full benefits of methadone treatment are not realized until days after initiation.

Rapid initiation of methadone may be feasible in hospitals and has been proposed as an option, but further study is necessary before widespread use, the authors wrote.
 

Short-acting opioids may address limitations of other opioids

Lofexidine, an alpha-2-adrenergic agonist, is the only drug approved by the Food and Drug Administration specifically for OWS.

“However,” the authors said, “more than half of patients with OWS treated with lofexidine in phase 3 efficacy trials dropped out by day five. Clonidine, another alpha-2-agonist used off label to treat OWS, has similar effects to those of lofexidine. “

Therefore, short-acting opioids may complement methadone and buprenorphine in treating OWS in the hospital by addressing their limitations, the authors wrote.

Dr. Kleinman and Dr. Wakeman also say short-acting opioids may help with starting buprenorphine for patients exposed to fentanyl, because short-acting opioids can relieve withdrawal symptoms while fentanyl is metabolized and excreted.

Supplementation with short-acting opioids within the hospital can relieve withdrawal symptoms and help keep patients comfortable while methadone is titrated to more effective doses for long-term treatment, they wrote.

With short-acting opioids, patients may become more engaged in their care with, for example, a tamper-proof, patient-controlled analgesia pump, which would allow them to have more autonomy in administration of opioids to relieve pain and withdrawal symptoms, the authors wrote.

Dr. Kleinman and Dr. Wakeman noted that many patients who inject drugs already consume short-acting illicit drugs in the hospital, typically in washrooms and smoking areas, so supervised use of short-acting opioids helps eliminate the risk for unwitnessed overdoses.

Barriers to short-acting opioid use

Despite use of short-acting opioids internationally, barriers in the United States include limited prospective, randomized, controlled research on their benefits. There is limited institutional support for such approaches, and concerns and stigma around providing opioids to patients with OUD.

“[M]any institutions have insufficient numbers of providers who are both confident and competent with standard buprenorphine and methadone initiation approaches, a prerequisite before adopting more complex regimens,” the authors wrote.

Short-acting, full-agonist opioids, as a complement to methadone or buprenorphine, is already recommended for inpatients with OUD who are experiencing acute pain.

But the authors argue it should be an option when pain is not present, but methadone or buprenorphine have not provided enough OWS relief.
 

When short-acting opioids are helpful, according to outside expert

Dr. Poorman agrees and says she has found short-acting opioids simple to use in the hospital and very helpful in two situations.

One is when patients are very clear that they don’t want any medication for opioid use disorder, but they do want to be treated for their acute medical issue.

“I thought that was a fantastic tool to have to demonstrate we’re listening to them and weren’t trying to impose something on them and left the door open to come back when they did want treatment, which many of them did,” Dr. Poorman said.

The second situation is when the patient is uncertain about options but very afraid of precipitated withdrawal from buprenorphine.

She said she then found it easy to switch from those medications to buprenorphine and methadone.

Dr. Poorman described a situation she encountered previously where the patient was injecting heroin several times a day for 30-40 years. He was very clear he wasn’t going to stop injecting heroin, but he needed medical attention. He was willing to get medical attention, but he told his doctor he didn’t want to be uncomfortable while in the hospital.

It was very hard for his doctor to accept relieving his symptoms of withdrawal as part of her job, because she felt as though she was condoning his drug use, Dr. Poorman explained.

But Dr. Poorman said it’s not realistic to think that someone who clearly does not want to stop using is going to stop using because a doctor made that person go through painful withdrawal “that they’ve structured their whole life around avoiding.”
 

Take-home message

“We need to understand that addiction is very complex. A lot of times people come to us distressed, and it’s a great time to engage them in care but engaging them in care doesn’t mean imposing discomfort or pain on them,” Dr. Poorman noted. Instead, it means “listening to them, helping them be comfortable in a really stressful situation and then letting them know we are always there for them wherever they are on their disease process or recovery journey so that they can come back to us.”

Dr. Wakeman previously served on clinical advisory board for Celero Systems and receives textbook royalties from Springer and author payment from UpToDate. Dr. Kleinman and Dr. Poorman declared no relevant financial relationships.

Short-acting opioids may complement methadone and buprenorphine for opioid withdrawal symptoms in U.S. hospitals, say authors of an opinion piece calling for rethinking current strategies for opioid withdrawal in this country.

The commentary by Robert A. Kleinman, MD, with the Centre for Addiction and Mental Health, and department of psychiatry, University of Toronto, and Sarah E. Wakeman, MD, with the division of general internal medicine at Massachusetts General Hospital, and Harvard Medical School, Boston, was published in Annals of Internal Medicine.

Currently, short-acting opioids are not recommended in the United States for opioid withdrawal symptoms (OWS) management in the hospital, the authors wrote. Instead, withdrawal symptoms are typically treated, followed by methadone or buprenorphine or nonopioid medications, but many patients don’t get enough relief. Undertreated withdrawal can result in patients leaving the hospital against medical advice, which is linked with higher risk of death.

Addiction specialist Elisabeth Poorman, MD, of the University of Illinois Chicago, said in an interview that she agrees it’s time to start shifting the thinking on using short-acting opioids for OWS in hospitals. Use varies greatly by hospital and by clinician, she said.

“It’s time to let evidence guide us and to be flexible,” Dr. Poorman said.

The commentary authors noted that with methadone, patients must wait several hours for maximal symptom reduction, and the full benefits of methadone treatment are not realized until days after initiation.

Rapid initiation of methadone may be feasible in hospitals and has been proposed as an option, but further study is necessary before widespread use, the authors wrote.
 

Short-acting opioids may address limitations of other opioids

Lofexidine, an alpha-2-adrenergic agonist, is the only drug approved by the Food and Drug Administration specifically for OWS.

“However,” the authors said, “more than half of patients with OWS treated with lofexidine in phase 3 efficacy trials dropped out by day five. Clonidine, another alpha-2-agonist used off label to treat OWS, has similar effects to those of lofexidine. “

Therefore, short-acting opioids may complement methadone and buprenorphine in treating OWS in the hospital by addressing their limitations, the authors wrote.

Dr. Kleinman and Dr. Wakeman also say short-acting opioids may help with starting buprenorphine for patients exposed to fentanyl, because short-acting opioids can relieve withdrawal symptoms while fentanyl is metabolized and excreted.

Supplementation with short-acting opioids within the hospital can relieve withdrawal symptoms and help keep patients comfortable while methadone is titrated to more effective doses for long-term treatment, they wrote.

With short-acting opioids, patients may become more engaged in their care with, for example, a tamper-proof, patient-controlled analgesia pump, which would allow them to have more autonomy in administration of opioids to relieve pain and withdrawal symptoms, the authors wrote.

Dr. Kleinman and Dr. Wakeman noted that many patients who inject drugs already consume short-acting illicit drugs in the hospital, typically in washrooms and smoking areas, so supervised use of short-acting opioids helps eliminate the risk for unwitnessed overdoses.

Barriers to short-acting opioid use

Despite use of short-acting opioids internationally, barriers in the United States include limited prospective, randomized, controlled research on their benefits. There is limited institutional support for such approaches, and concerns and stigma around providing opioids to patients with OUD.

“[M]any institutions have insufficient numbers of providers who are both confident and competent with standard buprenorphine and methadone initiation approaches, a prerequisite before adopting more complex regimens,” the authors wrote.

Short-acting, full-agonist opioids, as a complement to methadone or buprenorphine, is already recommended for inpatients with OUD who are experiencing acute pain.

But the authors argue it should be an option when pain is not present, but methadone or buprenorphine have not provided enough OWS relief.
 

When short-acting opioids are helpful, according to outside expert

Dr. Poorman agrees and says she has found short-acting opioids simple to use in the hospital and very helpful in two situations.

One is when patients are very clear that they don’t want any medication for opioid use disorder, but they do want to be treated for their acute medical issue.

“I thought that was a fantastic tool to have to demonstrate we’re listening to them and weren’t trying to impose something on them and left the door open to come back when they did want treatment, which many of them did,” Dr. Poorman said.

The second situation is when the patient is uncertain about options but very afraid of precipitated withdrawal from buprenorphine.

She said she then found it easy to switch from those medications to buprenorphine and methadone.

Dr. Poorman described a situation she encountered previously where the patient was injecting heroin several times a day for 30-40 years. He was very clear he wasn’t going to stop injecting heroin, but he needed medical attention. He was willing to get medical attention, but he told his doctor he didn’t want to be uncomfortable while in the hospital.

It was very hard for his doctor to accept relieving his symptoms of withdrawal as part of her job, because she felt as though she was condoning his drug use, Dr. Poorman explained.

But Dr. Poorman said it’s not realistic to think that someone who clearly does not want to stop using is going to stop using because a doctor made that person go through painful withdrawal “that they’ve structured their whole life around avoiding.”
 

Take-home message

“We need to understand that addiction is very complex. A lot of times people come to us distressed, and it’s a great time to engage them in care but engaging them in care doesn’t mean imposing discomfort or pain on them,” Dr. Poorman noted. Instead, it means “listening to them, helping them be comfortable in a really stressful situation and then letting them know we are always there for them wherever they are on their disease process or recovery journey so that they can come back to us.”

Dr. Wakeman previously served on clinical advisory board for Celero Systems and receives textbook royalties from Springer and author payment from UpToDate. Dr. Kleinman and Dr. Poorman declared no relevant financial relationships.

Treatment with intravenous ferric carboxymaltose significantly improved symptoms in restless legs syndrome (RLS) patients with iron-deficiency anemia (IDA), data from 29 adults show.

RLS occurs among individuals with normal iron but is at least six times higher among individuals with IDA, Hyoeun Bae, MD, of Keimyung University, Daegu, South Korea, and colleagues wrote. Previous studies have explored iron treatments for RLS patients with IDA, however, guidelines for treatment have not yet been published.

In a study published in Sleep Medicine, the researchers randomized 29 RLS patients with IDA to either 1,500 mg IV ferric carboxymaltose (FCM) or placebo for a short-term period of 6 weeks, followed by a phase 2 study for responders that lasted for 52 weeks. Baseline characteristics, including age, gender, iron parameters, and sleep and mood scales were similar between the groups.

At 6 weeks, patients in the FCM group showed significant improvement in RLS symptom severity based on changes from baseline International Restless Legs Syndrome Study Group scale (IRLS) scores, compared with placebo patients (–13.47 vs. 1.36, P < .001). A secondary outcome of sleep quality also improved significantly in the FCM group, compared with the placebo group.

After 6 weeks, 11 of the 14 patients in the placebo group also received 1,500 mg FCM for an open-label study. These patients also showed significant improvement in IRLS scores from baseline to 6 weeks.

All 23 responders from the short-term studies (13 who received FCM initially and 10 from the postplacebo group) enrolled in a phase 2 long-term study that lasted for 52 weeks; 14 of these completed the full 52-week study period.

Overall, 61% of participants in phase 2 of the study remained off their RLS medications at 52 weeks, and no serious adverse events were reported during the study period. Of these, 10 received one additional dose of FCM and 4 received more than one additional dose. The median change in IRLS score at 4 weeks after treatment was –4.00, compared with the score prior to treatment.

The study is the first of its design to show benefits of intravenous iron therapy for RLS in patients with IDA, the researchers said, noting that the findings of improved, but not cured, RLS symptoms might suggest that more than 1,500 mg of iron is needed to fully treat RLS in this patient population. “A second interpretation is that the RLS and IDA were separate events: a patient with idiopathic RLS who subsequently developed anemia,” they said. “Treating the IDA might improve symptoms but may not eliminate the symptoms.”

The study findings were limited by several factors, including the relatively small study population and inability to know the time frame for the development of IDA, the researchers noted. However, the results support the use of intravenous iron therapy for relief of RLS in IDA patients.

“Since IDA could result in epigenetic changes leading to irreversible state of RLS, then urgent and adequate management of the IDA in RLS patients would seem a very prudent and important clinical approach to this specific clinical condition,” they concluded.

The study received no outside funding. The researchers had no disclosures.

Treatment with intravenous ferric carboxymaltose significantly improved symptoms in restless legs syndrome (RLS) patients with iron-deficiency anemia (IDA), data from 29 adults show.

RLS occurs among individuals with normal iron but is at least six times higher among individuals with IDA, Hyoeun Bae, MD, of Keimyung University, Daegu, South Korea, and colleagues wrote. Previous studies have explored iron treatments for RLS patients with IDA, however, guidelines for treatment have not yet been published.

In a study published in Sleep Medicine, the researchers randomized 29 RLS patients with IDA to either 1,500 mg IV ferric carboxymaltose (FCM) or placebo for a short-term period of 6 weeks, followed by a phase 2 study for responders that lasted for 52 weeks. Baseline characteristics, including age, gender, iron parameters, and sleep and mood scales were similar between the groups.

At 6 weeks, patients in the FCM group showed significant improvement in RLS symptom severity based on changes from baseline International Restless Legs Syndrome Study Group scale (IRLS) scores, compared with placebo patients (–13.47 vs. 1.36, P < .001). A secondary outcome of sleep quality also improved significantly in the FCM group, compared with the placebo group.

After 6 weeks, 11 of the 14 patients in the placebo group also received 1,500 mg FCM for an open-label study. These patients also showed significant improvement in IRLS scores from baseline to 6 weeks.

All 23 responders from the short-term studies (13 who received FCM initially and 10 from the postplacebo group) enrolled in a phase 2 long-term study that lasted for 52 weeks; 14 of these completed the full 52-week study period.

Overall, 61% of participants in phase 2 of the study remained off their RLS medications at 52 weeks, and no serious adverse events were reported during the study period. Of these, 10 received one additional dose of FCM and 4 received more than one additional dose. The median change in IRLS score at 4 weeks after treatment was –4.00, compared with the score prior to treatment.

The study is the first of its design to show benefits of intravenous iron therapy for RLS in patients with IDA, the researchers said, noting that the findings of improved, but not cured, RLS symptoms might suggest that more than 1,500 mg of iron is needed to fully treat RLS in this patient population. “A second interpretation is that the RLS and IDA were separate events: a patient with idiopathic RLS who subsequently developed anemia,” they said. “Treating the IDA might improve symptoms but may not eliminate the symptoms.”

The study findings were limited by several factors, including the relatively small study population and inability to know the time frame for the development of IDA, the researchers noted. However, the results support the use of intravenous iron therapy for relief of RLS in IDA patients.

“Since IDA could result in epigenetic changes leading to irreversible state of RLS, then urgent and adequate management of the IDA in RLS patients would seem a very prudent and important clinical approach to this specific clinical condition,” they concluded.

The study received no outside funding. The researchers had no disclosures.

Treatment with intravenous ferric carboxymaltose significantly improved symptoms in restless legs syndrome (RLS) patients with iron-deficiency anemia (IDA), data from 29 adults show.

RLS occurs among individuals with normal iron but is at least six times higher among individuals with IDA, Hyoeun Bae, MD, of Keimyung University, Daegu, South Korea, and colleagues wrote. Previous studies have explored iron treatments for RLS patients with IDA, however, guidelines for treatment have not yet been published.

In a study published in Sleep Medicine, the researchers randomized 29 RLS patients with IDA to either 1,500 mg IV ferric carboxymaltose (FCM) or placebo for a short-term period of 6 weeks, followed by a phase 2 study for responders that lasted for 52 weeks. Baseline characteristics, including age, gender, iron parameters, and sleep and mood scales were similar between the groups.

At 6 weeks, patients in the FCM group showed significant improvement in RLS symptom severity based on changes from baseline International Restless Legs Syndrome Study Group scale (IRLS) scores, compared with placebo patients (–13.47 vs. 1.36, P < .001). A secondary outcome of sleep quality also improved significantly in the FCM group, compared with the placebo group.

After 6 weeks, 11 of the 14 patients in the placebo group also received 1,500 mg FCM for an open-label study. These patients also showed significant improvement in IRLS scores from baseline to 6 weeks.

All 23 responders from the short-term studies (13 who received FCM initially and 10 from the postplacebo group) enrolled in a phase 2 long-term study that lasted for 52 weeks; 14 of these completed the full 52-week study period.

Overall, 61% of participants in phase 2 of the study remained off their RLS medications at 52 weeks, and no serious adverse events were reported during the study period. Of these, 10 received one additional dose of FCM and 4 received more than one additional dose. The median change in IRLS score at 4 weeks after treatment was –4.00, compared with the score prior to treatment.

The study is the first of its design to show benefits of intravenous iron therapy for RLS in patients with IDA, the researchers said, noting that the findings of improved, but not cured, RLS symptoms might suggest that more than 1,500 mg of iron is needed to fully treat RLS in this patient population. “A second interpretation is that the RLS and IDA were separate events: a patient with idiopathic RLS who subsequently developed anemia,” they said. “Treating the IDA might improve symptoms but may not eliminate the symptoms.”

The study findings were limited by several factors, including the relatively small study population and inability to know the time frame for the development of IDA, the researchers noted. However, the results support the use of intravenous iron therapy for relief of RLS in IDA patients.

“Since IDA could result in epigenetic changes leading to irreversible state of RLS, then urgent and adequate management of the IDA in RLS patients would seem a very prudent and important clinical approach to this specific clinical condition,” they concluded.

The study received no outside funding. The researchers had no disclosures.

Women whose ovaries were surgically removed before the age of 46 had a higher risk of mild cognitive impairment (MCI) around 30 years later, compared with those who did not undergo bilateral oophorectomy, according to a population-based linkage study published in JAMA Network Open.

The findings suggest that “physicians treating women with premenopausal bilateral oophorectomy need to be aware of their patients’ risk of cognitive impairment or MCI and should consider implementing treatment-monitoring plans,” noted lead author Walter A. Rocca, MD, MPH, from the division of epidemiology, department of quantitative health sciences, at the Mayo Clinic, Rochester, Minn. and colleagues.

The results may particularly “help women at mean risk levels of ovarian cancer to better evaluate the risk-to-benefit ratio of undergoing bilateral oophorectomy prior to spontaneous menopause for the prevention of ovarian cancer,” they emphasized.

While the link between premenopausal bilateral oophorectomy and higher risk of cognitive impairment has been previously suggested, this new study “contributes valuable new data to a major public health importance issue and addresses a number of important shortcomings of existing literature,” Marios K. Georgakis, MD, PhD, and Eleni T. Petridou, MD, PhD, noted in an accompanying commentary.

“As bilateral oophorectomy is still a common procedure at least in well-resourced countries, the results of these studies should alert clinicians about its potential public health consequences. Given that the abrupt cessation of ovarian hormones might be accompanied by previously underestimated long-term adverse effects, treating physicians proposing the operation should weigh its benefits against potential long-term harmful effects, especially among women without an absolute indication,” noted Dr. Georgakis and Dr. Petridou, respectively from the Center for Genomic Medicine at Massachusetts General Hospital in Boston and the National and Kapodistrian University of Athens.

The case-control cross-sectional study used data from the Mayo Clinic Study of Aging (MCSA), a prospective, population-based study examining risk factors for, as well as prevalence and incidence of cognitive decline and MCI among a representative sample of women in Olmsted County, Minn. It included 2,732 women aged 50-89 years who participated in the MCSA study from 2004 to 2019 and underwent a clinical evaluation and comprehensive cognitive testing including nine tests covering four cognitive domains. Almost all of the subjects (98.4%) were White. The mean age of cognitive evaluation was 74 years – at which time 283 women (10.4%) were diagnosed with MCI (197 with amnestic and 86 with nonamnestic MCI). Data from the Rochester Epidemiology Project medical record–linkage system showed a total of 625 women (22.9%) had a history of bilateral oophorectomy. Among this group, 161 women underwent the procedure both before age 46, and before menopause, with 46 (28.6%) receiving oral conjugated equine estrogen (unopposed) and the remaining 95 (59.0%) receiving no estrogen therapy.

The study found that, compared with women who did not undergo bilateral oophorectomy, those who did so before age 46, but not after this age, had statistically significantly increased odds of MCI (adjusted odds ratio, 2.21; P < .001). When type of MCI was examined, the risk was statistically significant for nonamnestic MCI (aOR, 2.96; P < .001), and amnestic (aOR, 1.87; P =.03). The study also found no evidence that estrogen therapy was associated with decreased risk of MCI among women aged less than 46 years, with an aOR of 2.56 in those who received estrogen therapy and 2.05 in those who did not (P = .01 for both).

Finally, in women who had bilateral oophorectomy before menopause and before age 50, surgical indication for the procedure affected the association with MCI. Indications of either cancer or “no ovarian condition” (i.e., performed at the time of hysterectomy) were associated with no increased risk, whereas there was a statistically significantly increased risk associated with benign indications such as an adnexal mass, cyst or endometriosis (aOR, 2.43; P = .003). “This is important,” noted the commentators, “because in many of those cases removal of both ovaries could be avoided.”

The study also found that, compared with women who had not undergone bilateral oophorectomy, those who had also had increased frequency of cardiovascular risk factors, heart disease, and stroke at the time of their cognitive evaluation. “Additional research is needed to clarify the biological explanation of the association,” the investigators said.

The prevailing hypothesis for why premenopausal bilateral oophorectomy is associated with cognitive decline “is that the abrupt endocrine cessation of exposure to ovarian hormones accelerates the aging process,” the commentators noted. “Most important from a clinical perspective is whether these women would benefit from specific hormone replacement therapy schemes. Observational studies cannot reliably answer this question, and possibly it is time to rethink designing trials in specific groups of women who underwent bilateral oophorectomy before 46 years of age starting treatment immediately thereafter.”

In an interview Dr. Georgakis elaborated on this point, saying that, while the Women’s Health Study clearly showed no benefit of hormone replacement therapy for preventing dementia, it recruited women who were aged 65 years or older and had therefore undergone menopause more than 10-15 years earlier. “A hypothesis suggests that a critical vulnerability window exists shortly after menopause during which hormone replacement therapy might be needed to ameliorate any elevated risk,” he said. “Thus, it might make sense to reconsider a trial focused on this group of premenopausal women, who need to undergo oophorectomy at a young age (<46 years). Early initiation would be important. Unfortunately, such a trial would be difficult to conduct, because these women would need to be followed up for very long periods, as cognitive decline usually does not occur before the age of 65.”

Asked to comment on the study, Meadow Good, DO, an ob.gyn., female pelvic medicine and reconstructive surgeon, and physician adviser for Winnie Palmer Hospital for Women & Babies in Orlando, said this study adds credibility to previous studies showing the cognitive risk associated with premenopausal bilateral oophorectomy. “The literature is now pointing to a need to refrain from elective bilateral oophorectomy in women less than 60,” she said in an interview. “It should not be common that a women receives a bilateral oophorectomy before 60 for benign reasons.”

She added that cognition is not the only think at stake. “Bilateral oophorectomy before the age of 60 has a higher risk of incident heart disease, stroke, lung cancer and total cancers,” she said, citing a prospective cohort study within the Nurses’ Health Study.

Dr. Rocca reported financial support from the Mayo Clinic Research Committee during the conduct of the study. One coauthor reported unrestricted grants from Biogen and consulting fees from Brain Protection outside the submitted work. No other disclosures were reported from the authors. Dr. Georgakis, Dr. Petridou, and Dr. Good reported no conflicts of interest. The study was funded by the National Institute on Aging. It also used resources of the Rochester Epidemiology Project medical record–linkage system, which is supported by the NIA, the Mayo Clinic Research Committee, and user fees. Dr. Rocca was partly funded by the Ralph S. and Beverley E. Caulkins Professorship of Neurodegenerative Diseases Research of the Mayo Clinic.

Women whose ovaries were surgically removed before the age of 46 had a higher risk of mild cognitive impairment (MCI) around 30 years later, compared with those who did not undergo bilateral oophorectomy, according to a population-based linkage study published in JAMA Network Open.

The findings suggest that “physicians treating women with premenopausal bilateral oophorectomy need to be aware of their patients’ risk of cognitive impairment or MCI and should consider implementing treatment-monitoring plans,” noted lead author Walter A. Rocca, MD, MPH, from the division of epidemiology, department of quantitative health sciences, at the Mayo Clinic, Rochester, Minn. and colleagues.

The results may particularly “help women at mean risk levels of ovarian cancer to better evaluate the risk-to-benefit ratio of undergoing bilateral oophorectomy prior to spontaneous menopause for the prevention of ovarian cancer,” they emphasized.

While the link between premenopausal bilateral oophorectomy and higher risk of cognitive impairment has been previously suggested, this new study “contributes valuable new data to a major public health importance issue and addresses a number of important shortcomings of existing literature,” Marios K. Georgakis, MD, PhD, and Eleni T. Petridou, MD, PhD, noted in an accompanying commentary.

“As bilateral oophorectomy is still a common procedure at least in well-resourced countries, the results of these studies should alert clinicians about its potential public health consequences. Given that the abrupt cessation of ovarian hormones might be accompanied by previously underestimated long-term adverse effects, treating physicians proposing the operation should weigh its benefits against potential long-term harmful effects, especially among women without an absolute indication,” noted Dr. Georgakis and Dr. Petridou, respectively from the Center for Genomic Medicine at Massachusetts General Hospital in Boston and the National and Kapodistrian University of Athens.

The case-control cross-sectional study used data from the Mayo Clinic Study of Aging (MCSA), a prospective, population-based study examining risk factors for, as well as prevalence and incidence of cognitive decline and MCI among a representative sample of women in Olmsted County, Minn. It included 2,732 women aged 50-89 years who participated in the MCSA study from 2004 to 2019 and underwent a clinical evaluation and comprehensive cognitive testing including nine tests covering four cognitive domains. Almost all of the subjects (98.4%) were White. The mean age of cognitive evaluation was 74 years – at which time 283 women (10.4%) were diagnosed with MCI (197 with amnestic and 86 with nonamnestic MCI). Data from the Rochester Epidemiology Project medical record–linkage system showed a total of 625 women (22.9%) had a history of bilateral oophorectomy. Among this group, 161 women underwent the procedure both before age 46, and before menopause, with 46 (28.6%) receiving oral conjugated equine estrogen (unopposed) and the remaining 95 (59.0%) receiving no estrogen therapy.

The study found that, compared with women who did not undergo bilateral oophorectomy, those who did so before age 46, but not after this age, had statistically significantly increased odds of MCI (adjusted odds ratio, 2.21; P < .001). When type of MCI was examined, the risk was statistically significant for nonamnestic MCI (aOR, 2.96; P < .001), and amnestic (aOR, 1.87; P =.03). The study also found no evidence that estrogen therapy was associated with decreased risk of MCI among women aged less than 46 years, with an aOR of 2.56 in those who received estrogen therapy and 2.05 in those who did not (P = .01 for both).

Finally, in women who had bilateral oophorectomy before menopause and before age 50, surgical indication for the procedure affected the association with MCI. Indications of either cancer or “no ovarian condition” (i.e., performed at the time of hysterectomy) were associated with no increased risk, whereas there was a statistically significantly increased risk associated with benign indications such as an adnexal mass, cyst or endometriosis (aOR, 2.43; P = .003). “This is important,” noted the commentators, “because in many of those cases removal of both ovaries could be avoided.”

The study also found that, compared with women who had not undergone bilateral oophorectomy, those who had also had increased frequency of cardiovascular risk factors, heart disease, and stroke at the time of their cognitive evaluation. “Additional research is needed to clarify the biological explanation of the association,” the investigators said.

The prevailing hypothesis for why premenopausal bilateral oophorectomy is associated with cognitive decline “is that the abrupt endocrine cessation of exposure to ovarian hormones accelerates the aging process,” the commentators noted. “Most important from a clinical perspective is whether these women would benefit from specific hormone replacement therapy schemes. Observational studies cannot reliably answer this question, and possibly it is time to rethink designing trials in specific groups of women who underwent bilateral oophorectomy before 46 years of age starting treatment immediately thereafter.”

In an interview Dr. Georgakis elaborated on this point, saying that, while the Women’s Health Study clearly showed no benefit of hormone replacement therapy for preventing dementia, it recruited women who were aged 65 years or older and had therefore undergone menopause more than 10-15 years earlier. “A hypothesis suggests that a critical vulnerability window exists shortly after menopause during which hormone replacement therapy might be needed to ameliorate any elevated risk,” he said. “Thus, it might make sense to reconsider a trial focused on this group of premenopausal women, who need to undergo oophorectomy at a young age (<46 years). Early initiation would be important. Unfortunately, such a trial would be difficult to conduct, because these women would need to be followed up for very long periods, as cognitive decline usually does not occur before the age of 65.”

Asked to comment on the study, Meadow Good, DO, an ob.gyn., female pelvic medicine and reconstructive surgeon, and physician adviser for Winnie Palmer Hospital for Women & Babies in Orlando, said this study adds credibility to previous studies showing the cognitive risk associated with premenopausal bilateral oophorectomy. “The literature is now pointing to a need to refrain from elective bilateral oophorectomy in women less than 60,” she said in an interview. “It should not be common that a women receives a bilateral oophorectomy before 60 for benign reasons.”

She added that cognition is not the only think at stake. “Bilateral oophorectomy before the age of 60 has a higher risk of incident heart disease, stroke, lung cancer and total cancers,” she said, citing a prospective cohort study within the Nurses’ Health Study.

Dr. Rocca reported financial support from the Mayo Clinic Research Committee during the conduct of the study. One coauthor reported unrestricted grants from Biogen and consulting fees from Brain Protection outside the submitted work. No other disclosures were reported from the authors. Dr. Georgakis, Dr. Petridou, and Dr. Good reported no conflicts of interest. The study was funded by the National Institute on Aging. It also used resources of the Rochester Epidemiology Project medical record–linkage system, which is supported by the NIA, the Mayo Clinic Research Committee, and user fees. Dr. Rocca was partly funded by the Ralph S. and Beverley E. Caulkins Professorship of Neurodegenerative Diseases Research of the Mayo Clinic.

Women whose ovaries were surgically removed before the age of 46 had a higher risk of mild cognitive impairment (MCI) around 30 years later, compared with those who did not undergo bilateral oophorectomy, according to a population-based linkage study published in JAMA Network Open.

The findings suggest that “physicians treating women with premenopausal bilateral oophorectomy need to be aware of their patients’ risk of cognitive impairment or MCI and should consider implementing treatment-monitoring plans,” noted lead author Walter A. Rocca, MD, MPH, from the division of epidemiology, department of quantitative health sciences, at the Mayo Clinic, Rochester, Minn. and colleagues.

The results may particularly “help women at mean risk levels of ovarian cancer to better evaluate the risk-to-benefit ratio of undergoing bilateral oophorectomy prior to spontaneous menopause for the prevention of ovarian cancer,” they emphasized.

While the link between premenopausal bilateral oophorectomy and higher risk of cognitive impairment has been previously suggested, this new study “contributes valuable new data to a major public health importance issue and addresses a number of important shortcomings of existing literature,” Marios K. Georgakis, MD, PhD, and Eleni T. Petridou, MD, PhD, noted in an accompanying commentary.

“As bilateral oophorectomy is still a common procedure at least in well-resourced countries, the results of these studies should alert clinicians about its potential public health consequences. Given that the abrupt cessation of ovarian hormones might be accompanied by previously underestimated long-term adverse effects, treating physicians proposing the operation should weigh its benefits against potential long-term harmful effects, especially among women without an absolute indication,” noted Dr. Georgakis and Dr. Petridou, respectively from the Center for Genomic Medicine at Massachusetts General Hospital in Boston and the National and Kapodistrian University of Athens.

The case-control cross-sectional study used data from the Mayo Clinic Study of Aging (MCSA), a prospective, population-based study examining risk factors for, as well as prevalence and incidence of cognitive decline and MCI among a representative sample of women in Olmsted County, Minn. It included 2,732 women aged 50-89 years who participated in the MCSA study from 2004 to 2019 and underwent a clinical evaluation and comprehensive cognitive testing including nine tests covering four cognitive domains. Almost all of the subjects (98.4%) were White. The mean age of cognitive evaluation was 74 years – at which time 283 women (10.4%) were diagnosed with MCI (197 with amnestic and 86 with nonamnestic MCI). Data from the Rochester Epidemiology Project medical record–linkage system showed a total of 625 women (22.9%) had a history of bilateral oophorectomy. Among this group, 161 women underwent the procedure both before age 46, and before menopause, with 46 (28.6%) receiving oral conjugated equine estrogen (unopposed) and the remaining 95 (59.0%) receiving no estrogen therapy.

The study found that, compared with women who did not undergo bilateral oophorectomy, those who did so before age 46, but not after this age, had statistically significantly increased odds of MCI (adjusted odds ratio, 2.21; P < .001). When type of MCI was examined, the risk was statistically significant for nonamnestic MCI (aOR, 2.96; P < .001), and amnestic (aOR, 1.87; P =.03). The study also found no evidence that estrogen therapy was associated with decreased risk of MCI among women aged less than 46 years, with an aOR of 2.56 in those who received estrogen therapy and 2.05 in those who did not (P = .01 for both).

Finally, in women who had bilateral oophorectomy before menopause and before age 50, surgical indication for the procedure affected the association with MCI. Indications of either cancer or “no ovarian condition” (i.e., performed at the time of hysterectomy) were associated with no increased risk, whereas there was a statistically significantly increased risk associated with benign indications such as an adnexal mass, cyst or endometriosis (aOR, 2.43; P = .003). “This is important,” noted the commentators, “because in many of those cases removal of both ovaries could be avoided.”

The study also found that, compared with women who had not undergone bilateral oophorectomy, those who had also had increased frequency of cardiovascular risk factors, heart disease, and stroke at the time of their cognitive evaluation. “Additional research is needed to clarify the biological explanation of the association,” the investigators said.

The prevailing hypothesis for why premenopausal bilateral oophorectomy is associated with cognitive decline “is that the abrupt endocrine cessation of exposure to ovarian hormones accelerates the aging process,” the commentators noted. “Most important from a clinical perspective is whether these women would benefit from specific hormone replacement therapy schemes. Observational studies cannot reliably answer this question, and possibly it is time to rethink designing trials in specific groups of women who underwent bilateral oophorectomy before 46 years of age starting treatment immediately thereafter.”

In an interview Dr. Georgakis elaborated on this point, saying that, while the Women’s Health Study clearly showed no benefit of hormone replacement therapy for preventing dementia, it recruited women who were aged 65 years or older and had therefore undergone menopause more than 10-15 years earlier. “A hypothesis suggests that a critical vulnerability window exists shortly after menopause during which hormone replacement therapy might be needed to ameliorate any elevated risk,” he said. “Thus, it might make sense to reconsider a trial focused on this group of premenopausal women, who need to undergo oophorectomy at a young age (<46 years). Early initiation would be important. Unfortunately, such a trial would be difficult to conduct, because these women would need to be followed up for very long periods, as cognitive decline usually does not occur before the age of 65.”

Asked to comment on the study, Meadow Good, DO, an ob.gyn., female pelvic medicine and reconstructive surgeon, and physician adviser for Winnie Palmer Hospital for Women & Babies in Orlando, said this study adds credibility to previous studies showing the cognitive risk associated with premenopausal bilateral oophorectomy. “The literature is now pointing to a need to refrain from elective bilateral oophorectomy in women less than 60,” she said in an interview. “It should not be common that a women receives a bilateral oophorectomy before 60 for benign reasons.”

She added that cognition is not the only think at stake. “Bilateral oophorectomy before the age of 60 has a higher risk of incident heart disease, stroke, lung cancer and total cancers,” she said, citing a prospective cohort study within the Nurses’ Health Study.

Dr. Rocca reported financial support from the Mayo Clinic Research Committee during the conduct of the study. One coauthor reported unrestricted grants from Biogen and consulting fees from Brain Protection outside the submitted work. No other disclosures were reported from the authors. Dr. Georgakis, Dr. Petridou, and Dr. Good reported no conflicts of interest. The study was funded by the National Institute on Aging. It also used resources of the Rochester Epidemiology Project medical record–linkage system, which is supported by the NIA, the Mayo Clinic Research Committee, and user fees. Dr. Rocca was partly funded by the Ralph S. and Beverley E. Caulkins Professorship of Neurodegenerative Diseases Research of the Mayo Clinic.

When parents of children with autism spectrum disorder (ASD) participating in the largest clinical trial of intranasal oxytocin to date came in for follow-up visits with investigators, they reported marked improvement in the children’s social functioning.

Kids who rarely communicated with their families began to interact more. Those who usually preferred to isolate themselves started joining their parents for meals. It all seemed so promising – until the data came in.

“Those sounded like real improvements to me, and it seemed like they increased over the period of the study,” lead investigator Linmarie Sikich, MD, an associate clinical professor of psychiatry with Duke University School of Medicine and the Duke Center for Autism and Brain Development, Durham, N.C., told this news organization. “Turns out it wasn’t oxytocin that was making that difference.”

Researchers found that after 24 weeks of daily treatment with intranasal oxytocin, there were no significant differences in social functioning between children who received active treatment and those in the placebo group.

The much-anticipated results were published online in The New England Journal of Medicine. To say that they are disappointing, Dr. Sikich said, is an understatement.
 

Increase in off-label use

Most studies in mouse models of ASD and small trials in children produced conflicting results, although there were modest improvements in social functioning associated with the use of intranasal oxytocin. Some clinicians were already prescribing it off label.

On the basis of this research and early feedback from parents of children, Dr. Sikich and colleagues were hopeful.

However, results from a rigorous, 5-year, $11.4 million randomized trial were negative. Yet, parents were convinced their child improved during the study, and there was a significant increase in off-label prescribing of a treatment her research says doesn’t work. What’s next for oxytocin?

Known as the “love hormone,” oxytocin is a neurotransmitter that is primarily synthesized in the hypothalamus. It plays a role in childbirth and lactation and is also involved in the regulation of social functioning and emotions. Research suggests low oxytocin levels are associated with diminished social functioning, regardless of ASD status.

Its potential as an autism therapy for children has been under study for a decade. Some findings link its use to improvements in core deficits associated with ASD, including repetitive behaviors, fixated or restricted interest, and social communication. A study published in 2020 showed that the treatment improved symptoms in high-functioning adults with ASD.

These were mostly small studies and were underpowered to reliably detect an effect of the therapy on social functioning. They often involved only a single dose of oxytocin. Some studies showed improvements, but others did not.

Still, interest in the treatment grew. Physicians began prescribing it for children with ASD, and parents began buying products containing oxytocin on the internet. Researchers feared this off-label use was becoming widespread, despite inconclusive evidence of efficacy.
 

High hopes

With support from a National Institutes of Health grant, Dr. Sikich and her team designed a phase 2, multicenter, randomized, double-blind, placebo-controlled study to determine whether the use of oxytocin in children with ASD works and is safe.

The challenges began before they even enrolled a single child. A number of behavioral assessment tools are used to measure social function in ASD, but there is no consensus on which one is best.

A simple blood test could determine how much oxytocin from the nasal spray was absorbed in the blood, but identifying how much made it to the brain would require fMRI, which is expensive and is challenging to use in this study population. Then there was the acquisition of the drug itself.

The Food and Drug Administration has approved intravenous oxytocin for inducing labor. Intranasal oxytocin is not approved for any indication and isn’t available commercially in the United States. Patients or researchers must secure the drug from a manufacturer in a country where it is approved or order it from a U.S. pharmacy that is capable of compounding IV oxytocin into an intranasal formulation.

The pharmacy in Switzerland Dr. Sikich planned to use couldn’t make enough for the study. Contracting with a compounding pharmacy in the United States was significantly more expensive and time consuming, but it was the researchers’ only option.

“If it hadn’t been something we expected to have a major benefit, I think we would have given up the project at multiple points along the line due to all of these challenges,” said Dr. Sikich.

In August 2014, with all the pieces finally in place, researchers began enrolling children aged 3-17 years. The final cohort included 290 participants with ASD, 146 in the oxytocin group and 144 in the placebo group. Of these, 48% had minimal verbal fluency, and 52% had fluent verbal speech.

Participants received daily synthetic oxytocin or placebo via a nasal spray for 24 weeks. The daily oxytocin dose was 48 IU for the first 7 weeks. After that, the dosage could be titrated to a maximum of 80 IU/d. The mean maximal total daily dose of oxytocin throughout the study was 67.6 ± 16.9 IU.
 

‘It just didn’t work’

Both study groups showed improvement in social withdrawal beginning at 4 weeks and continuing throughout the trial, as determined on the basis of caretakers’ responses on the Aberrant Behavior Checklist Modified Social Withdrawal Subscale, the study’s primary outcome measure.

Sociability and social motivation also improved in both groups, as measured by the Pervasive Developmental Disorders Behavior Inventory and the Social Responsiveness Scale.

But by the end of the trial, the difference between the groups in improvement of social function wasn’t significant (difference, -0.2 points; P = .61) after adjusting for age, verbal fluency, and baseline oxytocin level.

“We were so convinced that it would work,” Dr. Sikich said, “but it just didn’t.”

From observation, parents were also convinced the therapy was working. At the trial’s conclusion, fewer than half of caregivers correctly guessed whether their child was in the treatment group or the placebo group.

A lot of development changes can happen in a child over 6 months. It’s possible the improvements would have occurred regardless of the trial, Dr. Sikich said. Parents’ perceptions could also be a placebo effect. Their child was in a clinical trial of a drug they believed could improve social functioning, so in their mind, it did.

Caregivers received training in how to identify certain behavioral changes, which may have helped them spot an existing positive change they had previously overlooked. Or they may have worked with their child more intently as a result of their participation in the trial.

“People may start doing more things or doing them more intensively or purposefully, consciously or subconsciously, to try to help their child improve the skills or behaviors targeted by the active therapy in the study,” Dr. Sikich said. “These are things that might really help the child move forward which are completely separate from the medication being studied.”

The safety analysis offered more hopeful results. Only one serious adverse event from the treatment was reported: A 17-year-old participant taking a daily dose of 48 IU experienced a sedating effect while driving and had an accident.
 

Too soon to walk away?

Perhaps the most important take-away from the study is that even if it’s safe, intranasal oxytocin as it is currently used doesn’t work and clinicians shouldn’t prescribe it, said Daniel Geschwind, MD, PhD, director of the University of California, Los Angeles (UCLA) Center for Autism Research, who penned a commentary on the study and discussed the findings with this news organization.

“This study shows that using oxytocin the way it’s used in the community right now is not helping anybody, so why put a child through that?” added Dr. Geschwind, who also is a professor of genetics, neurology, and psychiatry at UCLA.

The trial highlights areas that need to be addressed in order to improve research in the field, he said. Establishing a consensus process to measure social functioning and figuring out a better way to access intranasal oxytocin would lead to studies that are more conclusive, comparable, and less expensive. Dr. Sikich agrees.

Despite the findings, Dr. Geschwind and other autism researchers say it’s too soon to walk away from oxytocin altogether, although it may be time to change the approach to autism research.

“We have to take a page from the playbook of modern medicine in other areas and begin to recognize that these syndromes are incredibly heterogeneous,” Dr. Geschwind says. “We can surmise, although we don’t know, that there might be different biological forms of autism that have different pathways involved that are going to respond differently to different medications.”

Calling the researchers’ efforts “heroic,” Karen Parker, PhD, an associate professor and associate chair of psychiatry and behavioral sciences at Stanford (Calif.) University, says efficacy trials such as this one are critical. However, Dr. Parker said in an interview, there are a number of questions that the study didn’t address.

The majority of medication dispensed in a standard intranasal device is sprayed into the back of the throat. Regular blood tests confirmed that oxytocin was getting into participants’ system, but, given how quickly oxytocin degrades in the blood, Dr. Parker said it’s hard to know just how much reached the brain.

It’s also unclear whether the results would have been different had the treatment been paired with behavioral therapy, an approach Dr. Parker suggests might benefit a subset of children with ASD.

A 2017 study from Dr. Parker’s lab found that children with ASD whose use of oxytocin at baseline was low derived greater benefit from synthetic oxytocin, something the new study failed to find. Still, Dr. Parker said, it’s possible oxytocin might increase social motivation and increase a child’s receptiveness to behavioral therapy.

“When you see a negative trial like this, it decreases enthusiasm for the therapy for autism in this context,” Dr. Parker said. “I hope people who are studying these syndromes will continue to explore oxytocin as a therapy.”

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Autism Centers of Excellence Program and the Department of Psychiatry and Behavioral Sciences at Duke University. Full disclosures of the authors’ possible conflicts of interest are available online.

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

When parents of children with autism spectrum disorder (ASD) participating in the largest clinical trial of intranasal oxytocin to date came in for follow-up visits with investigators, they reported marked improvement in the children’s social functioning.

Kids who rarely communicated with their families began to interact more. Those who usually preferred to isolate themselves started joining their parents for meals. It all seemed so promising – until the data came in.

“Those sounded like real improvements to me, and it seemed like they increased over the period of the study,” lead investigator Linmarie Sikich, MD, an associate clinical professor of psychiatry with Duke University School of Medicine and the Duke Center for Autism and Brain Development, Durham, N.C., told this news organization. “Turns out it wasn’t oxytocin that was making that difference.”

Researchers found that after 24 weeks of daily treatment with intranasal oxytocin, there were no significant differences in social functioning between children who received active treatment and those in the placebo group.

The much-anticipated results were published online in The New England Journal of Medicine. To say that they are disappointing, Dr. Sikich said, is an understatement.
 

Increase in off-label use

Most studies in mouse models of ASD and small trials in children produced conflicting results, although there were modest improvements in social functioning associated with the use of intranasal oxytocin. Some clinicians were already prescribing it off label.

On the basis of this research and early feedback from parents of children, Dr. Sikich and colleagues were hopeful.

However, results from a rigorous, 5-year, $11.4 million randomized trial were negative. Yet, parents were convinced their child improved during the study, and there was a significant increase in off-label prescribing of a treatment her research says doesn’t work. What’s next for oxytocin?

Known as the “love hormone,” oxytocin is a neurotransmitter that is primarily synthesized in the hypothalamus. It plays a role in childbirth and lactation and is also involved in the regulation of social functioning and emotions. Research suggests low oxytocin levels are associated with diminished social functioning, regardless of ASD status.

Its potential as an autism therapy for children has been under study for a decade. Some findings link its use to improvements in core deficits associated with ASD, including repetitive behaviors, fixated or restricted interest, and social communication. A study published in 2020 showed that the treatment improved symptoms in high-functioning adults with ASD.

These were mostly small studies and were underpowered to reliably detect an effect of the therapy on social functioning. They often involved only a single dose of oxytocin. Some studies showed improvements, but others did not.

Still, interest in the treatment grew. Physicians began prescribing it for children with ASD, and parents began buying products containing oxytocin on the internet. Researchers feared this off-label use was becoming widespread, despite inconclusive evidence of efficacy.
 

High hopes

With support from a National Institutes of Health grant, Dr. Sikich and her team designed a phase 2, multicenter, randomized, double-blind, placebo-controlled study to determine whether the use of oxytocin in children with ASD works and is safe.

The challenges began before they even enrolled a single child. A number of behavioral assessment tools are used to measure social function in ASD, but there is no consensus on which one is best.

A simple blood test could determine how much oxytocin from the nasal spray was absorbed in the blood, but identifying how much made it to the brain would require fMRI, which is expensive and is challenging to use in this study population. Then there was the acquisition of the drug itself.

The Food and Drug Administration has approved intravenous oxytocin for inducing labor. Intranasal oxytocin is not approved for any indication and isn’t available commercially in the United States. Patients or researchers must secure the drug from a manufacturer in a country where it is approved or order it from a U.S. pharmacy that is capable of compounding IV oxytocin into an intranasal formulation.

The pharmacy in Switzerland Dr. Sikich planned to use couldn’t make enough for the study. Contracting with a compounding pharmacy in the United States was significantly more expensive and time consuming, but it was the researchers’ only option.

“If it hadn’t been something we expected to have a major benefit, I think we would have given up the project at multiple points along the line due to all of these challenges,” said Dr. Sikich.

In August 2014, with all the pieces finally in place, researchers began enrolling children aged 3-17 years. The final cohort included 290 participants with ASD, 146 in the oxytocin group and 144 in the placebo group. Of these, 48% had minimal verbal fluency, and 52% had fluent verbal speech.

Participants received daily synthetic oxytocin or placebo via a nasal spray for 24 weeks. The daily oxytocin dose was 48 IU for the first 7 weeks. After that, the dosage could be titrated to a maximum of 80 IU/d. The mean maximal total daily dose of oxytocin throughout the study was 67.6 ± 16.9 IU.
 

‘It just didn’t work’

Both study groups showed improvement in social withdrawal beginning at 4 weeks and continuing throughout the trial, as determined on the basis of caretakers’ responses on the Aberrant Behavior Checklist Modified Social Withdrawal Subscale, the study’s primary outcome measure.

Sociability and social motivation also improved in both groups, as measured by the Pervasive Developmental Disorders Behavior Inventory and the Social Responsiveness Scale.

But by the end of the trial, the difference between the groups in improvement of social function wasn’t significant (difference, -0.2 points; P = .61) after adjusting for age, verbal fluency, and baseline oxytocin level.

“We were so convinced that it would work,” Dr. Sikich said, “but it just didn’t.”

From observation, parents were also convinced the therapy was working. At the trial’s conclusion, fewer than half of caregivers correctly guessed whether their child was in the treatment group or the placebo group.

A lot of development changes can happen in a child over 6 months. It’s possible the improvements would have occurred regardless of the trial, Dr. Sikich said. Parents’ perceptions could also be a placebo effect. Their child was in a clinical trial of a drug they believed could improve social functioning, so in their mind, it did.

Caregivers received training in how to identify certain behavioral changes, which may have helped them spot an existing positive change they had previously overlooked. Or they may have worked with their child more intently as a result of their participation in the trial.

“People may start doing more things or doing them more intensively or purposefully, consciously or subconsciously, to try to help their child improve the skills or behaviors targeted by the active therapy in the study,” Dr. Sikich said. “These are things that might really help the child move forward which are completely separate from the medication being studied.”

The safety analysis offered more hopeful results. Only one serious adverse event from the treatment was reported: A 17-year-old participant taking a daily dose of 48 IU experienced a sedating effect while driving and had an accident.
 

Too soon to walk away?

Perhaps the most important take-away from the study is that even if it’s safe, intranasal oxytocin as it is currently used doesn’t work and clinicians shouldn’t prescribe it, said Daniel Geschwind, MD, PhD, director of the University of California, Los Angeles (UCLA) Center for Autism Research, who penned a commentary on the study and discussed the findings with this news organization.

“This study shows that using oxytocin the way it’s used in the community right now is not helping anybody, so why put a child through that?” added Dr. Geschwind, who also is a professor of genetics, neurology, and psychiatry at UCLA.

The trial highlights areas that need to be addressed in order to improve research in the field, he said. Establishing a consensus process to measure social functioning and figuring out a better way to access intranasal oxytocin would lead to studies that are more conclusive, comparable, and less expensive. Dr. Sikich agrees.

Despite the findings, Dr. Geschwind and other autism researchers say it’s too soon to walk away from oxytocin altogether, although it may be time to change the approach to autism research.

“We have to take a page from the playbook of modern medicine in other areas and begin to recognize that these syndromes are incredibly heterogeneous,” Dr. Geschwind says. “We can surmise, although we don’t know, that there might be different biological forms of autism that have different pathways involved that are going to respond differently to different medications.”

Calling the researchers’ efforts “heroic,” Karen Parker, PhD, an associate professor and associate chair of psychiatry and behavioral sciences at Stanford (Calif.) University, says efficacy trials such as this one are critical. However, Dr. Parker said in an interview, there are a number of questions that the study didn’t address.

The majority of medication dispensed in a standard intranasal device is sprayed into the back of the throat. Regular blood tests confirmed that oxytocin was getting into participants’ system, but, given how quickly oxytocin degrades in the blood, Dr. Parker said it’s hard to know just how much reached the brain.

It’s also unclear whether the results would have been different had the treatment been paired with behavioral therapy, an approach Dr. Parker suggests might benefit a subset of children with ASD.

A 2017 study from Dr. Parker’s lab found that children with ASD whose use of oxytocin at baseline was low derived greater benefit from synthetic oxytocin, something the new study failed to find. Still, Dr. Parker said, it’s possible oxytocin might increase social motivation and increase a child’s receptiveness to behavioral therapy.

“When you see a negative trial like this, it decreases enthusiasm for the therapy for autism in this context,” Dr. Parker said. “I hope people who are studying these syndromes will continue to explore oxytocin as a therapy.”

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Autism Centers of Excellence Program and the Department of Psychiatry and Behavioral Sciences at Duke University. Full disclosures of the authors’ possible conflicts of interest are available online.

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

When parents of children with autism spectrum disorder (ASD) participating in the largest clinical trial of intranasal oxytocin to date came in for follow-up visits with investigators, they reported marked improvement in the children’s social functioning.

Kids who rarely communicated with their families began to interact more. Those who usually preferred to isolate themselves started joining their parents for meals. It all seemed so promising – until the data came in.

“Those sounded like real improvements to me, and it seemed like they increased over the period of the study,” lead investigator Linmarie Sikich, MD, an associate clinical professor of psychiatry with Duke University School of Medicine and the Duke Center for Autism and Brain Development, Durham, N.C., told this news organization. “Turns out it wasn’t oxytocin that was making that difference.”

Researchers found that after 24 weeks of daily treatment with intranasal oxytocin, there were no significant differences in social functioning between children who received active treatment and those in the placebo group.

The much-anticipated results were published online in The New England Journal of Medicine. To say that they are disappointing, Dr. Sikich said, is an understatement.
 

Increase in off-label use

Most studies in mouse models of ASD and small trials in children produced conflicting results, although there were modest improvements in social functioning associated with the use of intranasal oxytocin. Some clinicians were already prescribing it off label.

On the basis of this research and early feedback from parents of children, Dr. Sikich and colleagues were hopeful.

However, results from a rigorous, 5-year, $11.4 million randomized trial were negative. Yet, parents were convinced their child improved during the study, and there was a significant increase in off-label prescribing of a treatment her research says doesn’t work. What’s next for oxytocin?

Known as the “love hormone,” oxytocin is a neurotransmitter that is primarily synthesized in the hypothalamus. It plays a role in childbirth and lactation and is also involved in the regulation of social functioning and emotions. Research suggests low oxytocin levels are associated with diminished social functioning, regardless of ASD status.

Its potential as an autism therapy for children has been under study for a decade. Some findings link its use to improvements in core deficits associated with ASD, including repetitive behaviors, fixated or restricted interest, and social communication. A study published in 2020 showed that the treatment improved symptoms in high-functioning adults with ASD.

These were mostly small studies and were underpowered to reliably detect an effect of the therapy on social functioning. They often involved only a single dose of oxytocin. Some studies showed improvements, but others did not.

Still, interest in the treatment grew. Physicians began prescribing it for children with ASD, and parents began buying products containing oxytocin on the internet. Researchers feared this off-label use was becoming widespread, despite inconclusive evidence of efficacy.
 

High hopes

With support from a National Institutes of Health grant, Dr. Sikich and her team designed a phase 2, multicenter, randomized, double-blind, placebo-controlled study to determine whether the use of oxytocin in children with ASD works and is safe.

The challenges began before they even enrolled a single child. A number of behavioral assessment tools are used to measure social function in ASD, but there is no consensus on which one is best.

A simple blood test could determine how much oxytocin from the nasal spray was absorbed in the blood, but identifying how much made it to the brain would require fMRI, which is expensive and is challenging to use in this study population. Then there was the acquisition of the drug itself.

The Food and Drug Administration has approved intravenous oxytocin for inducing labor. Intranasal oxytocin is not approved for any indication and isn’t available commercially in the United States. Patients or researchers must secure the drug from a manufacturer in a country where it is approved or order it from a U.S. pharmacy that is capable of compounding IV oxytocin into an intranasal formulation.

The pharmacy in Switzerland Dr. Sikich planned to use couldn’t make enough for the study. Contracting with a compounding pharmacy in the United States was significantly more expensive and time consuming, but it was the researchers’ only option.

“If it hadn’t been something we expected to have a major benefit, I think we would have given up the project at multiple points along the line due to all of these challenges,” said Dr. Sikich.

In August 2014, with all the pieces finally in place, researchers began enrolling children aged 3-17 years. The final cohort included 290 participants with ASD, 146 in the oxytocin group and 144 in the placebo group. Of these, 48% had minimal verbal fluency, and 52% had fluent verbal speech.

Participants received daily synthetic oxytocin or placebo via a nasal spray for 24 weeks. The daily oxytocin dose was 48 IU for the first 7 weeks. After that, the dosage could be titrated to a maximum of 80 IU/d. The mean maximal total daily dose of oxytocin throughout the study was 67.6 ± 16.9 IU.
 

‘It just didn’t work’

Both study groups showed improvement in social withdrawal beginning at 4 weeks and continuing throughout the trial, as determined on the basis of caretakers’ responses on the Aberrant Behavior Checklist Modified Social Withdrawal Subscale, the study’s primary outcome measure.

Sociability and social motivation also improved in both groups, as measured by the Pervasive Developmental Disorders Behavior Inventory and the Social Responsiveness Scale.

But by the end of the trial, the difference between the groups in improvement of social function wasn’t significant (difference, -0.2 points; P = .61) after adjusting for age, verbal fluency, and baseline oxytocin level.

“We were so convinced that it would work,” Dr. Sikich said, “but it just didn’t.”

From observation, parents were also convinced the therapy was working. At the trial’s conclusion, fewer than half of caregivers correctly guessed whether their child was in the treatment group or the placebo group.

A lot of development changes can happen in a child over 6 months. It’s possible the improvements would have occurred regardless of the trial, Dr. Sikich said. Parents’ perceptions could also be a placebo effect. Their child was in a clinical trial of a drug they believed could improve social functioning, so in their mind, it did.

Caregivers received training in how to identify certain behavioral changes, which may have helped them spot an existing positive change they had previously overlooked. Or they may have worked with their child more intently as a result of their participation in the trial.

“People may start doing more things or doing them more intensively or purposefully, consciously or subconsciously, to try to help their child improve the skills or behaviors targeted by the active therapy in the study,” Dr. Sikich said. “These are things that might really help the child move forward which are completely separate from the medication being studied.”

The safety analysis offered more hopeful results. Only one serious adverse event from the treatment was reported: A 17-year-old participant taking a daily dose of 48 IU experienced a sedating effect while driving and had an accident.
 

Too soon to walk away?

Perhaps the most important take-away from the study is that even if it’s safe, intranasal oxytocin as it is currently used doesn’t work and clinicians shouldn’t prescribe it, said Daniel Geschwind, MD, PhD, director of the University of California, Los Angeles (UCLA) Center for Autism Research, who penned a commentary on the study and discussed the findings with this news organization.

“This study shows that using oxytocin the way it’s used in the community right now is not helping anybody, so why put a child through that?” added Dr. Geschwind, who also is a professor of genetics, neurology, and psychiatry at UCLA.

The trial highlights areas that need to be addressed in order to improve research in the field, he said. Establishing a consensus process to measure social functioning and figuring out a better way to access intranasal oxytocin would lead to studies that are more conclusive, comparable, and less expensive. Dr. Sikich agrees.

Despite the findings, Dr. Geschwind and other autism researchers say it’s too soon to walk away from oxytocin altogether, although it may be time to change the approach to autism research.

“We have to take a page from the playbook of modern medicine in other areas and begin to recognize that these syndromes are incredibly heterogeneous,” Dr. Geschwind says. “We can surmise, although we don’t know, that there might be different biological forms of autism that have different pathways involved that are going to respond differently to different medications.”

Calling the researchers’ efforts “heroic,” Karen Parker, PhD, an associate professor and associate chair of psychiatry and behavioral sciences at Stanford (Calif.) University, says efficacy trials such as this one are critical. However, Dr. Parker said in an interview, there are a number of questions that the study didn’t address.

The majority of medication dispensed in a standard intranasal device is sprayed into the back of the throat. Regular blood tests confirmed that oxytocin was getting into participants’ system, but, given how quickly oxytocin degrades in the blood, Dr. Parker said it’s hard to know just how much reached the brain.

It’s also unclear whether the results would have been different had the treatment been paired with behavioral therapy, an approach Dr. Parker suggests might benefit a subset of children with ASD.

A 2017 study from Dr. Parker’s lab found that children with ASD whose use of oxytocin at baseline was low derived greater benefit from synthetic oxytocin, something the new study failed to find. Still, Dr. Parker said, it’s possible oxytocin might increase social motivation and increase a child’s receptiveness to behavioral therapy.

“When you see a negative trial like this, it decreases enthusiasm for the therapy for autism in this context,” Dr. Parker said. “I hope people who are studying these syndromes will continue to explore oxytocin as a therapy.”

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Autism Centers of Excellence Program and the Department of Psychiatry and Behavioral Sciences at Duke University. Full disclosures of the authors’ possible conflicts of interest are available online.

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

NEW ORLEANS – The increased use of digital screens for school during the COVID-19 pandemic may be causing convergence insufficiency in children, researchers say.

Although the long-term implications for current schoolchildren are not clear, convergence insufficiency sometimes persists for a lifetime, said Kammi Gunton, MD, interim chief of pediatric ophthalmology and strabismus at Wills Eye Hospital, Philadelphia.

“It’s important, if we use digital technology for education, that we are aware that it might contribute to increased eye symptoms in children,” Dr. Gunton told this news organization.

Dr. Gunton’s colleague, Jordan Hamburger, an MD candidate at Sidney Kimmel Medical College, Philadelphia, presented the finding at the American Academy of Ophthalmology 2021 Annual Meeting.

Convergence insufficiency is an impairment of binocularity. Symptoms include headaches while reading, words that seem to move around the page, blurriness, diplopia, and eye fatigue. It can be treated with exercise, prism glasses, or, rarely, surgery.

“We have some kids who improve with either time or maturity, then we have other patients who suffer from it for their entire lives,” Dr. Gunton said.

Previous research has linked the use of digital screens to convergence insufficiency, so when many schools shifted to distance learning for the pandemic, Dr. Gunton and her colleagues wanted to see whether it would have this effect on the students’ eyes.

They surveyed 110 healthy schoolchildren and adolescent students regarding eye symptoms before and after a day of virtual school. The mean age of the participants was 14 years (range, 10-17 years). The participants spent an average of 6.96 hours per day in virtual school. Forty-one percent also attended school in person part time. These students filled out the survey on days when they were in virtual school.

The participants answered questions on the Convergence Insufficiency Symptom Survey (CISS). The survey consists of 15 questions about eye complaints. On each question, the students rated symptoms from 0 to 4, with 4 indicating a severe symptom.

The average sum of the CISS scores rose from 5.17 before school to 9.82 after school, a statistically significant change (P < .001). Sixty-one percent of the participants reported an increase in convergence insufficiency symptoms.

Seventeen percent scored a total of at least 16, which is the threshold score considered suggestive of convergence insufficiency.

The researchers also found that, on average, the more hours each student spent in virtual school, the higher their CISS scores.

This makes sense, because reading requires convergence, Dr. Gunton said. The same problem might occur in traditional school if the students were looking at books all day instead of focusing on objects at various distances in their classrooms, such as the teacher or the whiteboard. “So, in the past, if you read a book, maybe you wouldn’t read for several hours, but now we’re asking children during virtual learning to stay on a device with the camera on,” she said.

Previous research has shown that people blink less when reading or using electronic devices, probably because of their increased concentration. This might explain symptoms such as burning and itching. Fifty-three percent of the students reported an increase in asthenopia symptoms.

The researchers would have liked to have compared the students in virtual school to a matched group of students in traditional school. However, almost all students were enrolled in virtual school when the study was conducted, making such a control difficult.

Although previous research has related virtual learning to myopia, as reported by this news organization, this study did not investigate myopia, and the researchers do not believe that convergence insufficiency causes myopia or vice versa.

Parents can help prevent convergence insufficiency during school by reminding their children to take breaks, Dr. Gunton said. She recommends the 20/20/20 rule: After 20 minutes of work that involves looking at objects nearby, students should take a 20-second break and look at something 20 feet away.

“I also think the take-home message is for parents to ask students if they’re having symptoms,” she said, “and if they hear complaints while kids are on the computers, to have them see an eye doctor and have an evaluation.”

Stephen Lipsky, MD, who wasn’t involved in the study, said he is seeing more cases of eye strain at Children’s Healthcare of Atlanta, where he is a consulting ophthalmologist.

“The study is very valuable in that it shines a light on the fact that these children do have symptoms, such as asthenopia or convergence insufficiency,” he told this news organization. “But I’m optimistic that with a return to more traditional learning, we will return the more traditional incidence of these problems.”

Dr. Gunton and Dr. Lipsky have disclosed no relevant financial relationships.

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

NEW ORLEANS – The increased use of digital screens for school during the COVID-19 pandemic may be causing convergence insufficiency in children, researchers say.

Although the long-term implications for current schoolchildren are not clear, convergence insufficiency sometimes persists for a lifetime, said Kammi Gunton, MD, interim chief of pediatric ophthalmology and strabismus at Wills Eye Hospital, Philadelphia.

“It’s important, if we use digital technology for education, that we are aware that it might contribute to increased eye symptoms in children,” Dr. Gunton told this news organization.

Dr. Gunton’s colleague, Jordan Hamburger, an MD candidate at Sidney Kimmel Medical College, Philadelphia, presented the finding at the American Academy of Ophthalmology 2021 Annual Meeting.

Convergence insufficiency is an impairment of binocularity. Symptoms include headaches while reading, words that seem to move around the page, blurriness, diplopia, and eye fatigue. It can be treated with exercise, prism glasses, or, rarely, surgery.

“We have some kids who improve with either time or maturity, then we have other patients who suffer from it for their entire lives,” Dr. Gunton said.

Previous research has linked the use of digital screens to convergence insufficiency, so when many schools shifted to distance learning for the pandemic, Dr. Gunton and her colleagues wanted to see whether it would have this effect on the students’ eyes.

They surveyed 110 healthy schoolchildren and adolescent students regarding eye symptoms before and after a day of virtual school. The mean age of the participants was 14 years (range, 10-17 years). The participants spent an average of 6.96 hours per day in virtual school. Forty-one percent also attended school in person part time. These students filled out the survey on days when they were in virtual school.

The participants answered questions on the Convergence Insufficiency Symptom Survey (CISS). The survey consists of 15 questions about eye complaints. On each question, the students rated symptoms from 0 to 4, with 4 indicating a severe symptom.

The average sum of the CISS scores rose from 5.17 before school to 9.82 after school, a statistically significant change (P < .001). Sixty-one percent of the participants reported an increase in convergence insufficiency symptoms.

Seventeen percent scored a total of at least 16, which is the threshold score considered suggestive of convergence insufficiency.

The researchers also found that, on average, the more hours each student spent in virtual school, the higher their CISS scores.

This makes sense, because reading requires convergence, Dr. Gunton said. The same problem might occur in traditional school if the students were looking at books all day instead of focusing on objects at various distances in their classrooms, such as the teacher or the whiteboard. “So, in the past, if you read a book, maybe you wouldn’t read for several hours, but now we’re asking children during virtual learning to stay on a device with the camera on,” she said.

Previous research has shown that people blink less when reading or using electronic devices, probably because of their increased concentration. This might explain symptoms such as burning and itching. Fifty-three percent of the students reported an increase in asthenopia symptoms.

The researchers would have liked to have compared the students in virtual school to a matched group of students in traditional school. However, almost all students were enrolled in virtual school when the study was conducted, making such a control difficult.

Although previous research has related virtual learning to myopia, as reported by this news organization, this study did not investigate myopia, and the researchers do not believe that convergence insufficiency causes myopia or vice versa.

Parents can help prevent convergence insufficiency during school by reminding their children to take breaks, Dr. Gunton said. She recommends the 20/20/20 rule: After 20 minutes of work that involves looking at objects nearby, students should take a 20-second break and look at something 20 feet away.

“I also think the take-home message is for parents to ask students if they’re having symptoms,” she said, “and if they hear complaints while kids are on the computers, to have them see an eye doctor and have an evaluation.”

Stephen Lipsky, MD, who wasn’t involved in the study, said he is seeing more cases of eye strain at Children’s Healthcare of Atlanta, where he is a consulting ophthalmologist.

“The study is very valuable in that it shines a light on the fact that these children do have symptoms, such as asthenopia or convergence insufficiency,” he told this news organization. “But I’m optimistic that with a return to more traditional learning, we will return the more traditional incidence of these problems.”

Dr. Gunton and Dr. Lipsky have disclosed no relevant financial relationships.

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

NEW ORLEANS – The increased use of digital screens for school during the COVID-19 pandemic may be causing convergence insufficiency in children, researchers say.

Although the long-term implications for current schoolchildren are not clear, convergence insufficiency sometimes persists for a lifetime, said Kammi Gunton, MD, interim chief of pediatric ophthalmology and strabismus at Wills Eye Hospital, Philadelphia.

“It’s important, if we use digital technology for education, that we are aware that it might contribute to increased eye symptoms in children,” Dr. Gunton told this news organization.

Dr. Gunton’s colleague, Jordan Hamburger, an MD candidate at Sidney Kimmel Medical College, Philadelphia, presented the finding at the American Academy of Ophthalmology 2021 Annual Meeting.

Convergence insufficiency is an impairment of binocularity. Symptoms include headaches while reading, words that seem to move around the page, blurriness, diplopia, and eye fatigue. It can be treated with exercise, prism glasses, or, rarely, surgery.

“We have some kids who improve with either time or maturity, then we have other patients who suffer from it for their entire lives,” Dr. Gunton said.

Previous research has linked the use of digital screens to convergence insufficiency, so when many schools shifted to distance learning for the pandemic, Dr. Gunton and her colleagues wanted to see whether it would have this effect on the students’ eyes.

They surveyed 110 healthy schoolchildren and adolescent students regarding eye symptoms before and after a day of virtual school. The mean age of the participants was 14 years (range, 10-17 years). The participants spent an average of 6.96 hours per day in virtual school. Forty-one percent also attended school in person part time. These students filled out the survey on days when they were in virtual school.

The participants answered questions on the Convergence Insufficiency Symptom Survey (CISS). The survey consists of 15 questions about eye complaints. On each question, the students rated symptoms from 0 to 4, with 4 indicating a severe symptom.

The average sum of the CISS scores rose from 5.17 before school to 9.82 after school, a statistically significant change (P < .001). Sixty-one percent of the participants reported an increase in convergence insufficiency symptoms.

Seventeen percent scored a total of at least 16, which is the threshold score considered suggestive of convergence insufficiency.

The researchers also found that, on average, the more hours each student spent in virtual school, the higher their CISS scores.

This makes sense, because reading requires convergence, Dr. Gunton said. The same problem might occur in traditional school if the students were looking at books all day instead of focusing on objects at various distances in their classrooms, such as the teacher or the whiteboard. “So, in the past, if you read a book, maybe you wouldn’t read for several hours, but now we’re asking children during virtual learning to stay on a device with the camera on,” she said.

Previous research has shown that people blink less when reading or using electronic devices, probably because of their increased concentration. This might explain symptoms such as burning and itching. Fifty-three percent of the students reported an increase in asthenopia symptoms.

The researchers would have liked to have compared the students in virtual school to a matched group of students in traditional school. However, almost all students were enrolled in virtual school when the study was conducted, making such a control difficult.

Although previous research has related virtual learning to myopia, as reported by this news organization, this study did not investigate myopia, and the researchers do not believe that convergence insufficiency causes myopia or vice versa.

Parents can help prevent convergence insufficiency during school by reminding their children to take breaks, Dr. Gunton said. She recommends the 20/20/20 rule: After 20 minutes of work that involves looking at objects nearby, students should take a 20-second break and look at something 20 feet away.

“I also think the take-home message is for parents to ask students if they’re having symptoms,” she said, “and if they hear complaints while kids are on the computers, to have them see an eye doctor and have an evaluation.”

Stephen Lipsky, MD, who wasn’t involved in the study, said he is seeing more cases of eye strain at Children’s Healthcare of Atlanta, where he is a consulting ophthalmologist.

“The study is very valuable in that it shines a light on the fact that these children do have symptoms, such as asthenopia or convergence insufficiency,” he told this news organization. “But I’m optimistic that with a return to more traditional learning, we will return the more traditional incidence of these problems.”

Dr. Gunton and Dr. Lipsky have disclosed no relevant financial relationships.

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

Mothers who use cannabis during pregnancy risk disrupting immune gene networks in the placenta and potentially increasing the risk of anxiety and hyperactivity in their children.

These findings emerged from a study led by Yasmin Hurd, PhD, a professor of psychiatry and director of the Addiction Institute at the Icahn School of Medicine at Mount Sinai, New York, and Yoko Nomura, PhD, a professor of behavioral neuroscience at Queen’s College, City University of New York, that was published online in Proceedings of the National Academy of Sciences.

The analysis assessed the effects of gestational maternal cannabis use on psychosocial and physiological measures in young children as well as its potentially immunomodulatory effect on the in utero environment as reflected in the placental transcriptome.

Participants were drawn from a larger cohort in a study launched in 2012; the investigators evaluated offspring aged 3-6 years for hair hormone levels, neurobehavioral traits on the Behavioral Assessment System for Children survey, and heart rate variability (HRV) at rest and during auditory startle.

The cohort consisted of 322 mother-child dyads and children with prenatal exposure to cannabis were compared with those having no exposure. The cohort consisted of 251 non–cannabis-using mothers and 71 cannabis-using mothers, with mean maternal ages in the two groups of 28.46 years and 25.91 years, respectively, The mothers gave birth at Mount Sinai and they and their children were assessed annually at affiliated medical centers in Mount Sinai’s catchment area.

For a subset of children with behavioral assessments, placental specimens collected at birth were processed for RNA sequencing.

Among the findings:

• Maternal cannabis use was associated with reduced maternal and paternal age, more single-mother pregnancies, state anxiety, trait anxiety, depression, cigarette smoking, and African American race.
• Hair hormone analysis revealed increased cortisol levels in the children of cannabis-using mothers, and was associated with greater anxiety, aggression, and hyperactivity.
• Affected children showed a reduction in the high-frequency component of HRV at baseline, reflecting reduced vagal tone.
• In the placenta, there was reduced expression of many genes involved in immune system function. These included genes for type I interferon, neutrophil, and cytokine-signaling pathways.

Several of these genes organized into coexpression networks that correlated with child anxiety and hyperactivity.

The principal active component of cannabis, tetrahydrocannabinol (THC), targets the endocannabinoid system in placental tissue and the developing brain, the authors noted. Exposure during pregnancy is associated with a range of adverse outcomes from fetal growth restriction to low birth weight and preterm birth.

“There are cannabinoid receptors on immune cells, and it is known that cannabinoids can alter immune function, which is important for maintaining maternal tolerance and protecting the fetus,” Dr. Hurd said. “It’s not surprising that something that affects the immune cells can have an impact on the developing fetus.”

“Overall, our findings reveal a relationship between [maternal cannabis use] and immune response gene networks in the placenta as a potential mediator of risk for anxiety-related problems in early childhood,” Dr. Hurd and colleagues wrote, adding that the results have significant implications for defining mental health issues in the children gestated by cannabis-smoking mothers.

Their results align with previous research indicating a greater risk for psychiatric illness in children with prenatal cannabis exposure from maternal use.

“While data are pretty limited in this realm, there are other studies that demonstrate a relationship between early child developmental and behavioral measures and cannabis use during pregnancy,” Camille Hoffman, MD, MSc, a high-risk obstetrics specialist and an associate professor at the University of Colorado at Denver, Aurora, said in an interview. “Our research group found children exposed to cannabis in utero at 10 weeks’ gestation and beyond were less interactive and more withdrawn than children who were not exposed.”

And THC remains in maternal breast milk even 6 weeks after usage stops.

The long-term effects of prenatal cannabis exposure remain to be determined and it is unknown whether the effects of gestational THC might attenuate as a child grows older. “We use early childhood measures in research as a proxy for the later development of diagnosed mental health conditions or behavioral problems,” Dr. Hoffman explained. “We know when we do this that not every child with an abnormal score early will go on to develop an actual condition. Fortunately, or unfortunately, other factors and exposures during childhood can change the trajectory for the better or worse.”

According to Dr. Hurd, child development is a dynamic process and epigenetic events in utero need not be deterministic. “The important thing is to identify children at risk early and to be able to go in and try to improve the environment they’re being raised in – not in terms of impoverishment but in terms of positive nurturing and giving the mother and family support.”

At the prenatal level, what’s the best advice for cannabis-using mothers-to-be? “If a woman doesn’t know she’s pregnant and has been using cannabis, taking extra choline for the remainder of the pregnancy can help buffer the potential negative impact of the cannabis exposure,” Dr. Hoffman said. The Food and Drug Administration and the American Medical Association recommend a dose of 550 mg daily. “The same is true for alcohol, which we know is also very bad for fetal brain development. This is not to say go ahead and use these substances and just take choline. The choline is more to try and salvage damage to the fetal brain that may have already occurred.”

This study was supported by the National Institute of Mental Health and the National Institute on Drug Abuse. The authors declared no competing interests. Dr. Hoffman disclosed no conflicts of interest with respect to her comments.

Mothers who use cannabis during pregnancy risk disrupting immune gene networks in the placenta and potentially increasing the risk of anxiety and hyperactivity in their children.

These findings emerged from a study led by Yasmin Hurd, PhD, a professor of psychiatry and director of the Addiction Institute at the Icahn School of Medicine at Mount Sinai, New York, and Yoko Nomura, PhD, a professor of behavioral neuroscience at Queen’s College, City University of New York, that was published online in Proceedings of the National Academy of Sciences.

The analysis assessed the effects of gestational maternal cannabis use on psychosocial and physiological measures in young children as well as its potentially immunomodulatory effect on the in utero environment as reflected in the placental transcriptome.

Participants were drawn from a larger cohort in a study launched in 2012; the investigators evaluated offspring aged 3-6 years for hair hormone levels, neurobehavioral traits on the Behavioral Assessment System for Children survey, and heart rate variability (HRV) at rest and during auditory startle.

The cohort consisted of 322 mother-child dyads and children with prenatal exposure to cannabis were compared with those having no exposure. The cohort consisted of 251 non–cannabis-using mothers and 71 cannabis-using mothers, with mean maternal ages in the two groups of 28.46 years and 25.91 years, respectively, The mothers gave birth at Mount Sinai and they and their children were assessed annually at affiliated medical centers in Mount Sinai’s catchment area.

For a subset of children with behavioral assessments, placental specimens collected at birth were processed for RNA sequencing.

Among the findings:

• Maternal cannabis use was associated with reduced maternal and paternal age, more single-mother pregnancies, state anxiety, trait anxiety, depression, cigarette smoking, and African American race.
• Hair hormone analysis revealed increased cortisol levels in the children of cannabis-using mothers, and was associated with greater anxiety, aggression, and hyperactivity.
• Affected children showed a reduction in the high-frequency component of HRV at baseline, reflecting reduced vagal tone.
• In the placenta, there was reduced expression of many genes involved in immune system function. These included genes for type I interferon, neutrophil, and cytokine-signaling pathways.

Several of these genes organized into coexpression networks that correlated with child anxiety and hyperactivity.

The principal active component of cannabis, tetrahydrocannabinol (THC), targets the endocannabinoid system in placental tissue and the developing brain, the authors noted. Exposure during pregnancy is associated with a range of adverse outcomes from fetal growth restriction to low birth weight and preterm birth.

“There are cannabinoid receptors on immune cells, and it is known that cannabinoids can alter immune function, which is important for maintaining maternal tolerance and protecting the fetus,” Dr. Hurd said. “It’s not surprising that something that affects the immune cells can have an impact on the developing fetus.”

“Overall, our findings reveal a relationship between [maternal cannabis use] and immune response gene networks in the placenta as a potential mediator of risk for anxiety-related problems in early childhood,” Dr. Hurd and colleagues wrote, adding that the results have significant implications for defining mental health issues in the children gestated by cannabis-smoking mothers.

Their results align with previous research indicating a greater risk for psychiatric illness in children with prenatal cannabis exposure from maternal use.

“While data are pretty limited in this realm, there are other studies that demonstrate a relationship between early child developmental and behavioral measures and cannabis use during pregnancy,” Camille Hoffman, MD, MSc, a high-risk obstetrics specialist and an associate professor at the University of Colorado at Denver, Aurora, said in an interview. “Our research group found children exposed to cannabis in utero at 10 weeks’ gestation and beyond were less interactive and more withdrawn than children who were not exposed.”

And THC remains in maternal breast milk even 6 weeks after usage stops.

The long-term effects of prenatal cannabis exposure remain to be determined and it is unknown whether the effects of gestational THC might attenuate as a child grows older. “We use early childhood measures in research as a proxy for the later development of diagnosed mental health conditions or behavioral problems,” Dr. Hoffman explained. “We know when we do this that not every child with an abnormal score early will go on to develop an actual condition. Fortunately, or unfortunately, other factors and exposures during childhood can change the trajectory for the better or worse.”

According to Dr. Hurd, child development is a dynamic process and epigenetic events in utero need not be deterministic. “The important thing is to identify children at risk early and to be able to go in and try to improve the environment they’re being raised in – not in terms of impoverishment but in terms of positive nurturing and giving the mother and family support.”

At the prenatal level, what’s the best advice for cannabis-using mothers-to-be? “If a woman doesn’t know she’s pregnant and has been using cannabis, taking extra choline for the remainder of the pregnancy can help buffer the potential negative impact of the cannabis exposure,” Dr. Hoffman said. The Food and Drug Administration and the American Medical Association recommend a dose of 550 mg daily. “The same is true for alcohol, which we know is also very bad for fetal brain development. This is not to say go ahead and use these substances and just take choline. The choline is more to try and salvage damage to the fetal brain that may have already occurred.”

This study was supported by the National Institute of Mental Health and the National Institute on Drug Abuse. The authors declared no competing interests. Dr. Hoffman disclosed no conflicts of interest with respect to her comments.

Mothers who use cannabis during pregnancy risk disrupting immune gene networks in the placenta and potentially increasing the risk of anxiety and hyperactivity in their children.

These findings emerged from a study led by Yasmin Hurd, PhD, a professor of psychiatry and director of the Addiction Institute at the Icahn School of Medicine at Mount Sinai, New York, and Yoko Nomura, PhD, a professor of behavioral neuroscience at Queen’s College, City University of New York, that was published online in Proceedings of the National Academy of Sciences.

The analysis assessed the effects of gestational maternal cannabis use on psychosocial and physiological measures in young children as well as its potentially immunomodulatory effect on the in utero environment as reflected in the placental transcriptome.

Participants were drawn from a larger cohort in a study launched in 2012; the investigators evaluated offspring aged 3-6 years for hair hormone levels, neurobehavioral traits on the Behavioral Assessment System for Children survey, and heart rate variability (HRV) at rest and during auditory startle.

The cohort consisted of 322 mother-child dyads and children with prenatal exposure to cannabis were compared with those having no exposure. The cohort consisted of 251 non–cannabis-using mothers and 71 cannabis-using mothers, with mean maternal ages in the two groups of 28.46 years and 25.91 years, respectively, The mothers gave birth at Mount Sinai and they and their children were assessed annually at affiliated medical centers in Mount Sinai’s catchment area.

For a subset of children with behavioral assessments, placental specimens collected at birth were processed for RNA sequencing.

Among the findings:

• Maternal cannabis use was associated with reduced maternal and paternal age, more single-mother pregnancies, state anxiety, trait anxiety, depression, cigarette smoking, and African American race.
• Hair hormone analysis revealed increased cortisol levels in the children of cannabis-using mothers, and was associated with greater anxiety, aggression, and hyperactivity.
• Affected children showed a reduction in the high-frequency component of HRV at baseline, reflecting reduced vagal tone.
• In the placenta, there was reduced expression of many genes involved in immune system function. These included genes for type I interferon, neutrophil, and cytokine-signaling pathways.

Several of these genes organized into coexpression networks that correlated with child anxiety and hyperactivity.

The principal active component of cannabis, tetrahydrocannabinol (THC), targets the endocannabinoid system in placental tissue and the developing brain, the authors noted. Exposure during pregnancy is associated with a range of adverse outcomes from fetal growth restriction to low birth weight and preterm birth.

“There are cannabinoid receptors on immune cells, and it is known that cannabinoids can alter immune function, which is important for maintaining maternal tolerance and protecting the fetus,” Dr. Hurd said. “It’s not surprising that something that affects the immune cells can have an impact on the developing fetus.”

“Overall, our findings reveal a relationship between [maternal cannabis use] and immune response gene networks in the placenta as a potential mediator of risk for anxiety-related problems in early childhood,” Dr. Hurd and colleagues wrote, adding that the results have significant implications for defining mental health issues in the children gestated by cannabis-smoking mothers.

Their results align with previous research indicating a greater risk for psychiatric illness in children with prenatal cannabis exposure from maternal use.

“While data are pretty limited in this realm, there are other studies that demonstrate a relationship between early child developmental and behavioral measures and cannabis use during pregnancy,” Camille Hoffman, MD, MSc, a high-risk obstetrics specialist and an associate professor at the University of Colorado at Denver, Aurora, said in an interview. “Our research group found children exposed to cannabis in utero at 10 weeks’ gestation and beyond were less interactive and more withdrawn than children who were not exposed.”

And THC remains in maternal breast milk even 6 weeks after usage stops.

The long-term effects of prenatal cannabis exposure remain to be determined and it is unknown whether the effects of gestational THC might attenuate as a child grows older. “We use early childhood measures in research as a proxy for the later development of diagnosed mental health conditions or behavioral problems,” Dr. Hoffman explained. “We know when we do this that not every child with an abnormal score early will go on to develop an actual condition. Fortunately, or unfortunately, other factors and exposures during childhood can change the trajectory for the better or worse.”

According to Dr. Hurd, child development is a dynamic process and epigenetic events in utero need not be deterministic. “The important thing is to identify children at risk early and to be able to go in and try to improve the environment they’re being raised in – not in terms of impoverishment but in terms of positive nurturing and giving the mother and family support.”

At the prenatal level, what’s the best advice for cannabis-using mothers-to-be? “If a woman doesn’t know she’s pregnant and has been using cannabis, taking extra choline for the remainder of the pregnancy can help buffer the potential negative impact of the cannabis exposure,” Dr. Hoffman said. The Food and Drug Administration and the American Medical Association recommend a dose of 550 mg daily. “The same is true for alcohol, which we know is also very bad for fetal brain development. This is not to say go ahead and use these substances and just take choline. The choline is more to try and salvage damage to the fetal brain that may have already occurred.”

This study was supported by the National Institute of Mental Health and the National Institute on Drug Abuse. The authors declared no competing interests. Dr. Hoffman disclosed no conflicts of interest with respect to her comments.

Erenumab, a calcitonin-gene related peptide receptor (CGRP) inhibitor, is more tolerable and effective than topiramate for treating patients with migraine, according to data from almost 800 patients in the first head-to-head trial of its kind.

The findings suggest that erenumab may help overcome longstanding issues with migraine medication adherence, and additional supportive data may alter treatment sequencing, reported lead author Uwe Reuter, MD, professor at Charité Universitätsmedizin Berlin, and colleagues.

“So far, no study has been done in order to compare the efficacy of a monoclonal antibody targeting the CGRP pathway to that of a standard of care oral preventive drug,” the investigators wrote in Cephalalgia.

The phase 4 HER-MES trial aimed to address this knowledge gap by enrolling 777 adult patients with a history of migraine. All patients reported migraine with or without aura for at least 1 year prior to screening. At baseline, most patients (65%) reported 8-14 migraine days per months, followed by 4-7 days (24.0%), and at least 15 days (11.0%). No patients had previously received topiramate or a CGRP-targeting agent.

“HER-MES includes a broad migraine population with two-thirds of the patients in the high-frequency migraine spectrum,” the investigators noted. “Despite a mean disease duration of about 20 years, almost 60% of the patients had not received previous prophylactic treatment, which underlines the long-standing problem of undertreatment in migraine.”

The trial had a double-dummy design; patients were randomized in a 1:1 ratio to receive either subcutaneous erenumab (70 or 140 mg/month) plus oral placebo, or oral topiramate (50-100 mg/day) plus subcutaneous placebo. The topiramate dose was uptitrated over the first 6 weeks. Treatments were given for a total of 24 weeks or until discontinuation due to adverse events, which was the primary endpoint. The secondary endpoint was efficacy over months 4-6, defined as at least 50% reduction in monthly migraine days, compared with baseline. Other patient-reported outcomes were also evaluated.

After 24 weeks, 95.1% of patients were still enrolled in the trial. Discontinuations due to adverse events were almost four times as common in the topiramate group than the erenumab group (38.9% vs. 10.6%; odds ratio [OR], 0.19; confidence interval, 0.13-0.27; P less than .001). Efficacy findings followed suit, with 55.4% of patients in the erenumab group reporting at least 50% reduction in monthly migraine days, compared with 31.2% of patients in the topiramate group (OR, 2.76; 95% CI, 2.06-3.71; P less than.001).

Erenumab significantly improved monthly migraine days, headache impact test (HIT-6) scores, and short form health survey version (SF-35v2) scores, including physical and mental components (P less than .001 for all).

Safety profiles aligned with previous findings.

“Compared to topiramate, treatment with erenumab has a superior tolerability profile and a significantly higher efficacy,” the investigators concluded. “HER-MES supports the potential of erenumab in overcoming issues of low adherence in clinical practice observed with topiramate, lessening migraine burden, and improving quality of life in a broad migraine population.”
 

Superior tolerability

Commenting on the study, Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, said this is “a very important, very well conducted trial that documents what many of us already suspected; erenumab clearly has better tolerability than topiramate as well as better efficacy.”

Dr. Rapoport, a past president of the International Headache Society, said the study highlights an area of unmet need in neurology practice.

“Despite most patients in the trial having chronic headaches for 20 years, 60% of them had never received preventive treatment,” he said, noting that this reflects current practice in the United States.

Dr. Rapoport said primary care providers in the United States prescribe preventive migraine medications to 10%-15% of eligible patients. Prescribing rates for general neurologists are slightly higher, he said, ranging from 35% to 40%, while headache specialists prescribe 70%-90% of the time.

“How can we improve this situation?” Dr. Rapoport asked. “For years we have tried to improve it with education, but we need to do a better job. We need to educate our primary care physicians in more practical ways. We have to teach them how to make a diagnosis of high frequency migraine and chronic migraine and strongly suggest that those patients be put on appropriate preventive medications.”

Barriers to care may be systemic, according to Dr. Rapoport.

“One issue in the U.S. is that patients with commercial insurance are almost always required to fail two or three categories of older oral preventive migraine medications before they can get a monoclonal antibody or gepants for prevention,” he said. “It would be good if we could change that system so that patients that absolutely need the better tolerated, more effective preventive medications could get them sooner rather than later. This will help them feel and function better, with less pain, and eventually bring down the cost of migraine therapy.”

While Dr. Reuter and colleagues concluded that revised treatment sequencing may be warranted after more trials show similar results, Dr. Rapoport suggested that “this was such a large, well-performed, 6-month study with few dropouts, that further trials to confirm these findings are unnecessary, in my opinion.”

The HER-MES trial was funded by Novartis. Dr. Reuter and colleagues disclosed additional relationships with Eli Lilly, Teva Pharmaceutical, Allergan, and others. Dr. Rapoport was involved in early topiramate trials for prevention and migraine, and is a speaker for Amgen.

Erenumab, a calcitonin-gene related peptide receptor (CGRP) inhibitor, is more tolerable and effective than topiramate for treating patients with migraine, according to data from almost 800 patients in the first head-to-head trial of its kind.

The findings suggest that erenumab may help overcome longstanding issues with migraine medication adherence, and additional supportive data may alter treatment sequencing, reported lead author Uwe Reuter, MD, professor at Charité Universitätsmedizin Berlin, and colleagues.

“So far, no study has been done in order to compare the efficacy of a monoclonal antibody targeting the CGRP pathway to that of a standard of care oral preventive drug,” the investigators wrote in Cephalalgia.

The phase 4 HER-MES trial aimed to address this knowledge gap by enrolling 777 adult patients with a history of migraine. All patients reported migraine with or without aura for at least 1 year prior to screening. At baseline, most patients (65%) reported 8-14 migraine days per months, followed by 4-7 days (24.0%), and at least 15 days (11.0%). No patients had previously received topiramate or a CGRP-targeting agent.

“HER-MES includes a broad migraine population with two-thirds of the patients in the high-frequency migraine spectrum,” the investigators noted. “Despite a mean disease duration of about 20 years, almost 60% of the patients had not received previous prophylactic treatment, which underlines the long-standing problem of undertreatment in migraine.”

The trial had a double-dummy design; patients were randomized in a 1:1 ratio to receive either subcutaneous erenumab (70 or 140 mg/month) plus oral placebo, or oral topiramate (50-100 mg/day) plus subcutaneous placebo. The topiramate dose was uptitrated over the first 6 weeks. Treatments were given for a total of 24 weeks or until discontinuation due to adverse events, which was the primary endpoint. The secondary endpoint was efficacy over months 4-6, defined as at least 50% reduction in monthly migraine days, compared with baseline. Other patient-reported outcomes were also evaluated.

After 24 weeks, 95.1% of patients were still enrolled in the trial. Discontinuations due to adverse events were almost four times as common in the topiramate group than the erenumab group (38.9% vs. 10.6%; odds ratio [OR], 0.19; confidence interval, 0.13-0.27; P less than .001). Efficacy findings followed suit, with 55.4% of patients in the erenumab group reporting at least 50% reduction in monthly migraine days, compared with 31.2% of patients in the topiramate group (OR, 2.76; 95% CI, 2.06-3.71; P less than.001).

Erenumab significantly improved monthly migraine days, headache impact test (HIT-6) scores, and short form health survey version (SF-35v2) scores, including physical and mental components (P less than .001 for all).

Safety profiles aligned with previous findings.

“Compared to topiramate, treatment with erenumab has a superior tolerability profile and a significantly higher efficacy,” the investigators concluded. “HER-MES supports the potential of erenumab in overcoming issues of low adherence in clinical practice observed with topiramate, lessening migraine burden, and improving quality of life in a broad migraine population.”
 

Superior tolerability

Commenting on the study, Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, said this is “a very important, very well conducted trial that documents what many of us already suspected; erenumab clearly has better tolerability than topiramate as well as better efficacy.”

Dr. Rapoport, a past president of the International Headache Society, said the study highlights an area of unmet need in neurology practice.

“Despite most patients in the trial having chronic headaches for 20 years, 60% of them had never received preventive treatment,” he said, noting that this reflects current practice in the United States.

Dr. Rapoport said primary care providers in the United States prescribe preventive migraine medications to 10%-15% of eligible patients. Prescribing rates for general neurologists are slightly higher, he said, ranging from 35% to 40%, while headache specialists prescribe 70%-90% of the time.

“How can we improve this situation?” Dr. Rapoport asked. “For years we have tried to improve it with education, but we need to do a better job. We need to educate our primary care physicians in more practical ways. We have to teach them how to make a diagnosis of high frequency migraine and chronic migraine and strongly suggest that those patients be put on appropriate preventive medications.”

Barriers to care may be systemic, according to Dr. Rapoport.

“One issue in the U.S. is that patients with commercial insurance are almost always required to fail two or three categories of older oral preventive migraine medications before they can get a monoclonal antibody or gepants for prevention,” he said. “It would be good if we could change that system so that patients that absolutely need the better tolerated, more effective preventive medications could get them sooner rather than later. This will help them feel and function better, with less pain, and eventually bring down the cost of migraine therapy.”

While Dr. Reuter and colleagues concluded that revised treatment sequencing may be warranted after more trials show similar results, Dr. Rapoport suggested that “this was such a large, well-performed, 6-month study with few dropouts, that further trials to confirm these findings are unnecessary, in my opinion.”

The HER-MES trial was funded by Novartis. Dr. Reuter and colleagues disclosed additional relationships with Eli Lilly, Teva Pharmaceutical, Allergan, and others. Dr. Rapoport was involved in early topiramate trials for prevention and migraine, and is a speaker for Amgen.

Erenumab, a calcitonin-gene related peptide receptor (CGRP) inhibitor, is more tolerable and effective than topiramate for treating patients with migraine, according to data from almost 800 patients in the first head-to-head trial of its kind.

The findings suggest that erenumab may help overcome longstanding issues with migraine medication adherence, and additional supportive data may alter treatment sequencing, reported lead author Uwe Reuter, MD, professor at Charité Universitätsmedizin Berlin, and colleagues.

“So far, no study has been done in order to compare the efficacy of a monoclonal antibody targeting the CGRP pathway to that of a standard of care oral preventive drug,” the investigators wrote in Cephalalgia.

The phase 4 HER-MES trial aimed to address this knowledge gap by enrolling 777 adult patients with a history of migraine. All patients reported migraine with or without aura for at least 1 year prior to screening. At baseline, most patients (65%) reported 8-14 migraine days per months, followed by 4-7 days (24.0%), and at least 15 days (11.0%). No patients had previously received topiramate or a CGRP-targeting agent.

“HER-MES includes a broad migraine population with two-thirds of the patients in the high-frequency migraine spectrum,” the investigators noted. “Despite a mean disease duration of about 20 years, almost 60% of the patients had not received previous prophylactic treatment, which underlines the long-standing problem of undertreatment in migraine.”

The trial had a double-dummy design; patients were randomized in a 1:1 ratio to receive either subcutaneous erenumab (70 or 140 mg/month) plus oral placebo, or oral topiramate (50-100 mg/day) plus subcutaneous placebo. The topiramate dose was uptitrated over the first 6 weeks. Treatments were given for a total of 24 weeks or until discontinuation due to adverse events, which was the primary endpoint. The secondary endpoint was efficacy over months 4-6, defined as at least 50% reduction in monthly migraine days, compared with baseline. Other patient-reported outcomes were also evaluated.

After 24 weeks, 95.1% of patients were still enrolled in the trial. Discontinuations due to adverse events were almost four times as common in the topiramate group than the erenumab group (38.9% vs. 10.6%; odds ratio [OR], 0.19; confidence interval, 0.13-0.27; P less than .001). Efficacy findings followed suit, with 55.4% of patients in the erenumab group reporting at least 50% reduction in monthly migraine days, compared with 31.2% of patients in the topiramate group (OR, 2.76; 95% CI, 2.06-3.71; P less than.001).

Erenumab significantly improved monthly migraine days, headache impact test (HIT-6) scores, and short form health survey version (SF-35v2) scores, including physical and mental components (P less than .001 for all).

Safety profiles aligned with previous findings.

“Compared to topiramate, treatment with erenumab has a superior tolerability profile and a significantly higher efficacy,” the investigators concluded. “HER-MES supports the potential of erenumab in overcoming issues of low adherence in clinical practice observed with topiramate, lessening migraine burden, and improving quality of life in a broad migraine population.”
 

Superior tolerability

Commenting on the study, Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, said this is “a very important, very well conducted trial that documents what many of us already suspected; erenumab clearly has better tolerability than topiramate as well as better efficacy.”

Dr. Rapoport, a past president of the International Headache Society, said the study highlights an area of unmet need in neurology practice.

“Despite most patients in the trial having chronic headaches for 20 years, 60% of them had never received preventive treatment,” he said, noting that this reflects current practice in the United States.

Dr. Rapoport said primary care providers in the United States prescribe preventive migraine medications to 10%-15% of eligible patients. Prescribing rates for general neurologists are slightly higher, he said, ranging from 35% to 40%, while headache specialists prescribe 70%-90% of the time.

“How can we improve this situation?” Dr. Rapoport asked. “For years we have tried to improve it with education, but we need to do a better job. We need to educate our primary care physicians in more practical ways. We have to teach them how to make a diagnosis of high frequency migraine and chronic migraine and strongly suggest that those patients be put on appropriate preventive medications.”

Barriers to care may be systemic, according to Dr. Rapoport.

“One issue in the U.S. is that patients with commercial insurance are almost always required to fail two or three categories of older oral preventive migraine medications before they can get a monoclonal antibody or gepants for prevention,” he said. “It would be good if we could change that system so that patients that absolutely need the better tolerated, more effective preventive medications could get them sooner rather than later. This will help them feel and function better, with less pain, and eventually bring down the cost of migraine therapy.”

While Dr. Reuter and colleagues concluded that revised treatment sequencing may be warranted after more trials show similar results, Dr. Rapoport suggested that “this was such a large, well-performed, 6-month study with few dropouts, that further trials to confirm these findings are unnecessary, in my opinion.”

The HER-MES trial was funded by Novartis. Dr. Reuter and colleagues disclosed additional relationships with Eli Lilly, Teva Pharmaceutical, Allergan, and others. Dr. Rapoport was involved in early topiramate trials for prevention and migraine, and is a speaker for Amgen.